MP64-20 A NOVEL NITROXOLINE TREATMENT, TARGETING THE PI3K PATHWAY, IN COMBINATION WITH PD-1 BLOCKAGE, EXERTS A POTENT PROSTATE CANCER ANTI-TUMOR EFFECT

Abstract PTEN is frequently mutated in prostate cancer. The tumor suppressor function of PTEN is attributed to its lipid phosphatase activity that counters PI3K action. Here, we report a PTEN-ARID4B-PI3K axis in which PTEN inhibits expression of ARID4B, while ARID4B is a transcriptional activator of the PI3K subunit genes PIK3CA and PIK3R2 that are crucial for activation of the PI3K/AKT pathway. Reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, suggesting a mechanism by which ARID4B activates these promoters. Functional analyses reveals that ARID4B is required for prostate tumorigenesis when PTEN is deficient. The biological significance is further substantiated by the existence of a PTEN/ARID4B/PIK3CA three-gene signature that improves the predictive power for prostate cancer recurrence in patients. In summary, we identify ARID4B as a master regulator in the PTEN-PI3K pathway, thus providing a potential therapeutic target for prostate cancer carrying PTEN mutations.

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Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial

JCO Precision Oncology ◽

10.1200/po.19.00388 ◽

2020 ◽

pp. 882-897 ◽

Cited By ~ 2

Author(s):

Clare Gilson ◽

Fiona Ingleby ◽

Duncan C. Gilbert ◽

Marina A. Parry ◽

Nafisah B. Atako ◽

...

Keyword(s):

Prostate Cancer ◽

Chromatin Remodeling ◽

Metastatic Prostate Cancer ◽

De Novo ◽

High Volume ◽

Pi3k Pathway ◽

Mismatch Repair Gene ◽

Copy Number Loss ◽

Hormone Sensitive ◽

Low Volume

PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor ( AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences ( AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.

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Targeting reciprocal feedback inhibition: Apalutamide and everolimus in patients with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.6_suppl.204 ◽

2017 ◽

Vol 35 (6_suppl) ◽

pp. 204-204 ◽

Cited By ~ 1

Author(s):

Dana E. Rathkopf ◽

Susan F. Slovin ◽

Michael J. Morris ◽

Daniel Costin Danila ◽

Anthony Delacruz ◽

...

Keyword(s):

Prostate Cancer ◽

Historical Data ◽

Feedback Inhibition ◽

Phase 1 ◽

Mtor Inhibitors ◽

Pi3k Pathway ◽

Abiraterone Acetate ◽

Fixed Dose ◽

Castration Resistant Prostate Cancer ◽

Pten Loss

204 Background: Studies in xenograft CRPC and PTEN-deficient prostate cancer models have shown synergistic anti-tumor activity of next-generation anti-androgens such as apalutamide when combined with PI3K/mTOR inhibitors such as everolimus. (Carver B et al., Cancer Cell 2011) The primary hypothesis of this study was that the combination of apalutamide with everolimus would overcome resistance to prior hormonal therapy with abiraterone acetate and prednisone (AAP). Methods: The primary endpoint in mCRPC patients with prior AAP was to evaluate the safety, pharmacokinetics (PK), and recommended phase 2 dose (RP2D) of fixed dose apalutamide 240 mg po qd when combined with everolimus 5 mg po qd (cohort 1, n = 3) and everolimus 10 mg po qd (cohort 2, n = 6). The plan was to expand to treat 40 patients at the RP2D. Results: Nine patients were enrolled in phase 1. The PK for the combination was consistent with historical data of either drug given as monotherapy. The most common treatment related adverse events were < = grade 2 fatigue (67%), diarrhea (56%), and anorexia (56%). In cohort 2, 1 patient had a DLT of grade 3 rash. The median time on treatment was 17 weeks (range 7-51+). The best response was SD in all 9 patients. Patients came off study for: progression (n = 3), investigator choice (n = 3) and toxicity unrelated to treatment (n = 2). Seven patients had detectable CTCs at baseline (EPIC Sciences). One patient had a rise in CTC number that then converted to undetectable and remained on study 37 weeks. One out of 6 evaluable patients had PTEN loss in tissue at baseline (MSK IMPACT) and remained on study 12 weeks. One patient with prior AAP and enzalutamide exposure has remained on study 51+ weeks with a > 50% decline in PSA (PTEN pending). Conclusions: Although the combination of apalutamide and everolimus was safe and well tolerated, the treatment response was similar to historical data of AAP followed by apalutamide alone. (Rathkopf D et al., ASCO 2014) We elected to close this study before expansion in favor of evaluating novel AR/PI3K pathway combinations in patients who have not yet been exposed to AAP. Drug provided by Janssen and Novartis. Trial support: PCF and MSK Experimental Therapeutics Center. Clinical trial information: NCT02106507.

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Development of a three-dimensional culture model of prostatic epithelial cells and its use for the study of epithelial-mesenchymal transition and inhibition of PI3K pathway in prostate cancer

The Prostate ◽

10.1002/pros.20897 ◽

2008 ◽

Vol 69 (4) ◽

pp. 428-442 ◽

Cited By ~ 32

Author(s):

Jian Hong Chu ◽

Shan Yu ◽

Simon W. Hayward ◽

Franky L. Chan

Keyword(s):

Prostate Cancer ◽

Epithelial Cells ◽

Epithelial Mesenchymal Transition ◽

Three Dimensional ◽

Pi3k Pathway ◽

Mesenchymal Transition ◽

Culture Model ◽

Three Dimensional Culture

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Abstract 1979: Interaction of atorvastatin and CX3CR1-fractalkine in androgen-dependent prostate cancer cells: Effect on PI3K pathway

10.1158/1538-7445.sabcs18-1979 ◽

2019 ◽

Author(s):

Belal Al-Husein

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Pi3k Pathway ◽

Prostate Cancer Cells

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Abstract 1979: Interaction of atorvastatin and CX3CR1-fractalkine in androgen-dependent prostate cancer cells: Effect on PI3K pathway

10.1158/1538-7445.am2019-1979 ◽

2019 ◽

Author(s):

Belal Al-Husein

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Pi3k Pathway ◽

Prostate Cancer Cells

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ALDH1A3 serves as a predictor for castration resistance in prostate cancer patients

10.21203/rs.2.21612/v1 ◽

2020 ◽

Author(s):

Shangqian Wang ◽

Xiang Zhou ◽

Chao Liang ◽

Meiling Bao ◽

Ye Tian ◽

...

Keyword(s):

Prostate Cancer ◽

Hormonal Therapy ◽

Acquired Resistance ◽

Pi3k Pathway ◽

Gene Set Enrichment Analysis ◽

Adjuvant Hormonal Therapy ◽

Castration Resistance ◽

Sequencing Data ◽

Knock Out ◽

Luminal Cells

Abstract Aldehyde dehydrogenase 1A3 (ALDH1A3) has been implicated in the survival and proliferation of prostate cancer cells. We retrospectively reviewed our patients with advanced disease on adjuvant hormonal therapy after prostatectomy. Time to castration resistance stage was documented. And Immunohistochemistry analysis for ALDH1A3 was performed for those patient samples on tissue microarray. Using bioinformatics analysis for RNA sequencing data of both primary prostate cancer and metastatic castration resistance prostate cancer (mCRPC) from online datasets, we have found that the expression level of ALDH1A3 is lower in mCRPC group than in primary cancer group. Crispr-Cas9 was used to knock out ALDH1A3 in prostate cancer luminal cells, and morphologic analysis as well as the Gene Set Enrichment Analysis (GSEA) were facilitated to discover the mechanisms of the resistance phenotype. We found that the patients with ALDH1A3 low expression had shorter time to progression to castration resistance compared with those of higher expression group on adjuvant hormonal therapy after radical prostatectomy. The ALDH1A3 knockout cells gradually acquired resistance to androgen deprivation therapy, few cells have been found in knockout group showing as that the spindle-like luminal cells in charcoal stripped medium. Furthermore, PI3K pathway activation has been confirmed by Western blot. The PI3K pathway inhibitor BEZ235 has been demonstrated that the acquired ADT resistance by ALDH1A3 down regulation could be rescued by PI3K pathway inhibitor. Together, these results suggested a novel function for ALDH1A3 in development of mCRPC, and indicated PI3K pathway inhibitor has the potential in the treatment of a subgroup of mCRPC patients.

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