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Jonathan Nyce

Androgens play a fundamental role in the morbidity and mortality of COVID-19, inducing both the ACE-2 receptor to which SARS-CoV-2 binds to gain entry into the cell, and TMPRS22, the transmembrane protease that primes the viral spike protein for efficient infection. The United States stands alone among developed nations in permitting one androgen, oral DHEA, to be freely available OTC and online as a ‘dietary supplement’. DHEA is widely used by males in the US to offset the age-related decline in circulating androgens. This fact may contribute to the disparate statistics of COVID-19 morbidity and mortality in this country. In regulatory antithesis, every other developed nation regulates DHEA as a controlled substance. DHEA is an extremely potent inhibitor of glucose-6-phosphate dehydrogenase (G6PD), with uniquely unstable uncompetitive inhibition kinetics. This has particular relevance to COVID-19 because G6PD-deficient human cells have been demonstrated to be exceptionally sensitive to infection by human coronavirus. Because DHEA is lipophilic and freely passes into cells, oral DHEA bypasses the normal controls regulating androgen biology and uncompetitive G6PD inhibition. DHEA’s status as a ‘dietary supplement’ means that no clinical trials demonstrating safety have been performed, and, in the absence of physician supervision, no data on adverse events have been collected. During the current pandemic, the unrestricted availability of oral DHEA as a ‘dietary supplement’ cannot be considered safe without proof from placebo-controlled clinical trials that it is not contributing to the severity of COVID-19. US physicians may therefore wish to query their patients’ use of DHEA.

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Ewan Michael Stephenson, Laura Emma Jane Usselmann, Vinay Tergaonkar, David Virshup, and Robert Dallmann

Circadian rhythms regulate a vast array of physiological and cellular processes, as well as the hormonal milieu, to keep our cells synchronised to the light-dark cycle. Epidemiologic studies have implicated circadian disruption in the development of breast and other cancers, and numerous clock genes are dysregulated in human tumours. Here we review the evidence that circadian rhythms, when altered at the molecular level, influence cancer growth. We also note some common pitfalls in circadian-cancer research and how they might be avoided to maximise comparable results and minimise misleading data. Studies of circadian gene mutant mice, and human cancer models in vitro and in vivo, demonstrate that clock genes can impact tumourigenesis. Clock genes influence important cancer related pathways, ranging from p53-mediated apoptosis to cell cycle progression. Confusingly, clock dysfunction can be both pro- or anti- tumourigenic in a model and cell type specific manner. Due to this duality, there is no canonical mechanism for clock interaction with tumourigenic pathways. To understand the role of the circadian clock in patients’ tumours requires analysis of the molecular clock status compared to healthy tissue. Novel mathematical approaches are under development, but this remains largely aspirational, and is hampered by a lack of temporal information in publicly available datasets. Current evidence broadly supports the notion that the circadian clock is important for cancer biology. More work is necessary to develop an overarching model of this connection. Future studies would do well to analyse the clock network in addition to alterations in single clock genes.

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Satya Das, Liping Du, Aimee Schad, Shikha Jain, Aaron Jessop, Chirayu Shah, David Eisner, Dana Cardin, Kristen Ciombor, Laura Goff, Marques Bradshaw, Dominique Delbeke, Martin Sandler, and Jordan Berlin

We developed a clinical score (CS) at Vanderbilt Ingram Cancer Center (VICC) that we hoped would predict outcomes for patients with progressive well-differentiated neuroendocrine tumors (NETs) receiving therapy with Lutetium-177 (177Lu)-DOTATATE. Patients under consideration for 177Lu-DOTATATE between 3/1/2016-3/17/2020 at VICC were assigned a CS prospectively. The CS included 5 categories: available treatments for tumor type outside of 177Lu-DOTATATE, prior systemic treatments, patient symptoms, tumor burden in critical organs and presence of peritoneal carcinomatosis. The primary outcome of the analysis was progression-free survival (PFS). To evaluate the effect of the CS on PFS, a multivariable Cox regression analysis was performed adjusting for tumor grade, primary tumor location, and the interaction between 177Lu-DOTATATE doses received (zero, 1-2, 3-4) and CS. A total of 91 patients and 31 patients received 3-4 doses and zero doses of 177Lu-DOTATATE, respectively. On multivariable analysis, in patients treated with 3-4 doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated hazard ratio (HR) for PFS was 2.0 (95% CI 1.61-2.48). On multivariable analysis, in patients who received zero doses of 177Lu-DOTATATE, for each 1-point increase in CS, the estimated HR for PFS was 1.22 (95% CI .91-1.65). Among patients treated with 3-4 doses of 177Lu-DOTATATE, those with lower CS experienced improved PFS with the treatment compared to patients with higher CS. This PFS difference, based upon CS, was not observed in patients who did not receive 177Lu-DOTATATE, suggesting the predictive utility of the score.

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Qi-Chang Wan and Bin Ji

We read with interest the article by Rosario et al., which summarized the practical applicability of accessible imaging method in the management of thyroid nodules with indeterminate cytologically (TNIC) (Rosario, et al. 2021). For 18F-FDG-PET, it was stated that “a nodule characterized by low or absent 18F-FDG uptake is considered at a very low risk of malignance”, and “thyroidectomy can be excluded if these tests suggest benignity”. We respectfully want to share a different opinion based on our previous work.

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Tim Schauer, Anne-Sophie Mazzoni, Anna Henriksson, Ingrid Demmelmaier, Sveinung Berntsen, Truls Raastad, Karin Nordin, Bente Klarlund Pedersen, and Jesper Frank Christensen

Exercise training has been hypothesized to lower the inflammatory burden for patients with cancer, but the role of exercise intensity is unknown. To this end, we compared the effects of high-intensity (HI) and low-to-moderate intensity (LMI) exercise on markers of inflammation in patients with curable breast, prostate and colorectal cancer undergoing primary adjuvant cancer treatment in a secondary analysis of the Phys-Can randomized trial (NCT02473003). Sub-group analyses focused on patients with breast cancer undergoing chemotherapy. Patients performed six months of combined aerobic and resistance exercise on either HI or LMI during and after primary adjuvant cancer treatment. Plasma taken at baseline, immediately post-treatment and post-intervention was analyzed for levels of interleukin (IL)-1β, IL-6, IL-8, IL-10, tumor necrosis factor (TNF)-α and C-reactive protein (CRP). Intention-to-treat analyses of 394 participants revealed no significant between-group differences. Regardless of exercise intensity, significant increases of IL-6, IL-8, IL-10 and TNF-α post-treatment followed by significant declines, except for IL-8, until post-intervention were observed with no difference for CRP or IL-1β. Subgroup analyses of 154 patients with breast cancer undergoing chemotherapy revealed that CRP (Estimated Mean Difference (95% CI): 0.59 (0.33; 1.06); p = 0.101) and TNF-α (EMD (95% CI): 0.88 (0.77; 1) ; p = 0.053) increased less with HI exercise post-treatment compared to LMI. Exploratory cytokine co-regulation analysis revealed no difference between the groups. In patients with breast cancer undergoing chemotherapy, HI exercise resulted in a lesser increase of CRP and TNF-α immediately post-treatment compared to LMI, potentially protecting against chemotherapy related inflammation.

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Zhi-yuan Pang, Yun-tao Wei, Mu-yan Shang, Shuang Li, Yang Li, Quan-xiu Jin, Zhi-xuan Liao, Ming-ke Cui, Xiao-yan Liu, and Qiang Zhang

Aberrant leptin signaling and overexpression of fibroblast growth factor receptor 1 (FGFR1) are both implicated in the pathogenesis of letrozole resistance in breast cancer (BCa), but it remains unknown whether these two pathways are involved in letrozole resistance in a coordinated manner. Here, we demonstrate that expression levels of the pre-B-cell leukemia homeobox transcription factor 3 (PBX3), a pioneer factor that governs divergent biological processes, were significantly upregulated in letrozole-resistant BCa cells and tissues, and this upregulation correlated to a poorer progression-free survival in patients. By leveraging a patient-derived xenograft model with pharmacological approaches, we demonstrated that leptin activated PBX3 expression in a STAT3 (signal transducer and activator of transcription 3)–dependent manner. Our loss- and gain-of-function study further showed that PBX3 attenuated response to letrozole by potentiating BCa cell survival and anchorage–independent growth in BCa cells. By profiling BCa cells with ectopic PBX3 expression, we revealed that PBX3 conferred letrozole resistance via transactivation of the FGFR1 signaling, and this molecular event must coordinate a synergistic transcription activation programs through interacting with MTA1-HDAC2 (metastasis associated 1-histone deacetylase 2) complex. Overall, the available data reveal a novel role of leptin/PBX3 cascade linking energy homeostasis (i.e. hyperleptinemia) and endocrine therapy failure (i.e. letrozole resistance) in BCa.

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Eliot B Blatt, Noa Kopplin, Shourya Kumar, Ping Mu, Suzanne D Conzen, and Ganesh V Raj

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.

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Nitya Raj, Youyun Zheng, Haley Hauser, JOanne Chou, Johnathan Rafailov, Jad Bou Ayache, Peter Sawan, Jamie Chaft, Jennifer Chan, Kimberly Perez, Charles Rudin, Laura Tang, and Diane Reidy Lagunes

The mammalian target of rapamycin inhibitor everolimus is an established therapy for well differentiated (WD) foregut neuroendocrine tumors (NETs). Pre-clinical data demonstrates a potential synergistic role for cyclin dependent kinase 4/6 inhibition and everolimus to treat this disease. In this phase II multicenter study, patients with advanced foregut WDNETs received combination ribociclib and everolimus until confirmed disease progression or unacceptable toxicity. The first 12 patients received ribociclib 300 mg three weeks in a row with a one week break and everolimus 2.5 mg daily (recommended phase II dose). Due to unexpected hematologic and infectious toxicities, the trial was put on hold, modified, and an additional 9 patients received ribociclib 200 mg and everolimus 2.5 mg daily. The primary end point was progression-free survival. Archived pre-treatment tumor was profiled by next-generation sequencing to evaluate for genomic markers of drug response. Twenty-one patients were treated (median age, 56; range, 24 to 77). The study did not meet the pre-specified criteria to advance to stage two. No patients experienced an objective response. Thirteen patients (62%) experienced stable disease. Median progression-free survival was 7.7 months (95% CI, 2.8 months to not reached). Eleven of the first 12 patients (92%) developed grade 2 or more myelosuppression. Ten patients (84%) experienced treatment interruption and 8 patients (67%) required dose reduction. Genetic testing in archival tumor tissue samples failed to identify a predictive biomarker of disease stabilization. The combination of ribociclib and everolimus had insufficient activity to warrant further investigation in foregut WDNETs.

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Mintallah Haider, Satya Das, Taymeyah Al-Toubah, Eleonora Pelle, Ghassan El-Haddad, and Jonathan Strosberg

Peptide receptor radionuclide therapy (PRRT) using 177Lu-DOTATATE has been approved for the treatment of gastroenteropancreatic NETs. An understanding of benefits and risks is important for the appropriate implementation of this therapy. This review summarizes study data supporting the use of radiolabeled somatostatin analogs for the treatment of advanced NETs and highlights risks, including potential toxicities in specific populations. Key ongoing clinical trials, including randomized studies, are designed to better define the position of PRRT within the broader therapeutic landscape. Preclinical and early-phase human studies are focused on the development of novel somatostatin-receptor agonists and antagonists, new radionuclides, and radiosensitizing combination therapies.