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The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is primarily known as a key regulator of calcium and phosphate homeostasis. It exerts its biological functions by binding to the vitamin D receptor (VDR), a transcription factor that regulates gene expression in vitamin D-target tissues such as intestine, kidney and bone. Yet, the VDR is expressed in many additional normal and cancerous tissues, where it moderates the antiproliferative, prodifferentiating and immune-modulating effects of 1,25(OH)2D3. Interestingly, several epidemiological studies show that low levels of 25(OH)D, a biological marker for 1,25(OH)2D3 status, are associated with an increased risk of breast cancer (BC) development. Mendelian randomization studies, however, did not find any relationship between single-nucleotide polymorphisms in genes associated with lower serum 25(OH)D and BC risk. Nevertheless, multiple and in vivo preclinical studies illustrate that 1,25(OH)2D3 or its less calcaemic structural analogues influence diverse cellular processes in BC such as proliferation, differentiation, apoptosis, autophagy and the epithelial–mesenchymal transition. Recent insights also demonstrate that 1,25(OH)2D3 treatment impacts on cell metabolism and on the cancer stem cell population. The presence of VDR in the majority of BCs, together with the various anti-tumoural effects of 1,25(OH)2D3, has supported the evaluation of the effects of vitamin D3 supplementation on BC development. However, most randomized controlled clinical trials do not demonstrate a clear decrease in BC incidence with vitamin D3 supplementation. However, 1,25(OH)2D3 or its analogues seem biologically more active and may have more potential anticancer activity in BC upon combination with existing cancer therapies.
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Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
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Aberrant lipid metabolism provides bioenergetic, biosynthetic, and redox supplies to cancer cells. Previous studies have reported differential lipid profiling in thyroid malignancies. Sterol regulatory element-binding protein 1 (SREBP1), encoded by the SREBF1 gene, is a master regulator of cellular lipid homeostasis. The clinical and functional significance of SREBP1 in thyroid cancer is not well understood. Here, we showed that SREBP1 expression is significantly upregulated in invasive thyroid cancer than in normal thyroid tissue or benign thyroid nodules. High tumoral SREBP1 expression was associated with extrathyroidal extension, advanced disease stage, and shorter disease-specific survival in patients with differentiated thyroid cancer. SREBP1 overexpression significantly increased the oxygen consumption rate, filopodia formation, and migratory and invasive capacities of thyroid cancer cells. Knockdown of SREBF1 or treatment with an SREBP1 activation inhibitor fatostatin had the opposite effect. RNA-Seq analysis showed that modulation of SREBP1 expression was accompanied by corresponding changes in the expression of epithelial–mesenchymal transition markers and CYR61/CTGF. SREBP1-facilitated cell invasion could be abrogated by treatment with a YAP inhibitor such as verteporfin or genetic silencing of CYR61 or CTGF. In summary, SREBP1 upregulation can be used as a prognostic indicator for thyroid cancer and SREBP1 overexpression is involved in cancer invasiveness, at least partly, through upregulation of CYR61/CTGF via the Hippo-YAP pathway.
Department of Oncology, Haukeland University Hospital, Bergen, Norway
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Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
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Department of Oncology, Haukeland University Hospital, Bergen, Norway
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Department of Oncology, Haukeland University Hospital, Bergen, Norway
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Department of Medical Radiation Physics, Lund University, Lund, Sweden
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Department of Oncology, St.Olavs Hospital, Trondheim, Norway
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Department of Clinical Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
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Department of Clinical Science, University of Bergen, Bergen, Norway
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Department of Oncology, Haukeland University Hospital, Bergen, Norway
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High-grade (HG) gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN) are rare but have a very poor prognosis and represent a severely understudied class of tumours. Molecular data for HG GEP-NEN are limited, and treatment strategies for the carcinoma subgroup (HG GEP-NEC) are extrapolated from small-cell lung cancer (SCLC). After pathological re-evaluation, we analysed DNA from tumours and matched blood samples from 181 HG GEP-NEN patients; 152 neuroendocrine carcinomas (NEC) and 29 neuroendocrine tumours (NET G3). Based on the sequencing of 360 cancer-related genes, we assessed mutations and copy number alterations (CNA). For NEC, frequently mutated genes were TP53 (64%), APC (28%), KRAS (22%) and BRAF (20%). RB1 was only mutated in 14%, but CNAs affecting RB1 were seen in 34%. Other frequent copy number losses were ARID1A (35%), ESR1 (25%) and ATM (31%). Frequent amplifications/gains were found in MYC (51%) and KDM5A (45%). While these molecular features had limited similarities with SCLC, we found potentially targetable alterations in 66% of the NEC samples. Mutations and CNA varied according to primary tumour site with BRAF mutations mainly seen in colon (49%), and FBXW7 mutations mainly seen in rectal cancers (25%). Eight out of 152 (5.3%) NEC were microsatellite instable (MSI). NET G3 had frequent mutations in MEN1 (21%), ATRX (17%), DAXX, SETD2 and TP53 (each 14%). We show molecular differences in HG GEP-NEN, related to morphological differentiation and site of origin. Limited similarities to SCLC and a high fraction of targetable alterations indicate a high potential for better-personalized treatments.
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Delta-like non-canonical Notch ligand 1 (DLK1) is a cleavable single-pass transmembrane protein and a member of the Notch/Delta/Serrate family. It is paternally expressed and belongs to a group of imprinted genes located on chromosome band 14q32 in humans and 12qF1 in mice. DLK1 is expressed in many human tissues during embryonic development but in adults expression is low and is mostly restricted to (neuro)endocrine tissues and other immature stem/progenitor cells (notably hepatoblasts). However, DLK1 is expressed at a high frequency in many common malignancies (liver, breast, brain, pancreas, colon and lung). More recently, high levels of expression have been identified in endocrine-related cancers such as ovarian and adrenocortical carcinoma. There is growing evidence that DLK1 expression in cancer is associated with worse prognosis and that DLK1 may be a marker of cancer stem cells. Although the exact mechanism through which DLK1 functions is not fully understood, it is known to maintain cells in an undifferentiated phenotype and has oncogenic properties. These effects are partly exacted through interaction with the Notch signalling pathway. In this review, we have detailed the functional role of DLK1 within physiology and malignancy and posited a mechanism for how it exacts its oncogenic effects. In describing the expression of DLK1 in cancer and in healthy tissue, we have highlighted the potential for its use both as a biomarker and as a potential therapeutic target.
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Based on experimental data, the inhibition of the MAPkinase pathway in patients with radioiodine-refractory thyroid cancer was capable of inducing a redifferentiation. Preliminary data obtained in a small series of patients were encouraging and this strategy might become an alternative treatment in those patients with a druggable mutation that induces a stimulation of the MAP kinase pathway. This is an active field of research to answer many still unresolved questions.
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Lineage plasticity and histologic transformation to small cell neuroendocrine prostate cancer (NEPC) is an increasingly recognized mechanism of treatment resistance in advanced prostate cancer. This is associated with aggressive clinical features and poor prognosis. Recent work has identified genomic, epigenomic, and transcriptome changes that distinguish NEPC from prostate adenocarcinoma, pointing to new mechanisms and therapeutic targets. Treatment-related NEPC arises clonally from prostate adenocarcinoma during the course of disease progression, retaining early genomic events and acquiring new molecular features that lead to tumor proliferation independent of androgen receptor activity, and ultimately demonstrating a lineage switch from a luminal prostate cancer phenotype to a small cell neuroendocrine carcinoma. Identifying the subset of prostate tumors most vulnerable to lineage plasticity and developing strategies for earlier detection and intervention for patients with NEPC may ultimately improve prognosis. Clinical trials focused on drug targeting of the lineage plasticity process and/or NEPC will require careful patient selection. Here, we review emerging targets and discuss biomarker considerations that may be informative for the design of future clinical studies.
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Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
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The landscape of cancer treatment has been transformed over the past decade by the success of immune-targeting therapies. However, despite sipuleucel-T being the first-ever approved vaccine for cancer and the first immunotherapy licensed for prostate cancer in 2010, immunotherapy has since seen limited success in the treatment of prostate cancer. The tumour microenvironment of prostate cancer presents particular barriers for immunotherapy. Moreover, prostate cancer is distinguished by being one of only two solid tumours where increased T cell-infiltration correlates with a poorer, rather than improved, outlook. Here, we discuss the specific aspects of the prostate cancer microenvironment that converge to create a challenging microenvironment, including myeloid-derived immune cells and cancer-associated fibroblasts. By exploring the immune microenvironment of defined molecular subgroups of prostate cancer, we propose an immunogenomic subtyping approach to single-agent and combination immune-targeting strategies that could lead to improved outcomes in prostate cancer treatment.
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Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI)-related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with the occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6–3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n = 62), the most common presentation was headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-ipilimumab (ipi) regimens, ipi has a stronger association with irH occurrence (P = 0.004) and a shorter time to irH development (P < 0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24, 58 and 0% patients, respectively. High-dose steroids (HDS) or ICI discontinuation was not associated with hormonal recovery. In the non-irH group (n = 19), one patient had isolated central hypothyroidism and six had isolated central adrenal insufficiency. All remained on hormone therapy at the last follow-up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long-term follow-up to assess recovery is needed.
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Division of Endocrinology, University of Texas Medical Branch, Galveston, Texas, USA
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Hürthle cell carcinoma (HCC) is a distinct type of thyroid cancer genetically characterized by DNA copy number alterations (CNA), typically of genome haploidization type (GH-type). However, whether CNA also occurs in benign Hürthle cell adenomas (HCA) or Hürthle cell hyperplastic nodules (HCHN), and have diagnostic impact in fine-needle aspiration (FNA) samples, remains unknown. To address these questions, we (1) analyzed 26 HCC, 24 HCA, and 8 HCHN tissues for CNA and other mutations using ThyroSeq v3 (TSv3) next-generation sequencing panel, and (2) determined cancer rate in 111 FNA samples with CNA and known surgical outcome. We identified CNA, more often of the GH-type, in 81% of HCC and in 38% HCA, but not in HCHN. Among four HCC with distant metastasis, all had CNA and three TERT mutations. Overall, positive TSv3 results were obtained in 24 (92%) HCC, including all with ATA high risk of recurrence or metastasis. Among 111 FNA cases with CNA, 38 (34%) were malignant and 73 (66%) benign. A significant correlation between cancer rate and nodule size was observed, particularly among cases with GH-type CNA, where every additional centimeter of nodule size increased the malignancy odds by 1.9 (95% CI 1.3–2.7; P = 0.001). In summary, the results of this study demonstrate that CNA characteristic of HCC also occur in HCA, although with lower frequency, and probability of cancer in nodules with CNA increases with nodule size. Detection of CNA, in conjunction with other mutations and nodule size, is helpful in predicting malignancy in thyroid nodules.
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Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) MAB, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% CI: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5 and 0%, respectively, and the 12-month overall survival was 73.5 and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort are encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.
