For example, the neuroleptics clozapine, paliperidone, and risperidone potently inhibited primary targets DRD2 and HTR2A as well as cAMP and calcium pathways...Additionally, precise potency data for LY2452473, an androgen receptor antagonist, that completed a phase 2 clinical trial for prostate cancer, are presented. The non-selective kinase inhibitor staurosporine was observed to potently inactivate the two RTKs EGFR and ERBB4 as well as MAPK signaling, while eliciting stress-related cAMP responses. Our findings underscore the value of comprehensive profiling in elucidating the pharmacological properties of established and novel therapeutics, thereby facilitating the development of novel multi-target drugs with enhanced efficacy and selectivity.

CDK8/19 inhibition significantly decreased PSA secretion in LNCaP and 22Rv1 cells and, when combined with enzalutamide, additively reduced proliferation in 22Rv1 cells. Our study revealed that MED12 and CDK8/19 regulate AR activity and that their inhibition may modulate response to enzalutamide in prostate cancer.

Inhibition or overexpression of miR-1271-5p levels affects prostate cancer cell growth, apoptosis and expression of both androgen receptor target genes and other genes that are likely direct targets, dependent on androgen receptor status, and tumour stage. We conclude that miR-1271-5p has the potential to drive progression of hormone-dependent disease and that the use of specific inhibitors of miR-1271-5p may have therapeutic potential in prostate cancer.

Adding the CDK4/6 inhibitor palbociclib enhanced the antitumor activity of EP0062 or fulvestrant in ESR1-mutant models but not in HER2-enriched or PTEN-mutant PDX models...EP0062 triggers an E2F1 downmodulation which mediates a potent antiproliferative activity. For EP0062-resistant tumors that remain ER-driven, the addition of palbociclib displays a potent antitumor effect.

P2, N=150, Active, not recruiting, Veru Inc. | Recruiting --> Active, not recruiting

P2, N=150, Recruiting, Veru Inc. | N=90 --> 150

P2, N=90, Recruiting, Veru Inc. | Not yet recruiting --> Recruiting

P2, N=22, Terminated, GTx | Completed --> Terminated

P2, N=90, Not yet recruiting, Veru Inc.

P3, N=5, Terminated, Veru Inc. | N=186 --> 5

P2, N=18, Completed, City of Hope Medical Center | Active, not recruiting --> Completed

Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer.

P3, N=186, Suspended, Veru Inc. | Trial completion date: Jan 2024 --> Dec 2025 | Trial primary completion date: Jan 2024 --> Dec 2025

P3, N=52, Terminated, Veru Inc. | N=210 --> 52 | Active, not recruiting --> Terminated; Business decision

P3, N=186, Suspended, Veru Inc. | Active, not recruiting --> Suspended | Trial primary completion date: Sep 2023 --> Jan 2024

Activity of enobosarm in this heavily pretreated patient population is encouraging and supports further clinical investigation. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm alone or in combination with abemaciclib for the second-line treatment of AR+ER+HER2- metastatic breast cancer in patients who have received a prior estrogen blocking agent and a CDK 4/6 inhibitor. Clinical trial information: NCT04869943.

P3, N=210, Active, not recruiting, Veru Inc. | Trial completion date: Jul 2023 --> Feb 2024 | Trial primary completion date: Jun 2023 --> Jan 2024

P3, N=186, Active, not recruiting, Veru Inc. | Recruiting --> Active, not recruiting

We identify a key GATA2-CDC6 signaling axis which is reciprocally regulated in enzalutamide-sensitive and -resistant prostate cancer environments. Upon acquired resistance, GATA2 repression leads to CDC6 stabilization, with detrimental effects in disease progression through exacerbation of EMT and abrogation of senescence. However, bypassing the GATA2-CDC6 axis by direct inhibition of CDC6 reverses oncogenic features and establishes senescence, thereby offering a therapeutic window even after acquiring resistance to therapy.

In xenograft studies, MPC309 produced significantly greater tumor suppression than enzalutamide. Altogether, MPC309 represents a promising new AR modulator that can combat resistant disease by promoting an AR anti-proliferative gene expression program.

Furthermore, we established that the anti-carcinogenic activity of andarine is not mediated by the PI3K/AKT/mTOR signaling pathway, a crucial regulator of cell survival. Our findings suggest that andarine might be considered as a prospective drug for PC.

P2, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jan 2023 --> Dec 2023

Since PI3K/AKT/mTOR signaling is frequently activated in HCC and contributes to its aggressiveness and poor prognosis, its negative regulation by the downregulation of critical components via S4 was a prominent finding. Further studies are necessary to investigate the S4 action mechanism and anti-tumorigenic capacity in in-vivo.

P3, N=210, Active, not recruiting, Veru Inc. | Trial completion date: Apr 2023 --> Jul 2023 | Trial primary completion date: Mar 2023 --> Jun 2023

P3, N=210, Active, not recruiting, Veru Inc. | Recruiting --> Active, not recruiting

Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates with worse clinical outcome compared to the low expression group, and that ADRB3 gene expression affects different immune-related pathways. Overall, results indicate that β3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.

Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

Clinic follow-up will be at 2 and 4 weeks, then every 4 weeks until disease progression. Recruitment is scheduled to initiate in Q4 2022.

HR+HER2- and TN patients who are Immune-Low and DRD-Low have very low pCR rates to all tested therapeutics in I-SPY2 including standard chemotherapy, platinum, and immunotherapy. Senolytics (possibly targeting Cyclin D1), HER2low agents, and AR modulators may overcome resistance in HR+HER2- /Immune-/DRD-, whereas an immune activator beyond checkpoint inhibition is suggested for TN/Immune-/DRD- patients. [1] Wolf et.

The results of this study suggest that gene selective regulation by SARMs results from differential DNA-binding and/or cofactor recruitment by ligands. These results provide novel insights into the mechanism of action of SARMs.

To determine the effects of an oral SARM (OPK-88004) on cholesterol efflux capacity, HDL particle number and size, apolipoprotein particle number and size and HDL subspecies...SARM-induced increase in HTGL could contribute to HDL-C suppression. These data do not support the simplistic notion that SARM-associated suppression of HDL-C is necessarily proatherogenic; randomized trials are needed to determine SARM's effects on cardiovascular events.

In vivo antitumor activity of RAD140 alone or in combination with palbociclib was tested in comparison to fulvestrant plus palbociclib. Conclusion RAD140 exhibits antitumor activity in hormone-independent and ESR1 -altered ER+/HER2- PDX models as single agent or in combination with CDK4/6i. Mechanistically, AR agonists decrease proliferation as shown by a decrease in Ki67 and S/G2-cell cycle cyclin levels.

P2, N=18, Active, not recruiting, City of Hope Medical Center | N=29 --> 18 | Trial completion date: Nov 2021 --> Jan 2023

Approximately 210 subjects with AR+, ER+, HER2– mBC and with AR nuclei staining of 40% or greater are being randomized 1:1 to either enobosarm 9-mg oral daily dose or an active comparator (either exemestane, everolimus [Afinitor], or a selective estrogen receptor modulator; physician’s choice). The secondary objectives/end points of this study include the objective response rate, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), and change in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ). Status The study is currently ongoing, and it is anticipated that enrollment will be completed this year

If first-line therapy for mBC was a nonsteroidal aromatase inhibitor (AI) plus palbociclib (Ibrance), then the patient is randomized to either enobosarm plus abemaciclib (Verzenio) or fulvestrant. Secondary end points include objective response rate, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ), and change in body composition as measured by dual-energy x-ray absorptiometry (DEXA). Status The study is currently ongoing, and it is anticipated that enrollment will be completed this year.

Our findings suggest that AR modulates the metabolism of BT-474 cells by affecting the expression of a large number of genes and proteins. Based on further pathway analysis, we suggest that androgen receptor acts as a tumor suppressor in the BT-474 cells.

Background: The poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib and rucaparib have been approved for the treatment of metastatic castration resistant prostate cancer (mCRPC) in the setting of homologous recombination deficiency (HRD)... The PARPi olaparib and talazoparib, and to a lesser extent veliparib, inhibited CRPC cell growth... We describe a novel sequela of PARPi therapy to alter AR localization and activity in CRPC. Single agent PARP inhibition can alter prostate cancer cell growth in vitro and in vivo. With PARPi treatment, AR localization is shifted to the cytoplasm, the AR interactome is altered, and AR transcriptional activity decreased.

The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA.

Med Pr. 2022;73(2).

P3, N=186, Recruiting, Veru Inc. | Not yet recruiting --> Recruiting