Sharifi, Nima

382 Background: Androgen receptor signaling drives prostate cancer (PC) progression, and genes involved in androgen production, uptake, and conversion (APUC) are key therapeutic targets. We previously defined a 6-APUC gene set ( HSD3B1, HSD3B2, CYP3A43, CYP11A1, CYP11B1, and CYP17A1 ), that identified metastatic PC with favorable prognosis and predict docetaxel benefit. However, the expression landscape and clinical relevance of APUC genes have not been interrogated in localized PC. Methods: We analyzed the expression of 21 APUC genes in 55,329 radical prostatectomy tumor samples that underwent Decipher prostate genomic classifier (GC) testing (Veracyte Inc) between 2016-2024. Baseline clinical/pathologic factors were retrieved from Decipher GRID database (NCT02609269). Associations between gene expression quartiles with PathoGenomic Risk Factors (PGRF) including Very High Decipher score >0.85 (VHD), Grade Group (GG) 4-5, LNI and SVI were examined. Associations with distant metastatic (DM) outcomes and metastasis free survival (MFS) were evaluated using logistic regression in Mayo545 and Cox regression in Meta855 RP cohorts, respectively. Results: High expression of SRD5A2 was associated with favorable PGRF (lower odds ratio (OR), p<0.0001), lower rate of development of DM (OR 0.36, p<0.05), and longer MFS (Hazard ratio (HR) 0.51, p<0.05). HSD17B6 showed similar results for PGRF (lower OR, p<0.0001), DM (OR 0.58, p<0.05) and longer MFS (HR 0.39, p<0.05) despite being associated with GG4-5 and SVI+ in samples with VHD. In contrast, high expression of SRD5A3 and HSD17B10 had high OR for PGRFs (p<0.0001). High expression of SLCO2B1 , an androgen uptake gene, had the strongest association with GG4-5 and SVI/LNI (p<0.001 for both). We noted that SRD5A2 lacked correlation with SRD5A1 and SRD5A3 , which instead correlated with each other. Compared to all APUC genes, SRD5A2 had limited correlations with almost all APUC genes, including ones that exhibited robust cross correlation with each other . Similar to our prior finding, most APUC genes demonstrated negative correlation with AR expression and AR activity signatures. Key outcomes were validated based on transcriptomic data from 492 samples from TCGA database. Conclusions: Comprehensive analysis of 21 APUC genes in over 55,000 PC identified distinct, context-dependent associations with metastatic outcomes and clinical and molecular risk factors. Notably, high SRD5A2 expression was associated with lower odds of high-risk features and metastatic outcomes, whereas SRD5A1 and SRD5A3 linked to adverse outcomes, suggesting critical yet divergent roles among 5-alpha-reductase family members. These findings underscoring androgen-metabolic heterogeneity and highlighting SRD5A2 as a potential biomarker of indolent biology in localized prostate cancer.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Abstract Description Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity, partially driven by sex hormones. While androgens are known to suppress anti-tumor T cell immunity in certain solid tumors, we found that androgens instead enhance anti-tumor immunity in brain tumors. Upon castration, tumor growth was accelerated in brain tumor models, while the opposite effect was observed for tumors located outside the brain. Decreased T cell function was observed in both tumors and peripheral lymphoid organs in castrated mice, indicated by reduced anti-tumor cytokines and increased T cell exhaustion. Mechanistically, this systemic immunosuppression was driven by hyperactivation of the hypothalamus-pituitary-adrenal (HPA) axis in castrated mice with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in these mice, confirming the role of HPA axis dysregulation. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Furthermore, elevated production of proinflammatory cytokines (IL-1β, TNF) in the brain of castrated mice was identified as a driver of HPA axis activation. Taken together, these findings reveal unique endocrine-mediated mechanisms by which brain tumor modulate systemic immunity in the androgen-deprived setting and highlight the importance of organ-specific effects of anti-tumor immunity. Funding Sources NIH P01CA245705; NIH R35NS127083; American Brain Tumor Association; Cleveland Clinic; Case comprehensive cancer center Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Many cancers, including glioblastoma (GBM), exhibit a male-biased incidence and outcome disparity. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further influenced by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity in other solid tumors. Using a series of pre-clinical models, we observed that androgens drive anti-tumor immunity in brain tumors, contrasting with their effect in other tumor types. Upon castration, tumor growth was accelerated in GBM and brain tumor models, while the opposite effect was observed when tumors were located outside the brain. This castration effect could be reversed by testosterone administration. Flow cytometry revealed decreased T cell function, indicated by reduced anti-tumor cytokines (IFNγ and TNFα), and increased T cell exhaustion in both tumors and peripheral tissues in castrated mice, suggesting systemic immunosuppression. Indeed, the survival difference was completely abrogated in T cell deficient mice (RAG1 knockout). Mechanistically, increased hypothalamus-pituitary-adrenal (HPA) axis activity in castrated mice was responsible for the observed systemic immunosuppression, particularly in those with brain tumors. Blocking glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that elevated glucocorticoid signaling mediated the castration effect. This mechanism was brain-specific rather than GBM-specific, as hyperactivation of the HPA axis was also observed with intracranial implantation of non-GBM tumors. Neuroinflammation caused by brain tumors was stronger in castrated mice, and proinflammatory cytokines like IL-1 and TNF induced HPA axis hyperactivation. Together, these findings highlight that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

Abstract Many cancers, including glioblastoma (GBM), have a male-biased sex difference in incidence and outcome. The underlying reasons for this sex bias are unclear but likely involve differences in tumor cell state and immune response. This effect is further amplified by sex hormones, including androgens, which have been shown to inhibit anti-tumor T cell immunity. Here, we show that androgens drive anti-tumor immunity in brain tumors, in contrast to its effect in other tumor types. Upon castration, tumor growth was accelerated with attenuated T cell function in GBM and brain tumor models, but the opposite was observed when tumors were located outside the brain. Activity of the hypothalamus-pituitary-adrenal gland (HPA) axis was increased in castrated mice, particularly in those with brain tumors. Blockade of glucocorticoid receptors reversed the accelerated tumor growth in castrated mice, indicating that the effect of castration was mediated by elevated glucocorticoid signaling. Furthermore, this mechanism was not GBM specific, but brain specific, as hyperactivation of the HPA axis was observed with intracranial implantation of non-GBM tumors in the brain. Together, our findings establish that brain tumors drive distinct endocrine-mediated mechanisms in the androgen-deprived setting and highlight the importance of organ-specific effects on anti-tumor immunity.

ImportanceSystematic data on the association between anticancer therapies and thromboembolic events (TEEs) in patients with COVID-19 are lacking.ObjectiveTo assess the association between anticancer therapy exposure within 3 months prior to COVID-19 and TEEs following COVID-19 diagnosis in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included patients who were hospitalized and had active cancer and laboratory-confirmed SARS-CoV-2 infection. Data were accrued from March 2020 to December 2021 and analyzed from December 2021 to October 2022.ExposureTreatments of interest (TOIs) (endocrine therapy, vascular endothelial growth factor inhibitors/tyrosine kinase inhibitors [VEGFis/TKIs], immunomodulators [IMiDs], immune checkpoint inhibitors [ICIs], chemotherapy) vs reference (no systemic therapy) in 3 months prior to COVID-19.Main Outcomes and MeasuresMain outcomes were (1) venous thromboembolism (VTE) and (2) arterial thromboembolism (ATE). Secondary outcome was severity of COVID-19 (rates of intensive care unit admission, mechanical ventilation, 30-day all-cause mortality following TEEs in TOI vs reference group) at 30-day follow-up.ResultsOf 4988 hospitalized patients with cancer (median [IQR] age, 69 [59-78] years; 2608 [52%] male), 1869 had received 1 or more TOIs. Incidence of VTE was higher in all TOI groups: endocrine therapy, 7%; VEGFis/TKIs, 10%; IMiDs, 8%; ICIs, 12%; and chemotherapy, 10%, compared with patients not receiving systemic therapies (6%). In multivariable log-binomial regression analyses, relative risk of VTE (adjusted risk ratio [aRR], 1.33; 95% CI, 1.04-1.69) but not ATE (aRR, 0.81; 95% CI, 0.56-1.16) was significantly higher in those exposed to all TOIs pooled together vs those with no exposure. Among individual drugs, ICIs were significantly associated with VTE (aRR, 1.45; 95% CI, 1.01-2.07). Also noted were significant associations between VTE and active and progressing cancer (aRR, 1.43; 95% CI, 1.01-2.03), history of VTE (aRR, 3.10; 95% CI, 2.38-4.04), and high-risk site of cancer (aRR, 1.42; 95% CI, 1.14-1.75). Black patients had a higher risk of TEEs (aRR, 1.24; 95% CI, 1.03-1.50) than White patients. Patients with TEEs had high intensive care unit admission (46%) and mechanical ventilation (31%) rates. Relative risk of death in patients with TEEs was higher in those exposed to TOIs vs not (aRR, 1.12; 95% CI, 0.91-1.38) and was significantly associated with poor performance status (aRR, 1.77; 95% CI, 1.30-2.40) and active/progressing cancer (aRR, 1.55; 95% CI, 1.13-2.13).Conclusions and RelevanceIn this cohort study, relative risk of developing VTE was high among patients receiving TOIs and varied by the type of therapy, underlying risk factors, and demographics, such as race and ethnicity. These findings highlight the need for close monitoring and perhaps personalized thromboprophylaxis to prevent morbidity and mortality associated with COVID-19–related thromboembolism in patients with cancer.

Abstract Background: Prostate cancer is the second leading cause of cancer-related death in men in the United States and is dependent on androgens and androgen receptor (AR) activation. Androgen deprivation therapy (ADT) is the mainstay treatment, but it as well as next-generation treatments eventually fail. Disease then progresses as castration-resistant prostate cancer (CRPC), which is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) catalyzes the rate-limiting step for potent androgen synthesis from adrenal-derived precursors, thereby stimulating CRPC. HSD3B1, which encodes for 3βHSD1, has a common missense-encoding germline variation that enhances conversion from adrenal DHEA to potent androgens. Clinical studies demonstrate that this “adrenal-permissive” HSD3B1 genotype confers more rapid progression on ADT, and recent studies show that overall survival is shorter in patients with the adrenal-permissive genotype who are treated with ADT + enzalutamide. The Etk/BMX kinase may be involved in the development and progression of CRPC. We sought to determine whether phosphorylation of 3βHSD1 is required for its activation and that the necessary kinase could be a potential target. Methods: In prostate cancer lines, mouse xenograft models, and fresh patient prostatectomy tissues, mass spectrometry and HPLC were used to identify steroid metabolites. Genetic and pharmacological methods were used to identify inhibition of BMX-mediated 3βHSD1 phosphorylation in CRPC. Results: BMX inhibition suppressed castration-resistant prostate cancer through targeting 3βHSD1 phosphorylation. 3βHSD1 transcription level and enzyme activity were induced in enzalutamide-resistant prostate cancer cell lines. 3βHSD1 and SF-1 transcription levels were positively correlated in prostate adenocarcinoma (TCGA database). BMX inhibition by zanubrutinib suppressed enzalutamide resistance induced 3βHSD1 enzyme activity. Conclusions: BMX promotes CRPC by regulating 3βHSD1 phosphorylation. BMX inhibition has potential as a new therapy to optimize CRPC treatment. Citation Format: Xiuxiu Li, Michael Berk, Christopher Goins, Mohammad Alyamani, Yoon-Mi Chung, Chenyao Wang, Monaben Patel, Nityam Rathi, Ziqi Zhu, Belinda Willard, Shaun Stauffer, Eric Klein, Nima Sharifi. BMX inhibition reverses HSD3B1-driven resistance in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A026.

144 Background: Kinase inhibitors have been ineffective in prostate cancer and have no known role in androgen biosynthesis. Inheritance of the adrenal-permissive HSD3B1(1245C) allele encodes a 3βHSD1 enzyme missense that up-regulates the rate-limiting step of androgen biosynthesis from non-gonadal precursor steroids and confers poor clinical outcomes in castration-resistant prostate cancer (CRPC). About half of all men with prostate cancer inherit the adrenal-permissive HSD3B1 allele. Multiple clinical studies demonstrate that adrenal-permissive HSD3B1 allele inheritance confers more rapid progression on ADT and others also suggest worse CRPC outcomes even after treatment with abiraterone or enzalutamide. However, there is no known method to clinically block 3βHSD1. Furthermore, 3βHSD1 is not known to be phosphorylated. Methods: Mass spectrometry was used to identify protein phosphorylation sites and steroid metabolites, genetic and pharmacologic methods were used to identify the kinase required for 3βHSD1 phosphorylation and mouse xenograft studies were performed with BMX inhibition. The identified mechanism was used to design and launch a multicenter phase 2 study of the BMX inhibitor abivertinib in combination with abiraterone in men with metastatic CRPC. Results: 3βHSD1 enzyme activity requires tyrosine phosphorylation at Y344 by the BMX kinase. Androgen biosynthesis is blocked by a phosphorylation-defective 3βHSD1 344F, or BMX genetic knockdown, or BMX pharmacologic inhibition. BMX inhibition using zanubrutinib suppresses CRPC growth in the C4-2 and VCaP xenograft models by blocking intratumoral androgen synthesis and tumor androgen receptor (AR) signaling. Discovery of this mechanism provides the rationale for the phase 2 Maverick trial of abivertinib, a BMX inhibitor, combined with abiraterone, in men with CRPC with adrenal-permissive HSD3B1 allele inheritance (NCT05361915). Eligibility includes 1) presence of metastatic CRPC, 2) measurable and/or non-measurable disease, and 3) confirmed positivity of adrenal-permissive HSD3B1(1245C) allele inheritance via central testing (cap heterozygosity at 50%). Patients will be enrolled in 2 arms: 1) abiraterone naïve (n=45) and 2) abiraterone progressing (n=55). All patients will receive treatment with abivertinib 200mg twice daily with abiraterone 1000mg daily and prednisone 5mg by mouth twice daily. The primary outcome is 6-month radiographic progression-free survival. On-treatment biopsies will be used to inform mechanisms of response and resistance in patients. Conclusions: BMX is required for 3βHSD1 phosphorylation, androgen biosynthesis and CRPC progression with the adrenal-permissive HSD3B1(1245C) allele. The Maverick trial will test clinical proof-of-concept of BMX inhibition in men with adrenal-permissive HSD3B1(1245C) inheritance. Clinical trial information: NCT05361915 .

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701