The discovery that persistent androgen signaling is present in castrate resistant prostate cancer has led to the development of second generation AR inhibitors that have demonstrated modest improvements in survival. In addition to alterations leading to aberrant AR signaling, a number of other molecular alterations are frequently observed in metastatic prostate cancer specimens, including loss of the tumor suppressors PTEN and TP53, and genomic rearrangements involving ERG. Several novel therapies targeting the PI3K pathway have been developed, with the goal of improving survival in patients with advanced malignancies. We have recently demonstrated that the PI3K and AR pathways cross- regulate each other by reciprocal feed-back whereby, inhibition of one activates the other, maintaining tumor cell survival. Importantly, we have shown that combined pharmacologic inhibition of PI3K and AR signaling caused near complete prostate cancer regressions in pre-clinical models. Based this data, and the success of the recently completed BOLERO2 trial demonstrating therapeutic efficacy of targeting the PI3K and ER pathways in breast cancer, we have initiated a phase Ib clinical trial evaluating PI3K and AR inhibition in patients with castrat resistant prostate cancer. The long-term objective of the current proposal is to define the molecular biology of response and resistance to PI3K/AR inhibition that will be informative for individual patients and the development of clinical trials. To accomplish these aims we will employ the use of GEM models and a novel methodology for the study of individual patient derived prostate cancer organoids (cell lines) derived from biopsy specimens of patients on clinical trials of PI3K/AR inhibitors.
Aim 1 will focus on evaluating pre-clinical response to PI3K and AR inhibitors in individual prostate cancer organoids and correlate these findings with the patient response observed in the clinic.
Aim 2 will address the role ERG plays in promoting resistance to combined PI3K and AR pathway inhibition using GEM models of prostate cancer and novel cell lines that have been derived. The focus of Aim 3 will be to identify mechanisms of acquired resistance to combination therapy. We will utilize the Pten p53 conditional null model of prostate cancer that displays an initial dramatic response to PI3K and AR inhibition followed by disease progression, as well as our newly derived prostate cancer organoids. Focused and broad genomic approaches will be used to identify alterations associated with resistance which will be validated. Collectively, this work will improve our molecular understanding of castrate resistant prostate cancer where alterations in AR and PI3K signaling coordinately regulate cell survival, guide the development of future clinical trials, and transform our approach to personalized medicine.

Public Health Relevance

Defining response and resistance to PI3K and AR inhibition in prostate cancer Lay Summary We recently published that the two most commonly altered pathways in metastatic prostate cancer, the AR and PI3K pathway cross-regulate one another leading to the requirement for combinatorial targeting both pathways. Our current proposal aims to 1) develop a novel method of culturing prostate cancer cells derived from patients with metastatic prostate cancer on PI3K/AR inhibitor clinical trials with the goal of defining pre-clinial response that will be informative to the patient, 2) define the impact of ERG over-expression, which is frequently present in prostate cancer, on promoting resistance to combined PI3K and AR inhibition, and 3) evaluate mechanisms of acquired resistance to PI3K and AR blockade. Through these approaches we are optimally positioned to directly inform and improve the development of clinical trials evaluating PI3K and AR inhibitors in prostate cancer, and develop future clinical trials evaluating novel therapies targeting mechanisms of resistance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Sloan-Kettering Institute for Cancer Research
New York
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