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Isabel Mayayo-Peralta, Wilbert Zwart, and Stefan Prekovic

Glucocorticoid receptor (GR) is a key homeostatic regulator involved in governing immune response, neuro-integration, metabolism and lung function. In conjunction with its pivotal role in human biology, GR action is critically linked to the pathology of various disease types, including cancer. While pharmacological activation of GR has been used for the treatment of various liquid cancers, its role in solid cancers is less clearly defined and seems to be cancer-type dependent. This review focuses on the molecular aspects of GR biology, spanning the structural and functional basis of response to glucocorticoids, as well as how this transcription factor operates in cancer, including the implications in disease development, progression and drug resistance.

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Salma Ben-Salem, Varadha Balaji Venkadakrishnan, and Hannelore V Heemers

The recent genomic characterization of patient specimens has started to reveal the landscape of somatic alterations in clinical prostate cancer (CaP) and its association with disease progression and treatment resistance. The extent to which such alterations impact hallmarks of cancer is still unclear. Here, we interrogate genomic data from thousands of clinical CaP specimens that reflect progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP for alterations in cell cycle-associated and -regulated genes, which are central to cancer initiation and progression. We evaluate gene signatures previously curated to evaluate G1-S and G2-M phase transitions or to represent the cell cycle-dependent proteome. The resulting CaP (stage)-specific overview confirmed the presence of well-known driver alterations impacting, for instance, the genes encoding p53 and MYC, and uncovered novel previously unrecognized mutations that affect others such as the PKMYT1 and MTBP genes. The cancer dependency and drugability of representative genomically altered cell cycle determinants were verified also. Taken together, these analyses on hundreds of often less-characterized cell cycle regulators expand considerably the scope of genomic alterations associated with CaP cell proliferation and cell cycle and isolate such regulatory proteins as putative drivers of CaP treatment resistance and entirely novel therapeutic targets for CaP therapy.

Free access

Salma Ben-Salem and Varadha Balaji Venkadakrishnan

Abstract

Prostate cancer (CaP) remains the second leading cause of cancer deaths in Western men. These deaths occur because metastatic CaP acquires resistance to available treatments. The novel and functionally diverse treatment options that have been introduced in the clinic over the past decade each eventually induce resistance for which the molecular basis is diverse. Both initiation and progression of CaP have been associated with enhanced cell proliferation and cell cycle dysregulation. A better understanding of the specific pro-proliferative molecular shifts that control cell division and proliferation during CaP progression may ultimately overcome treatment resistance. Here, we examine literature for support of this possibility. We start by reviewing recently renewed insights in prostate cell types and their proliferative and oncogenic potential. We then provide an overview of the basic knowledge on the molecular machinery in charge of cell cycle progression and its regulation by well-recognized drivers of CaP progression such as androgen receptor and retinoblastoma protein. In this respect, we pay particular attention to interactions and reciprocal interplay between cell cycle regulators and androgen receptor. Somatic alterations that impact the cell cycle-associated and -regulated genes encoding p53, PTEN and MYC during progression from treatment-naïve, to castration-recurrent, and in some cases, neuroendocrine CaP are discussed. We considered also non-genomic events that impact cell cycle determinants, including transcriptional, epigenetic and micro-environmental switches that occur during CaP progression. Finally, we evaluate the therapeutic potential of cell cycle regulators and address challenges and limitations in the approaches modulating their action for CaP treatment.

Open access

Mehtap Derya Aydemirli, Jaap D H van Eendenburg, Tom van Wezel, Jan Oosting, Willem E Corver, Ellen Kapiteijn, and Hans Morreau

Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a 6-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML4-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.

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Ophelie De Rycke, Thomas Walter, Marine Perrier, Olivia Hentic, Catherine Lombard-Bohas, Romain Coriat, Guillaume Cadiot, Anne Couvelard, Philippe Ruszniewski, Jerome Cros, and Louis De Mestier

A rechallenge is common after initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET. Secondly, to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (Cohort A). Primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (Cohort B). We foud that cohort A included 62 patients (median Ki67 8%), for which ALK1 followed by pause achieved an objective response rate of 55%, and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response, and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (p=0.032) and a pause longer than 12 months (p=0.041) were associated with a longer PFS2. In the cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK, to 100 (IQR 56-180) after ALK (p=0.003). We conclude that after initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain low efficacy of ALK rechallenge.

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Jingyuan Ma, Xinyu Huang, Jungong Zhao, Jingyi Lu, Wei Lu, Yuqian Bao, Jian Zhou, and Junfeng Han

Insulin release index (IRI) based on 72-h fasting test has been used for the definitive diagnosis of insulinoma; however, hospitalization and subsequent costs contribute to the disadvantage of IRI. Therefore, a simple and cost-effective screening procedure for the diagnosis of insulinoma for outpatients are crucially needed. Continuous glucose monitoring (CGM) has been widely used for monitoring high level of glucose in diabetic patients. The aim of the study is to determine the potential contribution or implementation of CGM in the screening of the insulinoma. We performed a single-center prospective study with the demographics and laboratory data including 28 patients with the pathological diagnosis of insulinoma and 25 patients with functional hypoglycemia as control group. The analysis showed that areas under the receiver operating characteristic (ROC) curve of coefficient of variation (CV) was 0.914. The CV cutoff point was 19% with the Youden 62.1%, the corresponding sensitivity and specificity were 82.1 and 80%, respectively. In patients with CV greater than the median, more than 60% of insulinomas were located in the head of the pancreas; most Ki-67 values were more than 2% and when compared with the group with CV smaller than the median, the average tumor size was 2.7 times larger. In conclusion, CGM can be used as a valuable tool in not only monitoring high glucose levels in diabetic patients but also identifying the etiology of insulinoma. CV greater than 19% can be highly effective for the screening of insulinoma in outpatients.

Free access

Krystallenia I Alexandraki, Ariadni Spyroglou, Stylianos Kykalos, Kosmas Daskalakis, Georgios Kyriakopoulos, Georgios C Sotiropoulos, Gregory A Kaltsas, and Ashley B Grossman

Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.

Open access

Kathleen A. Luckett, Jennifer R. Cracchiolo, Gnana P. Krishnamoorthy, Luis Javier Leandro-Garcia, James Nagarajah, Mahesh Saqcena, Rona Lester, Soo Y. Im, Zhen Zhao, Scott W Lowe, Elisa de Stanchina, Eric J Sherman, Alan L Ho, Steven D Leach, Jeffrey A Knauf, and James A Fagin

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFβ also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of Braf-PTC with thyroid-specific knockout of the TgfβR1 gene to investigate the role of TGFβ on thyroid differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of TgfβR1, pSmad levels remained high, indicating that ligands other than TGFβ1 were engaging this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BrafV600E mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFβR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BrafV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BrafV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting Tgfβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.

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Yu-Ling Lu, Yu-Tung Huang, Ming-Hsien Wu, Ting-Chao Chou, Richard J Wong, and Shu-Fu Lin

Wee1 is a kinase that regulates the G2/M progression by the inhibition of CDK1, which is critical for ensuring DNA damage repair before initiation of mitotic entry. Targeting Wee1 may be a potential strategy in the treatment of anaplastic thyroid cancer, a rare but lethal disease. The therapeutic effects of adavosertib, a Wee1 inhibitor for anaplastic thyroid cancer was evaluated in this study. Adavosertib inhibited cell growth in three anaplastic thyroid cancer cell lines in a dose-dependent manner. Cell cycle analysis revealed cells were accumulated in the G2/M phase. Adavosertib induced caspase-3 activity and led to apoptosis. Adavosertib monotherapy showed significant retardation of the growth of two anaplastic thyroid cancer tumor models. The combination of adavosertib with dabrafenib and trametinib revealed strong synergism in vitro and demonstrated robust suppression of tumor growth in vivo in anaplastic thyroid cancer xenograft models with BRAFV600E mutation. The combination of adavosertib with either sorafenib or lenvatinib also demonstrated synergism in vitro and had strong inhibition of tumor growth in vivo in an anaplastic thyroid cancer xenograft model. No appreciable toxicity appeared in mice treated with either a single agent or combination treatment. Our findings suggest adavosertib holds the promise for the treatment of patients with anaplastic thyroid cancer.

Open access

Georgios Kostopoulos, Ioannis Doundoulakis, Christina Antza, Emmanouil Bouras, Krishnarajah Nirantharakumar, Dimitrios Tsiachris, G Neil Thomas, Gregory Y H Lip, and Konstantinos A Toulis

Differentiated thyroid cancer (DTC) represents the most common form of thyroid neoplasms and is becoming increasingly prevalent. Evidence suggests a possible relationship between DTC diagnosis and subsequent atrial fibrillation (AF). If confirmed, this may present an alarming health risk (AF) in an otherwise condition with a relatively good prognosis (DTC). The aim of this systematic review and meta-analysis is to provide for the first time a pooled estimate of AF incidence in DTC patients in comparison to healthy controls. A detailed search in electronic databases, clinical trial registries and grey literature was performed to identify studies reporting the incidence of AF in DTC patients. Newcastle–Ottawa quality assessment scale was used to assess study quality. We used a random effects (RE) generalized linear mixed model (GLMM) in pooling of individual studies and also calculated a prediction interval for the estimate of a new study. Six observational studies met the eligibility criteria, which included totally 187,754 patients with DTC and 199,770 healthy controls. The median follow-up period was 4.3 to 18.8 years; the incidence rate of AF was 4.86 (95% CI, 3.29 to 7.17, I2 = 96%) cases per 1000 person-years, while the incidence rate ratio was 1.54 (95% CI, 1.44 to 1.65, I2 = 0%, 95% PI, 1.33 to 1.78).This is the first meta-analysis to confirm that patients with DTC are at a high risk for developing AF, which may be attributed to a state of iatrogenic hyperthyroidism due to long-term thyrotropin suppression therapy.