177Lu-Dotatate is increasingly used in patients with advanced neuroendocrine tumour (NET). However, few prognostic markers are available to stratify progression-free survival (PFS) of patients who received 177Lu-Dotatate. Clinicopathological data including baseline circulating biomarkers of patients with advanced NET who received 177Lu-Dotatate were routinely collected and were retrospectively analysed. Continuous variables were normalized by dividing them by their upper normal limits. The whole data set was randomly divided into a training set and a validation set. Univariate and multivariate logistic regression analyses were used to identify independent markers and to develop a scoring model to predict treatment failure at 1 year. In total, 195 patients were included. Elevated baseline chromogranin A (CgA), normal creatinine and previous chemotherapy were three risk factors independently associated with 1-year treatment failure. By combining these risk factors, a scoring model was developed which could accurately predict 1-year treatment failure both in the training set (area under curve, AUC, 0.813; 95% CI, 0.731–0.895; P< 0.001) and in the validation set (AUC, 0.816; 95% CI, 0.644–0.968; P< 0.001). After selecting a score of 29.7 as the cut-off value of the scoring model, patients could be stratified into two groups namely low-risk and high-risk with significantly different 1-year treatment failure rate, PFS and overall survival (OS; P< 0.001) both in the training set and validation set. In conclusion, baseline CgA, creatinine level and previous chemotherapy were independently associated with 1-year treatment failure of patients with advanced NET who received 177Lu-Dotatate and the scoring model and prognostic stratification based on these markers could accurately predict 1-year treatment failure, PFS and OS.
Luohai Chen, Gopinath Gnanasegaran, Dalvinder Mandair, Christos Toumpanakis, Martyn Caplin, and Shaunak Navalkissoor
Xianhui Ruan, Jiaoyu Yi, Linfei Hu, Jingtai Zhi, Yu Zeng, Xiukun Hou, Jianfeng Huang, Pengfei Gu, Weijing Hao, Ming Gao, Yi Pan, Songfeng Wei, and Xiangqian Zheng
Increasing body of recent studies determining the expression of tumor-specific major histocompatibility complex (MHC) class II protein supports its potential role in several malignancies, but little is known in human medullary thyroid cancer (MTC). Here, we report the expression of MHC-II and its clinicopathologic and prognostic relevance in MTC patients. Immunohistochemistry staining revealed a significant reduction in tumor cell-specific MHC-II expression in a higher AJCC stage and its poor prognostic correlation with human MTC development. Further statistical analysis identified the low MHC-II expression as a significant and independent risk factor for MTC recurrence and patient survival. Moreover, in vitro studies showed that the MHC-II expression was remarkably increased by RET inhibitors, which were prescribed to treat advanced MTC. Similarly, inhibitors blocking the MAPK/ERK and AKT/mTOR pathways also augmented MHC-II expression, suggesting their implications in RET-MHC-II signaling axis. Importantly, in vitro assays manifested enhanced peripheral blood leukocytes-mediated cytotoxicity in MTC cells treated with RET inhibitors, which were partially alleviated by HLA knock-down. Together, our study demonstrates that low MHC-II expression levels may serve as a prognostic biomarker for aggressive diseases in MTC patients and indicates that RET activation may promote MTC immune escape through downregulating MHC-II expression.
Justine Vanhevel, Lieve Verlinden, Stefanie Doms, Hans Wildiers, and Annemieke Verstuyf
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.
Cindy H Chau, Cathee Till, Douglas K Price, Phyllis J Goodman, Marian L Neuhouser, Michael N Pollak, Ian M Thompson, and William D Figg
Molecular mechanisms linking obesity to prostate cancer involve steroid hormone and insulin/insulin-like growth factor 1 (IGF1) pathways. We investigated the association of circulating serum markers (e.g. androgens and IGFs/IGFBPs) with BMI and in modifying the association of obesity with prostate cancer risk. Data and specimens for this nested case–control study are from the Prostate Cancer Prevention Trial, a randomized, placebo-controlled trial of finasteride for prostate cancer prevention. Presence or absence of cancer was determined by prostate biopsy. Serum samples were assayed for sex steroid hormone concentrations and IGF1 axis analytes. Logistic regression estimated odds ratio and 95% CIs for risk of overall, low-grade (Gleason 2–6), and high-grade (Gleason 7–10) cancers. We found significant associations between BMI with serum steroids and IGFs/IGFBPs; the IGF1 axis was significantly associated with several serum steroids. Serum steroid levels did not affect the association of BMI with prostate cancer risk; however, IGFBP2 and IGFs modified the association of obesity with low- and high-grade disease. While serum steroids and IGFs/IGFBPs are associated with BMI, only the IGF1 axis contributed to obesity-related prostate cancer risk. Understanding the biological mechanisms linking obesity to prostate cancer risk as it relates to circulating serum markers will aid in developing effective prostate cancer prevention strategies and treatments.
Chi-Yu Kuo, Yuan-Ching Chang, Ming-Nan Chien, Jie-Yang Jhuang, Yi-Chiung Hsu, Shih-Yuan Huang, and Shih-Ping Cheng
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.
Yang Zhao, Cangang Zhang, Yanan Zhu, Xi Ding, Yikun Zhou, Hongjun Lv, Yuxuan Lin, Yuan Wu, Bingyin Shi, and Jiao Fu
The immunosuppressive microenvironment is associated with poor prognosis in papillary thyroid cancer (PTC); however, the molecular mechanisms involved are unknown. Among the triggering receptors expressed on myeloid cell (TREM) family, we found that TREM1 expression in PTC was significantly higher than that in normal tissues. TREM1 overexpression was associated with BRAFV600E profiles and advanced tumor stages. Furthermore, TREM1 mRNA expression was negatively correlated with promoter methylation status. Specifically, hypomethylation of CpG site cg06196379 in the TREM1 promoter was related with poor patient disease-free survival (DFS) and a high PTC recurrence rate. Mechanistically, TREM1 was mainly expressed in malignant epithelial cells but not in macrophages in PTC by single-cell analysis. PTC tissues with high TREM1 levels had enhanced infiltration of regulatory T cells (Tregs) and decreased infiltration of CD8+ T cells. Our study confirms that hypomethylation-mediated overexpression of TREM1 in PTC cells promotes an immunosuppressive microenvironment by enhancing Treg infiltration. We recommend the future use of therapeutic strategy targeting TREM1 for the treatment of PTC.
Salma Kaochar, Aleksandra Rusin, Christopher Foley, Kimal Rajapakshe, Matthew Robertson, Darlene Skapura, Cammy Mason, Karen Berman De Ruiz, Alexey Mikhailovich Tyryshkin, Jenny Deng, Jin Na Shin, Warren Fiskus, Jianrong Dong, Shixia Huang, Nora M Navone, Christel M Davis, Erik A Ehli, Cristian Coarfa, and Nicholas Mitsiades
Castration-resistant prostate cancer (CRPC) remains highly lethal and in need of novel, actionable therapeutic targets. The pioneer factor GATA2 is a significant prostate cancer (PC) driver and is linked to poor prognosis. GATA2 directly promotes androgen receptor (AR) gene expression (both full-length and splice-variant) and facilitates AR binding to chromatin, recruitment of coregulators, and target gene transcription. Unfortunately, there is no clinically applicable GATA2 inhibitor available at the moment. Using a bioinformatics algorithm, we screened in silico 2650 clinically relevant drugs for a potential GATA2 inhibitor. Validation studies used cytotoxicity and proliferation assays, global gene expression analysis, RT-qPCR, reporter assay, reverse phase protein array analysis (RPPA), and immunoblotting. We examined target engagement via cellular thermal shift assay (CETSA), ChIP-qPCR, and GATA2 DNA-binding assay. We identified the vasodilator dilazep as a potential GATA2 inhibitor and confirmed on-target activity via CETSA. Dilazep exerted anticancer activity across a broad panel of GATA2-dependent PC cell lines in vitro and in a PDX model in vivo. Dilazep inhibited GATA2 recruitment to chromatin and suppressed the cell-cycle program, transcriptional programs driven by GATA2, AR, and c-MYC, and the expression of several oncogenic drivers, including AR, c-MYC, FOXM1, CENPF, EZH2, UBE2C, and RRM2, as well as of several mediators of metastasis, DNA damage repair, and stemness. In conclusion, we provide, via an extensive compendium of methodologies, proof-of-principle that a small molecule can inhibit GATA2 function and suppress its downstream AR, c-MYC, and other PC-driving effectors. We propose GATA2 as a therapeutic target in CRPC.
Andreas Venizelos, Hege Elvebakken, Aurel Perren, Oleksii Nikolaienko, Wei Deng, Inger Marie B Lothe, Anne Couvelard, Geir Olav Hjortland, Anna Sundlöv, Johanna Svensson, Harrish Garresori, Christian Kersten, Eva Hofsli, Sönke Detlefsen, Merete Krogh, Halfdan Sorbye, and Stian Knappskog
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.
Tania Moujaber, Rosemary L Balleine, Bo Gao, Ida Madsen, Paul R Harnett, and Anna DeFazio
Low-grade serous ovarian cancer (LGSC) is a morphologically and molecularly distinct subtype of ovarian cancer, accounting for ~10% of serous carcinomas. Women typically present at a younger age and have a protracted clinical course compared with the more common, high-grade serous ovarian cancer. Currently, the primary treatment of LGSC is the same as other epithelial ovarian cancer subtypes, with treatment for most patients comprised of debulking surgery and platinum/taxane chemotherapy. Primary surgical cytoreduction to no visible residual disease remains a key prognostic factor; however, the use of platinum-based chemotherapy in both upfront and relapsed setting is being questioned due to low response rates in LGSC. Most LGSC expresses steroid hormone receptors, and selected patients may benefit from endocrine maintenance therapy following chemotherapy, in particular, those with evidence of residual disease at completion of surgery. In the recurrent setting, while hormonal therapies may offer disease stabilisation with relatively low toxicity, objective response rates remain low. Strategies to increase response rates, including combining with CDK4/6 inhibitors, are being investigated. LGSC has a high prevalence of activating somatic mutations in mitogen-activated protein kinase pathway genes, most commonly in KRAS, BRAF and NRAS. Trametinib, a MEK inhibitor, has shown efficacy over chemotherapy and endocrine therapy. The use of combination targeted therapies, immunotherapy and anti-angiogenic agents, remain active areas of investigation for the treatment of LGSC.