HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The state of science in medullary thyroid carcinoma: current challenges and unmet needs

in Endocrine-Related Cancer
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  • 1 Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer, Houston, TX, USA
  • 2 Division of Endocrinology, Diabetes and Metabolism, The Ohio State University College of Medicine, Columbus, OH, USA
  • 3 Department of Surgical Oncology, The University of Texas MD Anderson Cancer, Houston, TX, USA
  • 4 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer, Houston, TX, USA
  • 5 Northern Clinical School, Kolling Institute of Medical Research, The University of Sydney School of Medicine, Sydney, Australia
  • 6 Khalifa Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX

Correspondence should be addressed to M I Hu: mhu@mdanderson.org

This paper is part of a thematic section on current knowledge and future research opportunities in hereditary endocrine tumours, as discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. This meeting was sponsored by Endocrine-Related Cancer

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.

Abstract

The 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) held in Houston, TX, USA, focused on emerging topics in the pathogenesis and therapy of malignant endocrine tumors associated with MEN syndromes. With MEN-2 syndromes, the most common malignancy is medullary thyroid carcinoma (MTC). In the spirit of the original MEN meeting workshop model, the conference included didactic lectures and interactive working groups of clinicians and researchers focused on the state of science in MTC and ongoing challenges or unmet needs in the understanding of MTC and to develop strategies to address these issues.

Introduction

Medullary thyroid cancer (MTC) is a rare malignancy of thyroid C cells derived from neural crest cells. In approximately 25% of cases, the etiology is an activating germline mutation of the RET proto-oncogene via autosomal dominant inheritance associated with the multiple endocrine neoplasia type 2 (MEN2) syndrome. Thyroidectomy offers the greatest chance for cure if the disease is detected early in its development or can effectively prevent the onset of disease in patients identified with MEN2 through genetic screening. However, many patients may already have evidence of cervical lymph node metastases or distant metastases at diagnosis. The disease course can be highly variable, although it is usually indolent and can remain so even in the setting of metastatic disease. Although factors such as specific RET codon mutation in hereditary MTC, somatic mutations, and calcitonin and carcinoembryonic antigen (CEA) doubling times have prognostic value, the heterogeneity of clinical behavior of MTC is not fully explained by these factors alone (Elisei et al. 2008, Meijer et al. 2010, Wells et al. 2015, Cote et al. 2017). A treatment with curative intent for patients with metastatic MTC still remains elusive. However, with increased understanding of pathogenic mechanisms over the last 15 years and development of novel agents targeting drivers of disease, the goal of identifying a cure is possible. During the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019), held in Houston, TX, USA, the objectives of the MTC Working Group were to explore the challenges or unmet needs in the understanding of this malignancy and to develop strategies to address those needs.

State of science in medullary thyroid carcinoma

Available therapies for advanced, metastatic medullary thyroid carcinoma

Aberrant activation of the RET receptor (in almost 100% cases of hereditary MTC and 45% of sporadic MTC) and overexpression of other receptor tyrosine kinases upregulate intracellular signaling pathways mediating tumorigenesis and angiogenesis (Fig. 1) (http://cancer.sanger.ac.uk/cosmic). This knowledge drove numerous clinical investigations with multi-kinase inhibitors (MKIs) and led to the approval of two systemic treatments (cabozantinib, vandetanib) for patients with advanced and progressive MTC not amenable to surgical or other locally targeted modalities. The ZETA phase III study evaluated the efficacy of vandetanib in patients with advanced MTC, measurable disease by response evaluation criteria in solid tumors (RECIST), and a calcitonin (Ctn) of at least 500 pg/mL (Wells et al. 2012). Vandetanib led to a significantly prolonged progression-free survival of 30.5 months (predicted) compared with placebo (19.3 months) (HR 0.46; 95% CI, 0.31–0.69, P < 0.001). The overall response rate observed in the trial was 45% in the vandetanib group compared with 13% in the placebo group. Although it was not designed to evaluate overall survival, there was no difference in overall survival between the treatment groups. The phase III EXAM trial with cabozantinib randomized MTC patients to study drug or placebo, who had progressive disease prior to study enrollment (Elisei et al. 2013). The median progression-free survival was significantly longer in the cabozantinib-treated patients (11.2 months) compared with the placebo group (4.0 months) (HR 0.28; 95% CI 0.19–0.40, P < 0.001), with a partial response of 28% for cabozantinib and 0% in placebo-treated patients. Responses were observed regardless of RET mutation status. Overall survival, a secondary endpoint in this study, was not different between the treatment groups (HR 0.85; 95% CI, 0.64–1.12; P = 0.24) (Schlumberger et al. 2017). MKIs are associated with numerous side effects including palmar-plantar erythrodysesthesia, photosensitivity, stomatitis, taste changes, hypertension, diarrhea, nausea, anorexia, fatigue and uncontrolled hypothyroidism. QTc prolongation was observed in 14% patients treated with vandetanib. Cabozantinib is a more potent inhibitor of VEGFR-2, which leads to a higher risk for hemorrhage, venous thrombosis, intestinal perforation, and fistula formation. Thus, it is advised to implement a patient-focused evaluation when recommending a therapeutic agent that conveys oncologic benefit balanced by a lower burden of side effects (Cabanillas et al. 2014).

Figure 1
Figure 1

Pathogenic pathways in medullary thyroid carcinoma. Pathogenic drivers of disease include: mutations leading to activated RET or RAS receptors; overexpression of EGFR, MET and VEGFR; genetic loss of CDKNs; and loss of ATF4 protein. ATF4, activating transcription factor 4; BRAF, serine/threonine-protein kinase B-Raf; CDK, cyclin-dependent kinases; CDKN, cyclin-dependent kinase inhibitor; E2F, family of DNA-binding transcription factors; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factor; MAPK, mitogen-activated protein kinase kinase; MET, hepatocyte growth factor; RAS, rat sarcoma viral oncogene homolog; Rb, retinoblastoma; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor.

Citation: Endocrine-Related Cancer 27, 8; 10.1530/ERC-20-0110

The development of novel, potent RET-specific inhibitors has led to a significant amount of excitement due to the responses observed in patients with thyroid cancer with RET alterations treated in phase I clinical trials and the overall well-tolerated side effect profiles. Since the MEN 2019 meeting, the updated results for BLU-667 and LOXO-292 were presented at the Annual Meetings of the American Society of Clinical Oncology (ASCO) Meeting in June 2019 and the 44th European Society for Medical Oncology (ESMO) Congress in September 2019, respectively (Hu et al. 2018, Wirth et al. 2018, 2019, Taylor et al. 2019). As of December 19, 2018, 60 patients with RET-mutated MTC received BLU-667 (pralsetinib). Among the 49 response-evaluable MTC patients, the objective response rate (ORR) was 47% (95% CI: 33, 62) with 2 complete responses (CR), 21 partial responses (PR), 25 stable disease (SD), and 1 progressive disease (PD) with a disease control rate (DCR) of 98% (Taylor et al. 2019). Ninety-six percent of the responding patients continue on treatment. Responses occurred regardless of prior MKI use or RET mutation (including patients with a RET V804M gatekeeper mutation), and the duration of response was ≥ 6 months in 15 patients. Treatment-related adverse events (AEs) were generally low-grade and reversible with no grade 4/5 AEs and 28% with grade 3 AEs including: leukopenia, increased ALT and AST/serum creatinine/phosphate, hypertension and neutropenia. As of June 17, 2019, 226 RET-mutated MTC received LOXO-292 (selpercatinib). For the first 55 consecutively enrolled MTC patients previously treated with cabozantinib and/or vandetanib, the ORR was 56% (95% CI: 42, 70) with 3 CRs, 28 PRs, 2 unconfirmed PRs, 19 SD, and 3 PD. Of the three patients with RET V804M/L gatekeeper mutations, one had a CR and two had PRs. Median duration of response had not been reached. Treatment-related AEs of ≥ 15% were dry mouth, diarrhea, hypertension, and increased AST and ALT with most AEs being grade 1–2. 1.7% of all 531 patients in the safety data set discontinued therapy due to treatment-related AE (Wirth et al. 2019). Based on the favorable overall response rate and duration of response, selpercatinib received accelerated approval by the US Food and Drug Administration on May 8, 2020 for patients over 12 years of age with advanced or metastatic RET-mutated MTC who require systemic therapy. Two additional RET inhibitors (TPX-0046 and BOS172738) are also being evaluated in ongoing phase I trials (Drilon et al. 2019, Schoffski et al. 2019). Notably, TPX-0046, a dual inhibitor of RET and SRC, also has activity against the solvent front mutation RET G810R, which is associated with acquired resistance to MKIs and other selective RET inhibitors under investigation (Drilon et al. 2019, Solomon et al. 2020).

Other than RET mutations seen with hereditary and sporadic MTC, approximately 14% of sporadic MTC will harbor a RAS mutation, most commonly HRAS or KRAS, which, at this time, is not a targetable mutation (Fig. 1) (http://cancer.sanger.ac.uk/cosmic). There have been investigations into other drivers of MTC described in this review.

Targeting CDKs and RB in medullary thyroid cancer

Over the past several decades, it has been well-defined that neuroendocrine cells, including C-cells of the thyroid, are highly sensitive to perturbations in cell cycle regulators in murine models (Williams et al. 1994, Harvey et al. 1995, Yamasaki et al. 1998). Cyclin-dependent kinases (CDKs) are a family of proteins that are required for cell cycle progression and/or gene transcription. CDKs that facilitate cell cycle progression are negatively regulated by a group of CDK inhibitors such as p18 and p27. Loss of expression of CDK inhibitors enhances CDK activity, cell proliferation, and eventually can lead to cancer development, thereby classifying them as tumor suppressors (Fig. 1). The first described tumor suppressor gene, RB1, encodes the retinoblastoma protein that is a downstream phosphorylation target of CDKs; an activity that results in RB inactivation allowing cell cycle progression. In addition, loss of RB expression through a variety of mechanisms also can lead to cancer formation. In parafollicular cells, mice with heterozygous loss of Rb or p18 develop medullary thyroid cancer (MTC) and other neuroendocrine tumors associated with loss of expression of the second allele (Williams et al. 1994, Harvey et al. 1995, Yamasaki et al. 1998, van Veelen et al. 2008). This striking incidence of these rare tumors in these generalized models suggest a tissue-specific sensitivity to carcinogenesis in this genetic context. In addition, CDK inhibitor loss (e.g. p18 and Rb) cooperates with mutant RET to enhance cancer aggressiveness (Park et al. 1999, van Veelen et al. 2008). Finally, activation of CDK5 independently is sufficient to cause MTC in mice and its inhibition reverses MTC development and progression (Pozo et al. 2013). While there are differences in the biology of C-cells in mice and humans (Madsen et al. 2012), these data have generated interest in analyzing human MTC tumors and cell lines for activation of CDKs to determine if CDK activity is a biomarker for aggressive disease and represents a therapeutic target.

In cell lines, it has been shown that the mitogenic effects of mutated RET require downregulation of p27 and p18 (Joshi et al. 2007) and that inhibition of RET results in increased expression of p27 (Vitagliano et al. 2004). These data suggest that, while CDK inhibitors might not be synergistic with RET inhibitors, CDKs themselves may be biomarkers and/or therapeutic targets in MTC independent of RET. To determine the frequency of CDK inhibitor loss in human MTC, several groups screened for and identified mutations or loss of expression of p16 and p18 in MTC (van Veelen et al. 2009, Grubbs et al. 2016, El Naofal et al. 2017). Similarly, a different set of investigators, using high resolution array genomic hybridization (Array CGH) from a second group of patients, determined that p18 loss is associated with more aggressive MTC tumor behavior (Flicker et al. 2012). In addition to loss of CDK inhibitors, overexpression of CDKs has been described in MTC, which results in phosphorylation and loss of nuclear RB and is associated with MTC progression, and its inhibition reduces MTC cell growth and has been shown to increase the growth of human MTC cells (Pozo et al. 2013). Because loss of CDK inhibitors and overexpression of CDKs result in loss of nuclear RB function (either by phosphorylation or loss of expression), RB phosphorylation or loss of nuclear RB has been evaluated as biomarkers for MTC (Anwar et al. 2000, Valenciaga et al. 2017). In the larger of these studies for MTC, loss of nuclear RB was associated with death from disease independent of activating RET mutations (Valenciaga et al. 2017). Together these data demonstrate that human MTCs are characterized by genetic alterations resulting in Rb inactivation and suggest that CDKs may represent therapeutic targets for this disease.

The work described has been extended into the preclinical space by examining the potential therapeutic use of CDK inhibitors in MTC cell lines. Several CDK inhibitors are FDA approved for other cancers including flavopiradol and dinaciclib (CDK 1, 2, 5, 9 inhibitors) and palbociclib, ribociclib, and abemaciclib (CDK4/6 inhibitors), while other CDKs have been targeted preclinically (CDK5, 7, and 9). Studies using flavopiradol and dinaciclib report low nM IC50 values for RET-mutated human MTC cells (Valenciaga et al. 2018). The sensitivity to dinaciclib was present even in cell lines selected for resistance to the FDA-approved multi-kinase inhibitor, vandetanib. In addition, dinaciclib was synergistic with vandetanib in vitro. Interestingly, inhibition of CDK4/6 is cytostatic rather than cytotoxic to MTC cells. Several groups have focused on more specific CDK targeting. As noted previously, in a genetic mouse model, MTC development and progression were dependent on CDK5 activation and CDK5 inhibitors demonstrate activity against human MTC cell lines (Pozo et al. 2013, Pozo & Bibb 2016). In addition to work on CDK5, it was observed that, at the IC50 for Dinaciclib, only CDK9 was inhibited. CDKs 7 and 9 regulate gene transcription by RNA polymerase 2 rather than cell cycle. Treatment of RET-mutated MTC cells with the CDK7 inhibitor THZ1 demonstrated nM-range IC50 in association with loss of RET gene expression. Subsequent studies confirmed the presence of a ‘super enhancer’ in intron 1 of RET that may be responsible for the high degree of sensitivity to RNA polymerase II inhibition (Valenciaga et al. 2018). Taken together, the data suggest that activation of CDKs and/or loss of their negative regulators are biomarkers for aggressive MTC and may be new non-RET therapeutic targets that are either downstream and/or independent of RET. Further studies and use of better tolerated and orally available agents may be important avenues for clinical trials in MTC.

Role of ATF4 in the pathogenesis of MTC

Cancer cells are often exposed to nutrient starvation, hypoxia, oxidative stress and other metabolic dysregulation. These various stress factors can interfere with correct protein folding leading to the accumulation of misfolded or unfolded protein, causing a condition called endoplasmic reticulum (ER) stress. In response to ER stress, cells activate a signal transduction pathway called unfolded protein response (UPR) to restore ER homeostasis. UPR restores homeostasis by reducing protein synthesis, which enhances degradation of misfolded protein and increases translation of activating transcription factor 4 (ATF4). Under overwhelming ER stress, the UPR promotes apoptosis, and ATF4 is a key deciding factor in cellular fate (Ameri & Harris 2008) (Maurel et al. 2015) (Wang et al. 2018). Therefore, induction of ER stress to a critical threshold could be a promising strategy to induce cancer cell death (Tabas & Ron 2011). Neuroendocrine cancers with secretory function like medullary thyroid cancer display enhanced ER stress, due to inappropriately high levels of protein synthesis, mutation load that leads to the accumulation of misfolded proteins and make them reliant on their UPR and ER associated degradation (ERAD) pathway (Clarke et al. 2014).

RET is recognized for its essential role in cell survival. There is a mechanistic link between RET activation and integrated stress response through regulation of ATF4 transcriptional activity that may explain, in part, the incomplete responses observed in patients treated with FDA-approved tyrosine kinase inhibitors (vandetanib and cabozantinib). In fact, RET activation promotes cancer cell survival by direct phosphorylation-dependent repression of ATF4 at the promoter of pro-apoptotic targets NOXA and PUMA thereby circumventing stress-induced apoptosis (Fig. 1) (Bagheri-Yarmand et al. 2015). Inducing ATF4 expression in MTC promotes RET degradation and inhibits RET downstream signaling pathways including ERK, AKT and mTOR pathway (Bagheri-Yarmand et al. 2017). It has been reported that ATF4 mediates ER-stress-induced apoptosis in response to drugs triggering ER stress, such as the proteasome inhibitor bortezomib, fenretinibe (Armstrong et al. 2010), inhibitor of ATPase p97 (Anderson et al. 2015); HA15 (a thiazole benzenesulfonamide), which targets GRP78/bip (Cerezo et al. 2016), ERAD inhibitor (eeyarestatin) (Wang et al. 2010). The combination of an ERAD inhibitor, eeyarestatin, with tyrosine kinase inhibitors (sunitinib and vandetanib) synergistically triggers irresolvable oxidative stress by inducing ATF4 mRNA leading to apoptosis in response to ER stress (Bagheri-Yarmand et al. 2019). The oxidative stress induced by this combination therapy is, in part, due to increase in KLF9 expression which is an ATF4 target gene and reported to promote oxidative-stress-induced cell death (Zucker et al. 2014). Furthermore, the analysis of MTC tumor tissues revealed that low protein levels of ATF4 was associated with increased RET protein levels and poor overall survival compared to patients whose tumors had high levels of ATF4 (Bagheri-Yarmand et al. 2017).

Recently, a small molecule ONC201 is reported to trigger cytotoxicity by inducing a stress response that is mediated by the induction of stress-related genes (Ishizawa et al. 2016, Kline et al. 2016). The mechanism of stress response induced is different between hematological malignancies and solid tumors, but ATF4 induction appeared to be a common mediator of ONC201-induced apoptosis in hematologic malignancies and solid tumors. Therefore, ATF4 could be used as a pharmacodynamic marker of ONC201 efficacy. The mechanism by which ONC201 induces stress-related genes and inhibits AKT, ERK and mTOR signaling pathway need to be elucidated. In summary, cancer-specific induction of ER stress and oxidative stress to activate programmed cell death could be a promising new approach to cancer treatment.

Immune environment in medullary thyroid cancer

In a study including 16 MTC tumors, very low expression of programmed cell death protein 1 ligand (PD-L1) in malignant and immune cells was reported(Bongiovanni et al. 2017). PD-L1 expression on malignant cells was ≤ 1% in 15/16 cases, with one case showing 5% positive cells. No correlation between PD-L1 expression and clinicopathological stage or survival was observed in this small study. A larger study including 87 MTC samples evaluated percentages of programmed cell death protein 1 (PD-1) and PD-L1 positive cells within the tumor. In this study, using a threshold of >1% positive cells, PD-1 expression was reported in 26% and PD-L1 expression in 22% of MTC tumors. Notably, most PD-L1 positive MTCs showed weak to moderate staining intensity (Bi et al. 2019).

Immunotherapy has been found to be an effective treatment modality in various solid tumors and hematologic malignancies. In MTC, various trials with vaccines and an anti-CTLA (cytotoxic T-lymphocyte-associated protein 4) inhibitor with radiation have been conducted.

Vaccines

From the late 1990s to the early 2000s, a targeted immunotherapy approach using tumor vaccines was attempted in patients with MTC. However, a major problem is the lack of defined tumor antigens. In MTC, CEA and calcitonin may represent feasible targets for the induction of cytotoxic immunity. Therefore, dendritic cell (DC) vaccination loaded with calcitonin and CEA has been tried in a prospective clinical trial (Schott et al. 2001). One trial included seven MTC patients (four patients with sporadic MTC and three patients with MEN2). In that trial, DCs were administered subcutaneously every week for 4 weeks and then at 4–8-week intervals. This treatment regimen was well-tolerated with no adverse effects, except fever in one patient. One of seven patients enrolled had regression of liver and lung metastases and two patients had mixed responses. A more refined DC therapy approach was subsequently attempted. Because no specific tumor antigens are yet discovered in MTC, tumor lysate was tried in another prospective study including ten sporadic MTC patients (Stift et al. 2003, 2004). This vaccine was well-tolerated with two patients developing fever up to 24–48 h after administration. Clinical benefit was demonstrated in six patients, which included one PR, one minor response, and two SD.

After autologous DC vaccination showed minimal efficacy as described previously, allogeneic tumor lysate-based DC therapy was tried. A pilot trial of autologous DCs pulsed with tumor cell lysate derived from allogeneic MTC cell lines in ten patients with metastatic MTC was performed (Bachleitner-Hofmann et al. 2009). DC vaccinations were well-tolerated and safe. After a median follow-up of 11 months, three patients had SD, while seven patients had PD.

A yeast-based therapeutic cancer vaccine targeting the CEA protein is under investigation in an MTC cohort, as part of a phase 2 clinical trial (NCT01856920). GI-6207 (Recombinant Saccharomyces cerevisiae-CEA (610D)) is an ‘off the shelf’ experimental cancer vaccine made with baker’s yeast. Upon administration, this vaccine may stimulate a host cytotoxic T-lymphocyte response against CEA-expressing tumor cells, which may result in tumor cell lysis. Preclinical studies have shown that GI-6207 can induce an immune response to CEA as well as therapeutic anti-tumor responses (Wansley et al. 2008). A previous phase I GI-6207 study has demonstrated safety and enhanced immune response in some patients (Bilusic et al. 2014). One patient with MTC was included in the phase 1 clinical trial, but was taken off study at 3.5 months for potential toxicity that was attributed to a possible manifestation of a strong immune response at the site of a metastatic focus. Final results from this study have not been released. Due to a limited number of patients in the MTC vaccine trials, conclusions regarding treatment efficacy of such approaches should be drawn with caution. Better strategies are needed.

In search for other tumor-associated antigens, a study noted that 65.2% of MTC tumors expressed NY-ESO-1 gene (Maio et al. 2003). This was higher than that seen in other malignancies (e.g. melanoma, hepatoma, breast, prostate, or ovarian cancer). Furthermore, antibodies to NY-ESO-1 were present in these patients, consistent with development of a spontaneous humoral immune response to this antigen. A more effective approach in MTC may be immunization with NY-ESO-1 peptides, which appear to be quite immunogenic.

Immunotherapies targeting immune checkpoint molecules such as CTLA-4, PD-1 and PD-L1 have been rapidly explored as promising treatment strategies in various types of cancers, including thyroid cancers. Very sparse data using these agents are available in MTC. In a phase 1 trial, one patient with MTC treated with an anti-PD-1 agent, nivolumab, has achieved a PR (Yamamoto et al. 2017). In a thyroid cancer expansion cohort, part of a phase I/II trial of ipilimumab (anti-CTLA-4 antibody) and hypofractionated stereotactic radiation therapy in patients with advanced solid malignancies (NCT02239900), three MTC patients were included. Two heavily pretreated patients (one KRAS and one RET M918T mutated) had rapid progressive disease and one patient (RET M918T mutated) had SD for 9 months (Dadu et al. 2018). A clinical trial using pembrolizumab (anti PD-1 antibody) as a single agent is currently being investigated (NCT03072160). The patients are divided in two groups based on their treatment history with an immune stimulating cancer vaccine (recombinant saccharomyces cerevisiae-CEA).

Challenges and unmet needs in medullary thyroid carcinoma

Lack of normal human C-cell lines

Further progress in understanding MTC and its pathogenesis is hindered by several factors: (1) a relatively small number of in vitro reagents for preclinical studies, (2) the absence of non-RET-mutated MTC cell lines, (3) technical challenges with the existing reagents, (4) difficulty expanding MTC cells ex vivo, and (5) the absence of data on normal C-cell biology. The state-of-the-science and barriers toward progress in the field of MTC were discussed in detail at the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019).

The majority of preclinical data on MTC derives from two human MTC cell lines: TT (RET C634W mutated) and MZ-CRC1 (RET M918T) (Berger et al. 1984, Cooley et al. 1995). Data generated using these cell lines have been useful to identify anti-RET functions of currently approved or developing compounds, and these cells can be grown in vitro in a variety of conditions, albeit slowly, and in vivo as s.c. and orthotopic xenografts (Rossfeld et al. 2017). However, it is notable that a cell line with the second most common driver mutation in HRAS does not exist and there are no normal human C-cell lines for fundamental studies in the field (the interspersed nature of C-cells within the thyroid makes their isolation impractical). Finally, MTC researchers recognize that these cells, while useful, are technically challenging to grow and expand and are relatively resistant to transfection and infection making them difficult to utilize for more global molecular and chemical screens. Genetically engineered mouse models (GEMM) have been developed for MTC. For example, mice develop MTC when mutated RET is overexpressed in the C-cells and when cell cycle regulators are perturbed (Williams et al. 1994, Harvey et al. 1995, Pozo et al. 2013). However, mice with a single copy of mutated RET only develop C-cell hyperplasia (Smith-Hicks et al. 2000), and GEMMs, while valuable, are costly to create and maintain and are not amenable for drug testing and/or development on a larger scale. Alternative models, such as ectopic expression of mutated ret in drosophila eye lens, have been utilized to identify RET inhibitors that have been verified in thyroid cells and eventually in clinical trials (Vidal et al. 2005, Wells et al. 2012, Levinson & Cagan 2016). Thus, while in vivo models of MTC can be highly successful and informative, they are time consuming, highly specialized, and as of now cannot be compared to normal C-cell biology. Thus, the development of new cellular models and data sets are required to enable expansion of knowledge regarding both a basic understanding of normal C-cell physiology and MTC biology and to allow for high-throughput preclinical testing in models that reflect MTC more broadly.

Over the past decade, the prior understanding, that C-cells develop from ectoderm precursors (Pearse & Carvalheira 1967), has been challenged and likely disproven with the advent of modern stem cell and lineage-tracing technologies (Johansson et al. 2015, Nilsson & Williams 2016, Kameda 2019). This may not be a complete surprise to clinicians as ‘collision tumors’ in which both MTC and follicular cell derived thyroid cancer are found in the same tumor (Sadat Alavi & Azarpira 2011). Moreover, immunohistochemical studies demonstrated that MTCs express the transcription factor NKX2.1 (also known as thyroid transcription factor 1, TTF1), similar to endoderm-derived thyroid follicular cells and lung cells (Johansson et al. 2015, Nilsson & Williams 2016, Kameda 2019). Another study had identified thyrotropin receptor (TSH-R) mRNA expression in some human MTC specimens (Elisei et al. 1994). Elegant studies have generated functional thyroid organoids in vitro through an endoderm developmental program (Martin et al. 2000, Antonica et al. 2012, Saito et al. 2018). Subsequently, lineage tracer studies have more fully characterized thyroid development and the roles and timing of the three transcription factors that create thyroid follicular epithelium (NKX2.1, FOXE1, PAX8). The thyroid derives from primordial endoderm cells located in the pharyngeal pouch that are separated by ectodermal cells into the thymus, parathyroid, and ultimobranchial body, the latter of which is destined to become the thyroid gland through the aforementioned three transcription factors (Mansouri et al. 1998, Kusakabe et al. 2006, Ozaki et al. 2011). It has previously been thought that the C-cells derived from the ectoderm that separates this body (Pearse & Carvalheira 1967). With a better understanding of stem-cell biology, this population has been shown to be derived from an endoderm-derived SOX-17 expressing precursor that expresses NKX2.1 and that NKX2.1 drives calcitonin expression (Johansson et al. 2015, Nilsson & Williams 2016, Kameda 2019). In fact, mice with loss of PAX8 do not develop a thyroid follicular epithelium but have two ultimobranchial bodies that are comprised of Nkx2.1 positive cells that express calcitonin (Mansouri et al. 1998). These data confirm that C-cells are an endoderm-derived cell type. Although not yet performed for human C-cells, stem-cell derived endoderm has served as the basis to develop neuroendocrine cell lineages and neuroendocrine tumors of the pancreas and lung. The importance of this information is that endoderm stem-lineages are malleable for development into tissues and tumors from derived stem cells, particularly when performed using 3D cellular matrices and/or organoid or ‘organ on chip’ technologies (Huh et al. 2010, Xu et al. 2016, Hassell et al. 2017).

In addition to using stem-cell technologies and biomimetic tissue matrices to develop normal C-cells, similar approaches have potential to more successfully propagate human MTCs ex vivo and/or develop them experimentally from the C-cell models. Finally, even without cell propagation, methods to more robustly analyze normal C-cell RNA signatures for comparison studies should be developed using single cell technologies to create baseline expression profiles. It was agreed at the MEN 2019 meeting that the development and testing of these systems should be a priority of basic researchers to enable an increased pace of translation toward clinical practice.

Lack of knowledge of drivers of MTC beyond RET and RAS

While RET and RAS alterations have been identified as oncogenic pathways for MTC, mutations of these genes account for only two-thirds of the disease. Attempts to identify additional oncogenic drivers have been limited and uninformative. To date, only two studies report relatively large volume exomic sequencing with 25 and 18 MTC tumor samples evaluated, respectively, with no identifiable novel recurrent driver mutation (Agrawal et al. 2013, Qu et al. 2020). Another possible reason is that MTC oncogenesis is also caused by gene copy number change, a poorly studied pathway compared with gene mutations. Copy number change has been reported in several high-density comparative genomic hybridization (CGH) array studies of MTC, with deletion of chromosome 1p, 19p and 22 being commonly reported (Marsh et al. 2003, Ye et al. 2008, Flicker et al. 2012).

Loss of CDKN2C (cyclin-dependent kinase inhibitor 2C), located on chromosome 1p, has been associated with poor prognosis in MTC patients and its role is further substantiated by a mouse knockout model with concordant findings (van Veelen et al. 2008, Grubbs et al. 2016, Maxwell et al. 2020). More broadly, the CDKN/retinoblastoma (RB) tumor suppressor pathway has been proposed as an alternative pathway in MTC (Valenciaga et al. 2017). Homozygous deletion of Rb1 leads to the development of aggressive MTC in mice, and decreased tumor RB expression is linked with worse prognosis in patients with MTC (Song et al. 2017, Valenciaga et al. 2017). Further investigation is needed to elucidate the role of the RB pathway in MTC oncogenesis. This is a worthwhile endeavor given that targeted therapies that inhibit CDK are being investigated across many cancer types.

A recent study, utilizing whole transcriptome sequencing in 29 MTC specimens, found that the tumors had a mesenchymal-like or a proliferative-like molecular subtype (Qu et al. 2020). A more aggressive phenotype was associated with the proliferative-like cluster, though the authors noted that further study with larger specimen numbers was warranted.

The taskforce discussed the importance of identifying additional pathogenic drivers in MTC and proposed an approach similar to the TCGA effort in order to achieve this goal. Given the rarity of this malignancy, collaboration with multiple centers worldwide will be essential. Identification of focused efforts to perform RNAseq of fresh frozen tumor specimens from primary, metastatic, and recurrent-progressive lesions from RET+, RAS+ and RET/RAS WT tumors was highlighted as a reasonable next step. Additionally, given the genotype-phenotype variability of somatic MTC, including among individuals who share common mutations, further correlation of tumor behavior and pathogenic drivers is necessary. Likewise, this effort is best approached in a collaborative manner with multiple centers contributing to allow adequate patient numbers.

The unknown role of immuno-oncology in MTC

Although tumor immunology has changed the landscape of treatment for cancer, not all patients (including those with MTC) benefit from immunotherapy approaches. Many lessons have been learned from other tumor types and it is now recognized that it is necessary to evaluate multiple components within the tumor microenvironment. Type, density and location of immune cells within the tumor site are all important and are linked to response to therapy and survival in other cancers. This analysis will allow for a better characterization of a ‘hot’ or immunogenic vs a ‘cold’ or nonimmunogenic tumor microenvironment. Preliminary data on a large subset of MTC tumors showed that both intra- and peritumoral expression of markers for cytotoxic, helper, memory T cells, regulatory T cells are low (Dadu et al. 2018). These findings suggest that MTC tumors have a ‘cold’ immune microenvironment. ‘Cold’ tumors tend to have lower expression of PD-L1, mutational burden, and antigen presentation markers (e.g. major histocompatibility complex class I) (Galon & Bruni 2019). These types of ‘cold’ tumors are the most challenging to treat. It was discussed at the MEN 2019 meeting that a potential approach will be to find a strategy to overcome the lack on immune response and turn the tumors into ‘hot’ tumors. Combining a priming therapy that enhances T-cell response, such as vaccines or adoptive T-cell transfer with immune checkpoint inhibitors could be a rational approach. Other promising priming strategies include radiation, chemotherapy and targeted therapies.

Mechanisms of resistance to treatments for MTC

Although patients with MTC can demonstrate PRs and SD with cabozantinib and vandetanib, many will eventually develop progression after a period of time despite therapeutic doses. The presence of RET V804M/L mutations has demonstrated resistance to vandetanib and cabozantinib in vitro with much higher IC50 values compared with other RET mutations (Carlomagno et al. 2004, Bentzien et al. 2013, Mologni et al. 2013). The mechanisms of acquired drug resistance in vivo may be related to acquisition of the RET V804M/L gatekeeper or RAS bypass mutations as demonstrated in a cohort of patients with somatic RET-mutated MTC treated with cabozantinib and/or vandetanib (Hu et al. 2019). Emergent RET G810 solvent front mutations have been reported in patients with RET-altered non-small-cell lung cancer and medullary thyroid cancer treated with the selective RET inhibitor, selpercatinib (Solomon et al. 2020). Glycine substitution in this region of the RET kinase prevents adequate binding of selpercatinib to the ATP-binding site. Solomon et al. reported that the inhibitory activity against RET G810S/R/C was significantly lower in vitro when exposed to selpercatinib, pralsetinib, cabozantinib and vandetanib. Thus, the consensus of the MEN 2019 meeting was that further investigation into treatment-emergent mutations is needed as possible resistance mechanisms to targeted systemic therapies.

Future directions

The era of targeted therapy for thyroid cancer began shortly after the turn of the century with the recognition that neoplastic growth depended on the upregulation of angiogenesis and pathogenic ‘driver’ mutations encoding kinases that activate critical intracellular pathways. Since then, there was an exponential development of targeted systemic therapies studied in successfully completed clinical trials led by an international community of investigators. Since 2011, two drugs were approved for use in advanced, progressive MTC (cabozantinib and vandetanib). It is very likely that highly potent RET-specific inhibitors will be approved in the near future. However, there are no effective treatments with a low side-effect profile for non-RET mutated MTC and a curative treatment has yet to be identified.

Future therapeutic trials may need to combine agents targeting different pathways to achieve greater ORRs and hopefully lead to cures without significant toxicity. A MKI may be able to generate sufficient immunogenic cells in the tumoral microenvironment to enhance the efficacy when combined with a checkpoint inhibitor. Use of a CDK inhibitor or ATF4 modulator in combination with a MKI or RET inhibitor may be considered.

For decades, surgery has been considered the most effective treatment with curative intent in early stages of MTC, but with palliative intent in patients with clinically appreciable lymph node or distant metastases. Approximately 38% of node-negative and 90% of node-positive MTC patients have residual disease after surgery, underscoring the need for more effective treatment options in this patient population. A neoadjuvant approach provides theoretical advantages of downstaging tumor (higher R0/R1 resection rate) and thereby increases surgical resectability and reduces surgical morbidity/complexity. It also has the potential of eradicating micrometastatic tumor cells to improve locoregional control and/or survival after surgical resection. To date, there have been no trials evaluating a neoadjuvant treatment for MTC, particularly because of the difficulties in patient accrual due to concerns regarding safety in surgery following neoadjuvant therapy. Additionally, it is critical to use endpoint measurements with meaningful clinical efficacy. Currently, no response evaluation criteria have been developed and gained acceptance for use in the neoadjuvant therapy followed by surgery paradigm. To overcome these barriers, planning neoadjuvant trials with multidisciplinary input are paramount. The currently approved agents for MTC, vandetanib and cabozantinib, are not ideal for neoadjuvant use due to their antiangiogenic properties, which have the potential to result in bleeding and poor wound healing. With the advent of RET inhibitors with relative low side-effect profiles with minimal antiangiogenic activity, implementing a RET inhibitor neoadjuvantly in patients with more locally advanced disease may lead to better surgical outcomes and reduce long-term recurrences.

The remarkable achievements attained over a relatively short time promise a hopeful future for patients with MTC. From the MTC Workshops at the MEN 2019, there was consensus that further research is much needed in the following areas: understanding the fundamental biology of C-cells by developing a normal C-cell model, establishing other mechanisms of oncogenesis beyond RET and RAS, understanding the mechanisms of heterogeneity of clinical behavior, clarifying mechanisms of drug resistance, and most importantly finding a treatment regimen that leads to sustainable control or cure for what has long been considered a chronic cancer.

Declaration of interest

R D received research support from Eisai, Merck, and Astra Zeneca and was a member of the advisory board of Bayer. R B Y, M R, and E G G have nothing to declare. M Z received research support from Eli Lilly and Co. G J C has nothing to declare. R F G was member of the Data Safety Monitoring Committee of Novo Nordisk. B R was member of the advisory board of Eisai, Loxo Oncology and speaker at Eisai and Loxo Oncology. K R S has nothing to declare. MIH received research support from Eli Lilly and Co and was member of the advisory board of Blueprint Medicines, Eli Lilly and Co, and Loxo Oncology.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • Agrawal N, Jiao Y, Sausen M, Leary R, Bettegowda C, Roberts NJ, Bhan S, Ho AS, Khan Z, Bishop J, 2013 Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. Journal of Clinical Endocrinology and Metabolism 98 E364E369. (https://doi.org/10.1210/jc.2012-2703)

    • Search Google Scholar
    • Export Citation
  • Ameri K & Harris AL 2008 Activating transcription factor 4. International Journal of Biochemistry and Cell Biology 40 1421. (https://doi.org/10.1016/j.biocel.2007.01.020)

    • Search Google Scholar
    • Export Citation
  • Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss Von Soly S, 2015 Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28 653665. (https://doi.org/10.1016/j.ccell.2015.10.002)

    • Search Google Scholar
    • Export Citation
  • Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, 2012 Generation of functional thyroid from embryonic stem cells. Nature 491 6671. (https://doi.org/10.1038/nature11525)

    • Search Google Scholar
    • Export Citation
  • Anwar F, Emond MJ, Schmidt RA, Hwang HC & Bronner MP 2000 Retinoblastoma expression in thyroid neoplasms. Modern Pathology 13 562569. (https://doi.org/10.1038/modpathol.3880097)

    • Search Google Scholar
    • Export Citation
  • Armstrong JL, Flockhart R, Veal GJ, Lovat PE & Redfern CP 2010 Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. Journal of Biological Chemistry 285 60916100. (https://doi.org/10.1074/jbc.M109.014092)

    • Search Google Scholar
    • Export Citation
  • Bachleitner-Hofmann T, Friedl J, Hassler M, Hayden H, Dubsky P, Sachet M, Rieder E, Pfragner R, Brostjan C, Riss S, 2009 Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma. Oncology Reports 21 15851592. (https://doi.org/10.3892/or_00000391)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Sinha KM, Gururaj AE, Ahmed Z, Rizvi YQ, Huang SC, Ladbury JE, Bogler O, Williams MD, Cote GJ, 2015 A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis. Journal of Biological Chemistry 290 1174911761. (https://doi.org/10.1074/jbc.M114.619833)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Sinha KM, Li L, Lu Y, Cote GJ, Sherman SI & Gagel RF 2019 Combinations of tyrosine kinase inhibitor and ERAD inhibitor promote oxidative stress-induced apoptosis through ATF4 and KLF9 in medullary thyroid cancer. Molecular Cancer Research 17 751760. (https://doi.org/10.1158/1541-7786.MCR-18-0354)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Williams MD, Grubbs EG & Gagel RF 2017 ATF4 targets RET for degradation and is a candidate tumor suppressor gene in medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 102 933941. (https://doi.org/10.1210/jc.2016-2878)

    • Search Google Scholar
    • Export Citation
  • Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L, Yu P, Engst S, Zhang W, Huang D, 2013 In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid 23 15691577. (https://doi.org/10.1089/thy.2013.0137)

    • Search Google Scholar
    • Export Citation
  • Berger CL, De Bustros A, Roos BA, Leong SS, Mendelsohn G, Gesell MS & Baylin SB 1984 Human medullary thyroid carcinoma in culture provides a model relating growth dynamics, endocrine cell differentiation, and tumor progression. Journal of Clinical Endocrinology and Metabolism 59 338343. (https://doi.org/10.1210/jcem-59-2-338)

    • Search Google Scholar
    • Export Citation
  • Bi Y, Ren X, Bai X, Meng Y, Luo Y, Cao J, Zhang Y & Liang Z 2019 PD-1/PD-L1 expressions in medullary thyroid carcinoma: clinicopathologic and prognostic analysis of Chinese population. European Journal of Surgical Oncology 45 353358. (https://doi.org/10.1016/j.ejso.2018.10.060)

    • Search Google Scholar
    • Export Citation
  • Bilusic M, Heery CR, Arlen PM, Rauckhorst M, Apelian D, Tsang KY, Tucker JA, Jochems C, Schlom J, Gulley JL, 2014 Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma. Cancer Immunology, Immunotherapy 63 225234. (https://doi.org/10.1007/s00262-013-1505-8)

    • Search Google Scholar
    • Export Citation
  • Bongiovanni M, Rebecchini C, Saglietti C, Bulliard JL, Marino L, De Leval L & Sykiotis GP 2017 Very low expression of PD-L1 in medullary thyroid carcinoma. Endocrine-Related Cancer 24 L35L38. (https://doi.org/10.1530/ERC-17-0104)

    • Search Google Scholar
    • Export Citation
  • Cabanillas ME, Hu MI & Jimenez C 2014 Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat – and with which drug – those are the questions. Journal of Clinical Endocrinology and Metabolism 99 43904396. (https://doi.org/10.1210/jc.2014-2811)

    • Search Google Scholar
    • Export Citation
  • Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, Billaud M & Santoro M 2004 Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23 60566063. (https://doi.org/10.1038/sj.onc.1207810)

    • Search Google Scholar
    • Export Citation
  • Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, Botton T, Ronco C, Abbe P, Amdouni H, 2016 Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Cancer Cell 29 805819. (https://doi.org/10.1016/j.ccell.2016.04.013)

    • Search Google Scholar
    • Export Citation
  • Clarke HJ, Chambers JE, Liniker E & Marciniak SJ 2014 Endoplasmic reticulum stress in malignancy. Cancer Cell 25 563573. (https://doi.org/10.1016/j.ccr.2014.03.015)

    • Search Google Scholar
    • Export Citation
  • Cooley LD, Elder FF, Knuth A & Gagel RF 1995 Cytogenetic characterization of three human and three rat medullary thyroid carcinoma cell lines. Cancer Genetics and Cytogenetics 80 138149. (https://doi.org/10.1016/0165-4608(94)00185-e)

    • Search Google Scholar
    • Export Citation
  • Cote GJ, Evers C, Hu MI, Grubbs EG, Williams MD, Hai T, Duose DY, Houston MR, Bui JH, Mehrotra M, 2017 Prognostic significance of circulating RET M918T mutated tumor DNA in patients With advanced medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 102 35913599. (https://doi.org/10.1210/jc.2017-01039)

    • Search Google Scholar
    • Export Citation
  • Dadu R, Cabanillas ME, De Groot P, Chang JY, Tang C, Sherman SI, Busaidy NL, Waguespack SG, Hu MI, Ying A, 2018 Short Call Poster 65: Ipilimumab with stereotactic ablative radiation therapy (SABR): results of a thyroid cancer expansion cohort. Thyroid 28 (S1) A-193. (https://doi.org/10.1089/thy.2018.29071.sc.abstracts)

    • Search Google Scholar
    • Export Citation
  • Drilon A, Rogers E, Zhai D, Deng W, Zhang X, Lee D, Ung J, Whitten J, Zhang H, Liu J, 2019 TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers. Annals of Oncology 30 (Supplement 5) v190v191. (https://doi.org/10.1093/annonc/mdz244.068)

    • Search Google Scholar
    • Export Citation
  • El Naofal M, Kim A, Yon HY, Baity M, Ming Z, Bui-Griffith J, Tang Z, Robinson M, Grubbs EG, Cote GJ, 2017 Role of CDKN2C fluorescence in situ hybridization in the management of medullary thyroid carcinoma. Annals of Clinical and Laboratory Science 47 523528.

    • Search Google Scholar
    • Export Citation
  • Elisei R, Pinchera A, Romei C, Gryczynska M, Pohl V, Maenhaut C, Fugazzola L & Pacini F 1994 Expression of thyrotropin receptor (TSH-R), thyroglobulin, thyroperoxidase, and calcitonin messenger ribonucleic acids in thyroid carcinomas: evidence of TSH-R gene transcript in medullary histotype. Journal of Clinical Endocrinology and Metabolism 78 867871. (https://doi.org/10.1210/jcem.78.4.8157713)

    • Search Google Scholar
    • Export Citation
  • Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F, 2008 Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. Journal of Clinical Endocrinology and Metabolism 93 682687. (https://doi.org/10.1210/jc.2007-1714)

    • Search Google Scholar
    • Export Citation
  • Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, 2013 Cabozantinib in progressive medullary thyroid cancer. Journal of Clinical Oncology 31 36393646. (https://doi.org/10.1200/JCO.2012.48.4659)

    • Search Google Scholar
    • Export Citation
  • Flicker K, Ulz P, Hoger H, Zeitlhofer P, Haas OA, Behmel A, Buchinger W, Scheuba C, Niederle B, Pfragner R, 2012 High-resolution analysis of alterations in medullary thyroid carcinoma genomes. International Journal of Cancer 131 E66E73. (https://doi.org/10.1002/ijc.26494)

    • Search Google Scholar
    • Export Citation
  • Galon J & Bruni D 2019 Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nature Reviews. Drug Discovery 18 197218. (https://doi.org/10.1038/s41573-018-0007-y)

    • Search Google Scholar
    • Export Citation
  • Grubbs EG, Williams MD, Scheet P, Vattathil S, Perrier ND, Lee JE, Gagel RF, Hai T, Feng L, Cabanillas ME, 2016 Role of CDKN2C copy number in sporadic medullary thyroid carcinoma. Thyroid 26 15531562. (https://doi.org/10.1089/thy.2016.0224)

    • Search Google Scholar
    • Export Citation
  • Harvey M, Vogel H, Lee EY, Bradley A & Donehower LA 1995 Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Research 55 11461151.

    • Search Google Scholar
    • Export Citation
  • Hassell BA, Goyal G, Lee E, Sontheimer-Phelps A, Levy O, Chen CS & Ingber DE 2017 Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Reports 21 508516. (https://doi.org/10.1016/j.celrep.2017.09.043)

    • Search Google Scholar
    • Export Citation
  • Hu MI, Taylor M, Wirth LJ, Zhu VW, Doebele RC, Lee D, Matos I, Baik C, Brose M, Curigliano G, 2018 Short Call Oral 5: Clinical activity of selective RET inhibitor, BLU-667, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study. Thyroid 28 (S1) A-170. (https://doi.org/10.1089/thy.2018.29071.sc.abstracts)

    • Search Google Scholar
    • Export Citation
  • Hu MI, Gote GJ, Hai T, Busaidy NL, Cabanillas ME, Dadu R, Gagel RF, Grubbs EG, Habra MA, Jimenez C, 2019 Oral 32: Emergence of resistance-associated mutations of RET V804M and KRAS in medullary thyroid carcinoma (MTC) patients treated iwth tyrosine kinase inhibitors (TKI) cabozantinib and vandetanib. Thyroid 29 (S1) A-13. (https://doi.org/10.1089/thy.2019.29085.abstracts)

    • Search Google Scholar
    • Export Citation
  • Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY & Ingber DE 2010 Reconstituting organ-level lung functions on a chip. Science 328 16621668. (https://doi.org/10.1126/science.1188302)

    • Search Google Scholar
    • Export Citation
  • Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, 2016 ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Science Signaling 9 ra17. (https://doi.org/10.1126/scisignal.aac4380)

    • Search Google Scholar
    • Export Citation
  • Johansson E, Andersson L, Ornros J, Carlsson T, Ingeson-Carlsson C, Liang S, Dahlberg J, Jansson S, Parrillo L, Zoppoli P, 2015 Revising the embryonic origin of thyroid C cells in mice and humans. Development 142 35193528. (https://doi.org/10.1242/dev.126581)

    • Search Google Scholar
    • Export Citation
  • Joshi PP, Kulkarni MV, Yu BK, Smith KR, Norton DL, Van Veelen W, Hoppener JW & Franklin DS 2007 Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Oncogene 26 554570. (https://doi.org/10.1038/sj.onc.1209811)

    • Search Google Scholar
    • Export Citation
  • Kameda Y 2019 Follicular cell lineage in persistent ultimobranchial remnants of mammals. Cell and Tissue Research 376 118. (https://doi.org/10.1007/s00441-018-02982-9)

    • Search Google Scholar
    • Export Citation
  • Kline CL, Van Den Heuvel AP, Allen JE, Prabhu VV, Dicker DT & El-Deiry WS 2016 ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2alpha kinases. Science Signaling 9 ra18. (https://doi.org/10.1126/scisignal.aac4374)

    • Search Google Scholar
    • Export Citation
  • Kusakabe T, Hoshi N & Kimura S 2006 Origin of the ultimobranchial body cyst: T/ebp/Nkx2.1 expression is required for development and fusion of the ultimobranchial body to the thyroid. Developmental Dynamics 235 13001309. (https://doi.org/10.1002/dvdy.20655)

    • Search Google Scholar
    • Export Citation
  • Levinson S & Cagan RL 2016 Drosophila cancer models identify functional differences between ret fusions. Cell Reports 16 30523061. (https://doi.org/10.1016/j.celrep.2016.08.019)

    • Search Google Scholar
    • Export Citation
  • Madsen LW, Knauf JA, Gotfredsen C, Pilling A, Sjogren I, Andersen S, Andersen L, De Boer AS, Manova K, Barlas A, 2012 GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology 153 15381547. (https://doi.org/10.1210/en.2011-1864)

    • Search Google Scholar
    • Export Citation
  • Maio M, Coral S, Sigalotti L, Elisei R, Romei C, Rossi G, Cortini E, Colizzi F, Fenzi G, Altomonte M, 2003 Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1. Journal of Clinical Endocrinology and Metabolism 88 748754. (https://doi.org/10.1210/jc.2002-020830)

    • Search Google Scholar
    • Export Citation
  • Mansouri A, Chowdhury K & Gruss P 1998 Follicular cells of the thyroid gland require Pax8 gene function. Nature Genetics 19 8790. (https://doi.org/10.1038/ng0598-87)

    • Search Google Scholar
    • Export Citation
  • Marsh DJ, Theodosopoulos G, Martin-Schulte K, Richardson AL, Philips J, Roher HD, Delbridge L & Robinson BG 2003 Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 88 18661872. (https://doi.org/10.1210/jc.2002-021155)

    • Search Google Scholar
    • Export Citation
  • Martin A, Zhou A, Gordon RE, Henderson SC, Schwartz AE, Schwartz AE, Friedman EW & Davies TF 2000 Thyroid organoid formation in simulated microgravity: influence of keratinocyte growth factor. Thyroid 10 481487. (https://doi.org/10.1089/thy.2000.10.481)

    • Search Google Scholar
    • Export Citation
  • Maurel M, Mcgrath EP, Mnich K, Healy S, Chevet E & Samali A 2015 Controlling the unfolded protein response-mediated life and death decisions in cancer. Seminars in Cancer Biology 33 5766. (https://doi.org/10.1016/j.semcancer.2015.03.003)

    • Search Google Scholar
    • Export Citation
  • Maxwell JE, Gule-Monroe MK, Subbiah V, Hu M, Perrier ND, Cabanillas ME, Lee JE, Graham PH, Cote GJ, Busaidy NL, 2020 Novel use of a Clinical Laboratory Improvements Amendments (CLIA)-certified cyclin-dependent kinase N2C (CDKN2C) loss assay in sporadic medullary thyroid carcinoma. Surgery 167 8086. (https://doi.org/10.1016/j.surg.2019.03.041)

    • Search Google Scholar
    • Export Citation
  • Meijer JA, Le Cessie S, Van Den Hout WB, Kievit J, Schoones JW, Romijn JA & Smit JW 2010 Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clinical Endocrinology 72 534542. (https://doi.org/10.1111/j.1365-2265.2009.03666.x)

    • Search Google Scholar
    • Export Citation
  • Mologni L, Redaelli S, Morandi A, Plaza-Menacho I & Gambacorti-Passerini C 2013 Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Molecular and Cellular Endocrinology 377 16. (https://doi.org/10.1016/j.mce.2013.06.025)

    • Search Google Scholar
    • Export Citation
  • Nilsson M & Williams D 2016 On the origin of cells and derivation of thyroid cancer: C cell story revisited. European Thyroid Journal 5 7993. (https://doi.org/10.1159/000447333)

    • Search Google Scholar
    • Export Citation
  • Ozaki T, Nagashima K, Kusakabe T, Kakudo K & Kimura S 2011 Development of thyroid gland and ultimobranchial body cyst is independent of p63. Laboratory Investigation 91 138146. (https://doi.org/10.1038/labinvest.2010.137)

    • Search Google Scholar
    • Export Citation
  • Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C & Koff A 1999 p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. PNAS 96 63826387. (https://doi.org/10.1073/pnas.96.11.6382)

    • Search Google Scholar
    • Export Citation
  • Pearse AG & Carvalheira AF 1967 Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 214 929930. (https://doi.org/10.1038/214929a0)

    • Search Google Scholar
    • Export Citation
  • Pozo K, Castro-Rivera E, TAN C, Plattner F, Schwach G, Siegl V, Meyer D, Guo A, Gundara J, Mettlach G, 2013 The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24 499511. (https://doi.org/10.1016/j.ccr.2013.08.027)

    • Search Google Scholar
    • Export Citation
  • Pozo K & Bibb JA 2016 The emerging role of Cdk5 in cancer. Trends in Cancer 2 606618. (https://doi.org/10.1016/j.trecan.2016.09.001)

  • Qu N, Shi X, Zhao JJ, Guan H, Zhang TT, Wen SS, Liao T, Hu JQ, Liu WY, Wang YL, 2020 Genomic and transcriptomic characterization of sporadic medullary thyroid carcinoma. Thyroid [epub]. (https://doi.org/10.1089/thy.2019.0531)

    • Search Google Scholar
    • Export Citation
  • Rossfeld KK, Justiniano SE, Ding H, Gong L, Kothandaraman S, Sawant D, Saji M, Wright CL, Kirschner LS, Ringel MD, 2017 Biological evaluation of a fluorescent-imaging agent for medullary thyroid cancer in an orthotopic model. Journal of Clinical Endocrinology and Metabolism 102 32683277. (https://doi.org/10.1210/jc.2017-00573)

    • Search Google Scholar
    • Export Citation
  • Sadat Alavi M & Azarpira N 2011 Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: a case report. Journal of Medical Case Reports 5 590. (https://doi.org/10.1186/1752-1947-5-590)

    • Search Google Scholar
    • Export Citation
  • Saito Y, Onishi N, Takami H, Seishima R, Inoue H, Hirata Y, Kameyama K, Tsuchihashi K, Sugihara E, Uchino S, 2018 Development of a functional thyroid model based on an organoid culture system. Biochemical and Biophysical Research Communications 497 783789. (https://doi.org/10.1016/j.bbrc.2018.02.154)

    • Search Google Scholar
    • Export Citation
  • Schlumberger M, Elisei R, Muller S, Schoffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, 2017 Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Annals of Oncology 28 28132819. (https://doi.org/10.1093/annonc/mdx479)

    • Search Google Scholar
    • Export Citation
  • Schoffski P, Aftimos PG, Massard C, Italiano A, Jungels C, Andreas K, Keegan M & Ho PTC 2019 A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer. Journal of Clinical Oncology 37 (Supplement 15) TPS3162. (https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS3162)

    • Search Google Scholar
    • Export Citation
  • Schott M, Seissler J, Lettmann M, Fouxon V, Scherbaum WA & Feldkamp J 2001 Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. Journal of Clinical Endocrinology and Metabolism 86 49654969. (https://doi.org/10.1210/jcem.86.10.7949)

    • Search Google Scholar
    • Export Citation
  • Smith-Hicks CL, Sizer KC, Powers JF, Tischler AS & Costantini F 2000 C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO Journal 19 612622. (https://doi.org/10.1093/emboj/19.4.612)

    • Search Google Scholar
    • Export Citation
  • Solomon BJ, Tan L, Lin JJ, Wong SQ, Hollizeck S, Ebata K, Tuch BB, Yoda S, Gainor JF, Sequist LV, 2020 RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. Journal of Thoracic Oncology 15 541549. (https://doi.org/10.1016/j.jtho.2020.01.006)

    • Search Google Scholar
    • Export Citation
  • Song H, Lin C, Yao E, Zhang K, Li X, Wu Q & Chuang PT 2017 Selective ablation of tumor suppressors in parafollicular C Cells elicits medullary thyroid carcinoma. Journal of Biological Chemistry 292 38883899. (https://doi.org/10.1074/jbc.M116.765727)

    • Search Google Scholar
    • Export Citation
  • Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Schueller G, Zontsich T, Benkoe T, Radelbauer K, Brostjan C, Jakesz R, 2003 Dendritic cell-based vaccination in solid cancer. Journal of Clinical Oncology 21 135142. (https://doi.org/10.1200/JCO.2003.02.135)

    • Search Google Scholar
    • Export Citation
  • Stift A, Sachet M, Yagubian R, Bittermann C, Dubsky P, Brostjan C, Pfragner R, Niederle B, Jakesz R, Gnant M, 2004 Dendritic cell vaccination in medullary thyroid carcinoma. Clinical Cancer Research 10 29442953. (https://doi.org/10.1158/1078-0432.ccr-03-0698)

    • Search Google Scholar
    • Export Citation
  • Tabas I & Ron D 2011 Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature Cell Biology 13 184190. (https://doi.org/10.1038/ncb0311-184)

    • Search Google Scholar
    • Export Citation
  • Taylor MH, Gainor JF, Hu MI, Zhu VW, Lopes G, Leboulleux S, Brose MB, Schuler MH, Bowles DW, Kim DW, 2019 Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers. Journal of Clinical Oncology 37 (15 Suppl) 6018. (https://doi.org/10.1200/JCO.2019.37.15_suppl.6018)

    • Search Google Scholar
    • Export Citation
  • Valenciaga A, Grubbs EG, Porter K, Wakely PE, Williams MD, Cote GJ, Vasko VV, Saji M & Ringel MD 2017 Reduced retinoblastoma protein expression is associated with decreased patient survival in medullary thyroid cancer. Thyroid 27 15231533. (https://doi.org/10.1089/thy.2017.0113)

    • Search Google Scholar
    • Export Citation
  • Valenciaga A, Saji M, Yu L, Zhang X, Bumrah C, Yilmaz AS, Knippler CM, Miles W, Giordano TJ, Cote GJ, 2018 Transcriptional targeting of oncogene addiction in medullary thyroid cancer. JCI Insight 3 e122225. (https://doi.org/10.1172/jci.insight.122225)

    • Search Google Scholar
    • Export Citation
  • Van Veelen W, Van Gasteren CJ, Acton DS, Franklin DS, Berger R, Lips CJ & Hoppener JW 2008 Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer Research 68 13291337. (https://doi.org/10.1158/0008-5472.CAN-07-5754)

    • Search Google Scholar
    • Export Citation
  • Van Veelen W, Klompmaker R, Gloerich M, Van Gasteren CJ, Kalkhoven E, Berger R, Lips CJ, Medema RH, Hoppener JW & Acton DS 2009 P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. International Journal of Cancer 124 339345. (https://doi.org/10.1002/ijc.23977)

    • Search Google Scholar
    • Export Citation
  • Vidal M, Wells S, Ryan A & Cagan R 2005 ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Research 65 35383541. (https://doi.org/10.1158/0008-5472.CAN-04-4561)

    • Search Google Scholar
    • Export Citation
  • Vitagliano D, Carlomagno F, Motti ML, Viglietto G, Nikiforov YE, Nikiforova MN, Hershman JM, Ryan AJ, Fusco A, Melillo RM, 2004 Regulation of p27Kip1 protein levels contributes to mitogenic effects of the RET/PTC kinase in thyroid carcinoma cells. Cancer Research 64 38233829. (https://doi.org/10.1158/0008-5472.CAN-03-3918)

    • Search Google Scholar
    • Export Citation
  • Wang Q, Shinkre BA, Lee JG, Weniger MA, Liu Y, Chen W, Wiestner A, Trenkle WC & Ye Y 2010 The ERAD inhibitor Eeyarestatin I is a bifunctional compound with a membrane-binding domain and a p97/VCP inhibitory group. PLoS One 5 e15479. (https://doi.org/10.1371/journal.pone.0015479)

    • Search Google Scholar
    • Export Citation
  • Wang M, Law ME, Castellano RK & Law BK 2018 The unfolded protein response as a target for anticancer therapeutics. Critical Reviews in Oncology/Hematology 127 6679. (https://doi.org/10.1016/j.critrevonc.2018.05.003)

    • Search Google Scholar
    • Export Citation
  • Wansley EK, Chakraborty M, Hance KW, Bernstein MB, Boehm AL, Guo Z, Quick D, Franzusoff A, Greiner JW, Schlom J, 2008 Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clinical Cancer Research 14 43164325. (https://doi.org/10.1158/1078-0432.CCR-08-0393)

    • Search Google Scholar
    • Export Citation
  • Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, vasselli JR, 2012 Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. Journal of Clinical Oncology 30 134141. (https://doi.org/10.1200/JCO.2011.35.5040)

    • Search Google Scholar
    • Export Citation
  • Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, 2015 Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 567610. (https://doi.org/10.1089/thy.2014.0335)

    • Search Google Scholar
    • Export Citation
  • Williams BO, Remington L, Albert DM, Mukai S, Bronson RT & Jacks T 1994 Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genetics 7 480484. (https://doi.org/10.1038/ng0894-480)

    • Search Google Scholar
    • Export Citation
  • Wirth LJ, Cabanillas ME, Sherman E, Solomon B, Leboulleux S, Robinson B, Taylor M, Bauer T, Patel J, Reckamp K, 2018 Short Call Oral 6: Clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET-altered thyroid cancers. Thyroid 28 (S1) A-171. (https://doi.org/10.1089/thy.2018.29071.sc.abstracts)

    • Search Google Scholar
    • Export Citation
  • Wirth LJ, Sherman E, Drilon A, Solomon B, Robinson B, Lorch J, Mccoach C, Patel J, Leboulleux S, Worden F, 2019 LBA93: Registrational results of LOXO-292 in patients with RET-altered thyroid cancers. Annals of Oncology 30 (Supplement 5) v933. (https://doi.org/10.1093/annonc/mdz394.093)

    • Search Google Scholar
    • Export Citation
  • Xu Z, Li E, Guo Z, Yu R, Hao H, Xu Y, Sun Z, Li X, Lyu J & Wang Q 2016 Design and construction of a multi-organ microfluidic chip mimicking the in vivo microenvironment of lung cancer metastasis. ACS Applied Materials and Interfaces 8 2584025847. (https://doi.org/10.1021/acsami.6b08746)

    • Search Google Scholar
    • Export Citation
  • Yamamoto N, Nokihara H, Yamada Y, Shibata T, Tamura Y, Seki Y, Honda K, Tanabe Y, Wakui H & Tamura T 2017 Phase I study of Nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Investigational New Drugs 35 207216. (https://doi.org/10.1007/s10637-016-0411-2)

    • Search Google Scholar
    • Export Citation
  • Yamasaki L, Bronson R, Williams BO, Dyson NJ, Harlow E & Jacks T 1998 Loss of E2F-1 reduces tumorigenesis and extends the lifespan of Rb1(+/-)mice. Nature Genetics 18 360364. (https://doi.org/10.1038/ng0498-360)

    • Search Google Scholar
    • Export Citation
  • Ye L, Santarpia L, Cote GJ, El-Naggar AK & Gagel RF 2008 High resolution array-comparative genomic hybridization profiling reveals deoxyribonucleic acid copy number alterations associated with medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 93 43674372. (https://doi.org/10.1210/jc.2008-0912)

    • Search Google Scholar
    • Export Citation
  • Zucker SN, Fink EE, Bagati A, Mannava S, Bianchi-Smiraglia A, Bogner PN, Wawrzyniak JA, Foley C, Leonova KI, Grimm MJ, 2014 Nrf2 amplifies oxidative stress via induction of Klf9. Molecular Cell 53 916928. (https://doi.org/10.1016/j.molcel.2014.01.033)

    • Search Google Scholar
    • Export Citation

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    Pathogenic pathways in medullary thyroid carcinoma. Pathogenic drivers of disease include: mutations leading to activated RET or RAS receptors; overexpression of EGFR, MET and VEGFR; genetic loss of CDKNs; and loss of ATF4 protein. ATF4, activating transcription factor 4; BRAF, serine/threonine-protein kinase B-Raf; CDK, cyclin-dependent kinases; CDKN, cyclin-dependent kinase inhibitor; E2F, family of DNA-binding transcription factors; EGFR, epidermal growth factor receptor; FGF, fibroblast growth factor; MAPK, mitogen-activated protein kinase kinase; MET, hepatocyte growth factor; RAS, rat sarcoma viral oncogene homolog; Rb, retinoblastoma; RET, rearranged during transfection; VEGFR, vascular endothelial growth factor receptor.

  • Agrawal N, Jiao Y, Sausen M, Leary R, Bettegowda C, Roberts NJ, Bhan S, Ho AS, Khan Z, Bishop J, 2013 Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. Journal of Clinical Endocrinology and Metabolism 98 E364E369. (https://doi.org/10.1210/jc.2012-2703)

    • Search Google Scholar
    • Export Citation
  • Ameri K & Harris AL 2008 Activating transcription factor 4. International Journal of Biochemistry and Cell Biology 40 1421. (https://doi.org/10.1016/j.biocel.2007.01.020)

    • Search Google Scholar
    • Export Citation
  • Anderson DJ, Le Moigne R, Djakovic S, Kumar B, Rice J, Wong S, Wang J, Yao B, Valle E, Kiss Von Soly S, 2015 Targeting the AAA ATPase p97 as an approach to treat cancer through disruption of protein homeostasis. Cancer Cell 28 653665. (https://doi.org/10.1016/j.ccell.2015.10.002)

    • Search Google Scholar
    • Export Citation
  • Antonica F, Kasprzyk DF, Opitz R, Iacovino M, Liao XH, Dumitrescu AM, Refetoff S, Peremans K, Manto M, Kyba M, 2012 Generation of functional thyroid from embryonic stem cells. Nature 491 6671. (https://doi.org/10.1038/nature11525)

    • Search Google Scholar
    • Export Citation
  • Anwar F, Emond MJ, Schmidt RA, Hwang HC & Bronner MP 2000 Retinoblastoma expression in thyroid neoplasms. Modern Pathology 13 562569. (https://doi.org/10.1038/modpathol.3880097)

    • Search Google Scholar
    • Export Citation
  • Armstrong JL, Flockhart R, Veal GJ, Lovat PE & Redfern CP 2010 Regulation of endoplasmic reticulum stress-induced cell death by ATF4 in neuroectodermal tumor cells. Journal of Biological Chemistry 285 60916100. (https://doi.org/10.1074/jbc.M109.014092)

    • Search Google Scholar
    • Export Citation
  • Bachleitner-Hofmann T, Friedl J, Hassler M, Hayden H, Dubsky P, Sachet M, Rieder E, Pfragner R, Brostjan C, Riss S, 2009 Pilot trial of autologous dendritic cells loaded with tumor lysate(s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma. Oncology Reports 21 15851592. (https://doi.org/10.3892/or_00000391)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Sinha KM, Gururaj AE, Ahmed Z, Rizvi YQ, Huang SC, Ladbury JE, Bogler O, Williams MD, Cote GJ, 2015 A novel dual kinase function of the RET proto-oncogene negatively regulates activating transcription factor 4-mediated apoptosis. Journal of Biological Chemistry 290 1174911761. (https://doi.org/10.1074/jbc.M114.619833)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Sinha KM, Li L, Lu Y, Cote GJ, Sherman SI & Gagel RF 2019 Combinations of tyrosine kinase inhibitor and ERAD inhibitor promote oxidative stress-induced apoptosis through ATF4 and KLF9 in medullary thyroid cancer. Molecular Cancer Research 17 751760. (https://doi.org/10.1158/1541-7786.MCR-18-0354)

    • Search Google Scholar
    • Export Citation
  • Bagheri-Yarmand R, Williams MD, Grubbs EG & Gagel RF 2017 ATF4 targets RET for degradation and is a candidate tumor suppressor gene in medullary thyroid cancer. Journal of Clinical Endocrinology and Metabolism 102 933941. (https://doi.org/10.1210/jc.2016-2878)

    • Search Google Scholar
    • Export Citation
  • Bentzien F, Zuzow M, Heald N, Gibson A, Shi Y, Goon L, Yu P, Engst S, Zhang W, Huang D, 2013 In vitro and in vivo activity of cabozantinib (XL184), an inhibitor of RET, MET, and VEGFR2, in a model of medullary thyroid cancer. Thyroid 23 15691577. (https://doi.org/10.1089/thy.2013.0137)

    • Search Google Scholar
    • Export Citation
  • Berger CL, De Bustros A, Roos BA, Leong SS, Mendelsohn G, Gesell MS & Baylin SB 1984 Human medullary thyroid carcinoma in culture provides a model relating growth dynamics, endocrine cell differentiation, and tumor progression. Journal of Clinical Endocrinology and Metabolism 59 338343. (https://doi.org/10.1210/jcem-59-2-338)

    • Search Google Scholar
    • Export Citation
  • Bi Y, Ren X, Bai X, Meng Y, Luo Y, Cao J, Zhang Y & Liang Z 2019 PD-1/PD-L1 expressions in medullary thyroid carcinoma: clinicopathologic and prognostic analysis of Chinese population. European Journal of Surgical Oncology 45 353358. (https://doi.org/10.1016/j.ejso.2018.10.060)

    • Search Google Scholar
    • Export Citation
  • Bilusic M, Heery CR, Arlen PM, Rauckhorst M, Apelian D, Tsang KY, Tucker JA, Jochems C, Schlom J, Gulley JL, 2014 Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma. Cancer Immunology, Immunotherapy 63 225234. (https://doi.org/10.1007/s00262-013-1505-8)

    • Search Google Scholar
    • Export Citation
  • Bongiovanni M, Rebecchini C, Saglietti C, Bulliard JL, Marino L, De Leval L & Sykiotis GP 2017 Very low expression of PD-L1 in medullary thyroid carcinoma. Endocrine-Related Cancer 24 L35L38. (https://doi.org/10.1530/ERC-17-0104)

    • Search Google Scholar
    • Export Citation
  • Cabanillas ME, Hu MI & Jimenez C 2014 Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat – and with which drug – those are the questions. Journal of Clinical Endocrinology and Metabolism 99 43904396. (https://doi.org/10.1210/jc.2014-2811)

    • Search Google Scholar
    • Export Citation
  • Carlomagno F, Guida T, Anaganti S, Vecchio G, Fusco A, Ryan AJ, Billaud M & Santoro M 2004 Disease associated mutations at valine 804 in the RET receptor tyrosine kinase confer resistance to selective kinase inhibitors. Oncogene 23 60566063. (https://doi.org/10.1038/sj.onc.1207810)

    • Search Google Scholar
    • Export Citation
  • Cerezo M, Lehraiki A, Millet A, Rouaud F, Plaisant M, Jaune E, Botton T, Ronco C, Abbe P, Amdouni H, 2016 Compounds triggering ER stress exert anti-melanoma effects and overcome BRAF inhibitor resistance. Cancer Cell 29 805819. (https://doi.org/10.1016/j.ccell.2016.04.013)

    • Search Google Scholar
    • Export Citation
  • Clarke HJ, Chambers JE, Liniker E & Marciniak SJ 2014 Endoplasmic reticulum stress in malignancy. Cancer Cell 25 563573. (https://doi.org/10.1016/j.ccr.2014.03.015)

    • Search Google Scholar
    • Export Citation
  • Cooley LD, Elder FF, Knuth A & Gagel RF 1995 Cytogenetic characterization of three human and three rat medullary thyroid carcinoma cell lines. Cancer Genetics and Cytogenetics 80 138149. (https://doi.org/10.1016/0165-4608(94)00185-e)

    • Search Google Scholar
    • Export Citation
  • Cote GJ, Evers C, Hu MI, Grubbs EG, Williams MD, Hai T, Duose DY, Houston MR, Bui JH, Mehrotra M, 2017 Prognostic significance of circulating RET M918T mutated tumor DNA in patients With advanced medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 102 35913599. (https://doi.org/10.1210/jc.2017-01039)

    • Search Google Scholar
    • Export Citation
  • Dadu R, Cabanillas ME, De Groot P, Chang JY, Tang C, Sherman SI, Busaidy NL, Waguespack SG, Hu MI, Ying A, 2018 Short Call Poster 65: Ipilimumab with stereotactic ablative radiation therapy (SABR): results of a thyroid cancer expansion cohort. Thyroid 28 (S1) A-193. (https://doi.org/10.1089/thy.2018.29071.sc.abstracts)

    • Search Google Scholar
    • Export Citation
  • Drilon A, Rogers E, Zhai D, Deng W, Zhang X, Lee D, Ung J, Whitten J, Zhang H, Liu J, 2019 TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers. Annals of Oncology 30 (Supplement 5) v190v191. (https://doi.org/10.1093/annonc/mdz244.068)

    • Search Google Scholar
    • Export Citation
  • El Naofal M, Kim A, Yon HY, Baity M, Ming Z, Bui-Griffith J, Tang Z, Robinson M, Grubbs EG, Cote GJ, 2017 Role of CDKN2C fluorescence in situ hybridization in the management of medullary thyroid carcinoma. Annals of Clinical and Laboratory Science 47 523528.

    • Search Google Scholar
    • Export Citation
  • Elisei R, Pinchera A, Romei C, Gryczynska M, Pohl V, Maenhaut C, Fugazzola L & Pacini F 1994 Expression of thyrotropin receptor (TSH-R), thyroglobulin, thyroperoxidase, and calcitonin messenger ribonucleic acids in thyroid carcinomas: evidence of TSH-R gene transcript in medullary histotype. Journal of Clinical Endocrinology and Metabolism 78 867871. (https://doi.org/10.1210/jcem.78.4.8157713)

    • Search Google Scholar
    • Export Citation
  • Elisei R, Cosci B, Romei C, Bottici V, Renzini G, Molinaro E, Agate L, Vivaldi A, Faviana P, Basolo F, 2008 Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. Journal of Clinical Endocrinology and Metabolism 93 682687. (https://doi.org/10.1210/jc.2007-1714)

    • Search Google Scholar
    • Export Citation
  • Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH, Licitra L, Jarzab B, Medvedev V, Kreissl MC, 2013 Cabozantinib in progressive medullary thyroid cancer. Journal of Clinical Oncology 31 36393646. (https://doi.org/10.1200/JCO.2012.48.4659)

    • Search Google Scholar
    • Export Citation
  • Flicker K, Ulz P, Hoger H, Zeitlhofer P, Haas OA, Behmel A, Buchinger W, Scheuba C, Niederle B, Pfragner R, 2012 High-resolution analysis of alterations in medullary thyroid carcinoma genomes. International Journal of Cancer 131 E66E73. (https://doi.org/10.1002/ijc.26494)

    • Search Google Scholar
    • Export Citation
  • Galon J & Bruni D 2019 Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nature Reviews. Drug Discovery 18 197218. (https://doi.org/10.1038/s41573-018-0007-y)

    • Search Google Scholar
    • Export Citation
  • Grubbs EG, Williams MD, Scheet P, Vattathil S, Perrier ND, Lee JE, Gagel RF, Hai T, Feng L, Cabanillas ME, 2016 Role of CDKN2C copy number in sporadic medullary thyroid carcinoma. Thyroid 26 15531562. (https://doi.org/10.1089/thy.2016.0224)

    • Search Google Scholar
    • Export Citation
  • Harvey M, Vogel H, Lee EY, Bradley A & Donehower LA 1995 Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Research 55 11461151.

    • Search Google Scholar
    • Export Citation
  • Hassell BA, Goyal G, Lee E, Sontheimer-Phelps A, Levy O, Chen CS & Ingber DE 2017 Human organ chip models recapitulate orthotopic lung cancer growth, therapeutic responses, and tumor dormancy in vitro. Cell Reports 21 508516. (https://doi.org/10.1016/j.celrep.2017.09.043)

    • Search Google Scholar
    • Export Citation
  • Hu MI, Taylor M, Wirth LJ, Zhu VW, Doebele RC, Lee D, Matos I, Baik C, Brose M, Curigliano G, 2018 Short Call Oral 5: Clinical activity of selective RET inhibitor, BLU-667, in advanced RET-altered thyroid cancers: updated results from the phase 1 ARROW study. Thyroid 28 (S1) A-170. (https://doi.org/10.1089/thy.2018.29071.sc.abstracts)

    • Search Google Scholar
    • Export Citation
  • Hu MI, Gote GJ, Hai T, Busaidy NL, Cabanillas ME, Dadu R, Gagel RF, Grubbs EG, Habra MA, Jimenez C, 2019 Oral 32: Emergence of resistance-associated mutations of RET V804M and KRAS in medullary thyroid carcinoma (MTC) patients treated iwth tyrosine kinase inhibitors (TKI) cabozantinib and vandetanib. Thyroid 29 (S1) A-13. (https://doi.org/10.1089/thy.2019.29085.abstracts)

    • Search Google Scholar
    • Export Citation
  • Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY & Ingber DE 2010 Reconstituting organ-level lung functions on a chip. Science 328 16621668. (https://doi.org/10.1126/science.1188302)

    • Search Google Scholar
    • Export Citation
  • Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, 2016 ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Science Signaling 9 ra17. (https://doi.org/10.1126/scisignal.aac4380)

    • Search Google Scholar
    • Export Citation
  • Johansson E, Andersson L, Ornros J, Carlsson T, Ingeson-Carlsson C, Liang S, Dahlberg J, Jansson S, Parrillo L, Zoppoli P, 2015 Revising the embryonic origin of thyroid C cells in mice and humans. Development 142 35193528. (https://doi.org/10.1242/dev.126581)

    • Search Google Scholar
    • Export Citation
  • Joshi PP, Kulkarni MV, Yu BK, Smith KR, Norton DL, Van Veelen W, Hoppener JW & Franklin DS 2007 Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis. Oncogene 26 554570. (https://doi.org/10.1038/sj.onc.1209811)

    • Search Google Scholar
    • Export Citation
  • Kameda Y 2019 Follicular cell lineage in persistent ultimobranchial remnants of mammals. Cell and Tissue Research 376 118. (https://doi.org/10.1007/s00441-018-02982-9)

    • Search Google Scholar
    • Export Citation
  • Kline CL, Van Den Heuvel AP, Allen JE, Prabhu VV, Dicker DT & El-Deiry WS 2016 ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2alpha kinases. Science Signaling 9 ra18. (https://doi.org/10.1126/scisignal.aac4374)

    • Search Google Scholar
    • Export Citation
  • Kusakabe T, Hoshi N & Kimura S 2006 Origin of the ultimobranchial body cyst: T/ebp/Nkx2.1 expression is required for development and fusion of the ultimobranchial body to the thyroid. Developmental Dynamics 235 13001309. (https://doi.org/10.1002/dvdy.20655)

    • Search Google Scholar
    • Export Citation
  • Levinson S & Cagan RL 2016 Drosophila cancer models identify functional differences between ret fusions. Cell Reports 16 30523061. (https://doi.org/10.1016/j.celrep.2016.08.019)

    • Search Google Scholar
    • Export Citation
  • Madsen LW, Knauf JA, Gotfredsen C, Pilling A, Sjogren I, Andersen S, Andersen L, De Boer AS, Manova K, Barlas A, 2012 GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology 153 15381547. (https://doi.org/10.1210/en.2011-1864)

    • Search Google Scholar
    • Export Citation
  • Maio M, Coral S, Sigalotti L, Elisei R, Romei C, Rossi G, Cortini E, Colizzi F, Fenzi G, Altomonte M, 2003 Analysis of cancer/testis antigens in sporadic medullary thyroid carcinoma: expression and humoral response to NY-ESO-1. Journal of Clinical Endocrinology and Metabolism 88 748754. (https://doi.org/10.1210/jc.2002-020830)

    • Search Google Scholar
    • Export Citation
  • Mansouri A, Chowdhury K & Gruss P 1998 Follicular cells of the thyroid gland require Pax8 gene function. Nature Genetics 19 8790. (https://doi.org/10.1038/ng0598-87)

    • Search Google Scholar
    • Export Citation
  • Marsh DJ, Theodosopoulos G, Martin-Schulte K, Richardson AL, Philips J, Roher HD, Delbridge L & Robinson BG 2003 Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 88 18661872. (https://doi.org/10.1210/jc.2002-021155)

    • Search Google Scholar
    • Export Citation
  • Martin A, Zhou A, Gordon RE, Henderson SC, Schwartz AE, Schwartz AE, Friedman EW & Davies TF 2000 Thyroid organoid formation in simulated microgravity: influence of keratinocyte growth factor. Thyroid 10 481487. (https://doi.org/10.1089/thy.2000.10.481)

    • Search Google Scholar
    • Export Citation
  • Maurel M, Mcgrath EP, Mnich K, Healy S, Chevet E & Samali A 2015 Controlling the unfolded protein response-mediated life and death decisions in cancer. Seminars in Cancer Biology 33 5766. (https://doi.org/10.1016/j.semcancer.2015.03.003)

    • Search Google Scholar
    • Export Citation
  • Maxwell JE, Gule-Monroe MK, Subbiah V, Hu M, Perrier ND, Cabanillas ME, Lee JE, Graham PH, Cote GJ, Busaidy NL, 2020 Novel use of a Clinical Laboratory Improvements Amendments (CLIA)-certified cyclin-dependent kinase N2C (CDKN2C) loss assay in sporadic medullary thyroid carcinoma. Surgery 167 8086. (https://doi.org/10.1016/j.surg.2019.03.041)

    • Search Google Scholar
    • Export Citation
  • Meijer JA, Le Cessie S, Van Den Hout WB, Kievit J, Schoones JW, Romijn JA & Smit JW 2010 Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clinical Endocrinology 72 534542. (https://doi.org/10.1111/j.1365-2265.2009.03666.x)

    • Search Google Scholar
    • Export Citation
  • Mologni L, Redaelli S, Morandi A, Plaza-Menacho I & Gambacorti-Passerini C 2013 Ponatinib is a potent inhibitor of wild-type and drug-resistant gatekeeper mutant RET kinase. Molecular and Cellular Endocrinology 377 16. (https://doi.org/10.1016/j.mce.2013.06.025)

    • Search Google Scholar
    • Export Citation
  • Nilsson M & Williams D 2016 On the origin of cells and derivation of thyroid cancer: C cell story revisited. European Thyroid Journal 5 7993. (https://doi.org/10.1159/000447333)

    • Search Google Scholar
    • Export Citation
  • Ozaki T, Nagashima K, Kusakabe T, Kakudo K & Kimura S 2011 Development of thyroid gland and ultimobranchial body cyst is independent of p63. Laboratory Investigation 91 138146. (https://doi.org/10.1038/labinvest.2010.137)

    • Search Google Scholar
    • Export Citation
  • Park MS, Rosai J, Nguyen HT, Capodieci P, Cordon-Cardo C & Koff A 1999 p27 and Rb are on overlapping pathways suppressing tumorigenesis in mice. PNAS 96 63826387. (https://doi.org/10.1073/pnas.96.11.6382)

    • Search Google Scholar
    • Export Citation
  • Pearse AG & Carvalheira AF 1967 Cytochemical evidence for an ultimobranchial origin of rodent thyroid C cells. Nature 214 929930. (https://doi.org/10.1038/214929a0)

    • Search Google Scholar
    • Export Citation
  • Pozo K, Castro-Rivera E, TAN C, Plattner F, Schwach G, Siegl V, Meyer D, Guo A, Gundara J, Mettlach G, 2013 The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24 499511. (https://doi.org/10.1016/j.ccr.2013.08.027)

    • Search Google Scholar
    • Export Citation
  • Pozo K & Bibb JA 2016 The emerging role of Cdk5 in cancer. Trends in Cancer 2 606618. (https://doi.org/10.1016/j.trecan.2016.09.001)

  • Qu N, Shi X, Zhao JJ, Guan H, Zhang TT, Wen SS, Liao T, Hu JQ, Liu WY, Wang YL, 2020 Genomic and transcriptomic characterization of sporadic medullary thyroid carcinoma. Thyroid [epub]. (https://doi.org/10.1089/thy.2019.0531)

    • Search Google Scholar
    • Export Citation
  • Rossfeld KK, Justiniano SE, Ding H, Gong L, Kothandaraman S, Sawant D, Saji M, Wright CL, Kirschner LS, Ringel MD, 2017 Biological evaluation of a fluorescent-imaging agent for medullary thyroid cancer in an orthotopic model. Journal of Clinical Endocrinology and Metabolism 102 32683277. (https://doi.org/10.1210/jc.2017-00573)

    • Search Google Scholar
    • Export Citation
  • Sadat Alavi M & Azarpira N 2011 Medullary and papillary carcinoma of the thyroid gland occurring as a collision tumor with lymph node metastasis: a case report. Journal of Medical Case Reports 5 590. (https://doi.org/10.1186/1752-1947-5-590)

    • Search Google Scholar
    • Export Citation
  • Saito Y, Onishi N, Takami H, Seishima R, Inoue H, Hirata Y, Kameyama K, Tsuchihashi K, Sugihara E, Uchino S, 2018 Development of a functional thyroid model based on an organoid culture system. Biochemical and Biophysical Research Communications 497 783789. (https://doi.org/10.1016/j.bbrc.2018.02.154)

    • Search Google Scholar
    • Export Citation
  • Schlumberger M, Elisei R, Muller S, Schoffski P, Brose M, Shah M, Licitra L, Krajewska J, Kreissl MC, Niederle B, 2017 Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Annals of Oncology 28 28132819. (https://doi.org/10.1093/annonc/mdx479)

    • Search Google Scholar
    • Export Citation
  • Schoffski P, Aftimos PG, Massard C, Italiano A, Jungels C, Andreas K, Keegan M & Ho PTC 2019 A phase I study of BOS172738 in patients with advanced solid tumors with RET gene alterations including non-small cell lung cancer and medullary thyroid cancer. Journal of Clinical Oncology 37 (Supplement 15) TPS3162. (https://doi.org/10.1200/JCO.2019.37.15_suppl.TPS3162)

    • Search Google Scholar
    • Export Citation
  • Schott M, Seissler J, Lettmann M, Fouxon V, Scherbaum WA & Feldkamp J 2001 Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. Journal of Clinical Endocrinology and Metabolism 86 49654969. (https://doi.org/10.1210/jcem.86.10.7949)

    • Search Google Scholar
    • Export Citation
  • Smith-Hicks CL, Sizer KC, Powers JF, Tischler AS & Costantini F 2000 C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO Journal 19 612622. (https://doi.org/10.1093/emboj/19.4.612)

    • Search Google Scholar
    • Export Citation
  • Solomon BJ, Tan L, Lin JJ, Wong SQ, Hollizeck S, Ebata K, Tuch BB, Yoda S, Gainor JF, Sequist LV, 2020 RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. Journal of Thoracic Oncology 15 541549. (https://doi.org/10.1016/j.jtho.2020.01.006)

    • Search Google Scholar
    • Export Citation
  • Song H, Lin C, Yao E, Zhang K, Li X, Wu Q & Chuang PT 2017 Selective ablation of tumor suppressors in parafollicular C Cells elicits medullary thyroid carcinoma. Journal of Biological Chemistry 292 38883899. (https://doi.org/10.1074/jbc.M116.765727)

    • Search Google Scholar
    • Export Citation
  • Stift A, Friedl J, Dubsky P, Bachleitner-Hofmann T, Schueller G, Zontsich T, Benkoe T, Radelbauer K, Brostjan C, Jakesz R, 2003 Dendritic cell-based vaccination in solid cancer. Journal of Clinical Oncology 21 135142. (https://doi.org/10.1200/JCO.2003.02.135)

    • Search Google Scholar
    • Export Citation
  • Stift A, Sachet M, Yagubian R, Bittermann C, Dubsky P, Brostjan C, Pfragner R, Niederle B, Jakesz R, Gnant M, 2004 Dendritic cell vaccination in medullary thyroid carcinoma. Clinical Cancer Research 10 29442953. (https://doi.org/10.1158/1078-0432.ccr-03-0698)

    • Search Google Scholar
    • Export Citation
  • Tabas I & Ron D 2011 Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature Cell Biology 13 184190. (https://doi.org/10.1038/ncb0311-184)

    • Search Google Scholar
    • Export Citation
  • Taylor MH, Gainor JF, Hu MI, Zhu VW, Lopes G, Leboulleux S, Brose MB, Schuler MH, Bowles DW, Kim DW, 2019 Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers. Journal of Clinical Oncology 37 (15 Suppl) 6018. (https://doi.org/10.1200/JCO.2019.37.15_suppl.6018)

    • Search Google Scholar
    • Export Citation
  • Valenciaga A, Grubbs EG, Porter K, Wakely PE, Williams MD, Cote GJ, Vasko VV, Saji M & Ringel MD 2017 Reduced retinoblastoma protein expression is associated with decreased patient survival in medullary thyroid cancer. Thyroid 27 15231533. (https://doi.org/10.1089/thy.2017.0113)

    • Search Google Scholar
    • Export Citation
  • Valenciaga A, Saji M, Yu L, Zhang X, Bumrah C, Yilmaz AS, Knippler CM, Miles W, Giordano TJ, Cote GJ, 2018 Transcriptional targeting of oncogene addiction in medullary thyroid cancer. JCI Insight 3 e122225. (https://doi.org/10.1172/jci.insight.122225)

    • Search Google Scholar
    • Export Citation
  • Van Veelen W, Van Gasteren CJ, Acton DS, Franklin DS, Berger R, Lips CJ & Hoppener JW 2008 Synergistic effect of oncogenic RET and loss of p18 on medullary thyroid carcinoma development. Cancer Research 68 13291337. (https://doi.org/10.1158/0008-5472.CAN-07-5754)

    • Search Google Scholar
    • Export Citation
  • Van Veelen W, Klompmaker R, Gloerich M, Van Gasteren CJ, Kalkhoven E, Berger R, Lips CJ, Medema RH, Hoppener JW & Acton DS 2009 P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development. International Journal of Cancer 124 339345. (https://doi.org/10.1002/ijc.23977)

    • Search Google Scholar
    • Export Citation
  • Vidal M, Wells S, Ryan A & Cagan R 2005 ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for