Activation of the PI3K pathway (loss of PTEN) has garnered great interest in prostate cancer as 42% of primary tumors and nearly 100% of metastatic castration-resistant prostate cancers have molecular alterations in this pathway. Thus therapeutic targeting of the PI3K pathway in prostate cancer appears very attractive. Recently, a number of novel inhibitors targeting various components of the PI3K pathway (P13K, AKT, mTORCI, and mTORCI/2) have emerged in early, but promising, clinical development Using preclinical models, we have found that inhibition of the PI3K pathway alone is insufficient to promote tumor regression or apoptosis in PTEN loss prostate cancer. We have generated preliminary data showing that inhibition of the PI3K pathway results in feedback activation of a number of receptor tyrosine kinases (RTK), such as IGF1R and HER2/HER3, that promote prostate cancer cell survival. Furthermore, we find that inhibition of the PI3K pathway induces AR activity in a RTK-dependent manner and concomitant inhibition of AR results in a synergistic profound tumor response in preclinical models. We hypothesize that both AR and PI3K activation suppress prostate cancer cell apoptosis and that inhibition of either pathway alone results in compensatory activation of the other pathway. In this project, we will test this hypothesis and undertake the aggressive preclinical development of combinatorial AR and PI3K pathway inhibition.
Specific Aims : 1. To determine the effects of PI3K pathway inhibition in prostate cancer 2. To determine the effects of AR Inhibition on signaling and prostate cancer biology 3. To determine the biologic consequences and antitumor activity of combined PI3K and AR pathway inhibition in prostate cancer
We hope to establish a paradigm for which novel therapeutic agents for prostate cancer will be evaluated in relevant preclinical models and molecular correlates developed. This work will guide the development of future phase II/III clinical trials evaluating the role of androgen blockade combined with novel P13K pathway inhibitors in patients with high-risk prostate cancer undergoing radical prostatectomy or patients with metastatic prostrate cancer.
|Loeb, Stacy; Lilja, Hans; Vickers, Andrew (2016) Beyond prostate-specific antigen: utilizing novel strategies to screen men for prostate cancer. Curr Opin Urol 26:459-65|
|Fleshner, Katherine; Assel, Melissa; Benfante, Nicole et al. (2016) Clinical Findings and Treatment Outcomes in Patients with Extraprostatic Extension Identified on Prostate Biopsy. J Urol 196:703-8|
|Carlsson, Sigrid V; de Carvalho, Tiago M; Roobol, Monique J et al. (2016) Estimating the harms and benefits of prostate cancer screening as used in common practice versus recommended good practice: A microsimulation screening analysis. Cancer 122:3386-3393|
|Zelefsky, Michael J; Poon, Bing Ying; Eastham, James et al. (2016) Longitudinal assessment of quality of life after surgery, conformal brachytherapy, and intensity-modulated radiation therapy for prostate cancer. Radiother Oncol 118:85-91|
|Kent, Matthew; Penson, David F; Albertsen, Peter C et al. (2016) Successful external validation of a model to predict other cause mortality in localized prostate cancer. BMC Med 14:25|
|Scher, Howard I; Lu, David; Schreiber, Nicole A et al. (2016) Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker With Outcomes and Survival in Castration-Resistant Prostate Cancer. JAMA Oncol 2:1441-1449|
|Sood, Anup; Miller, Alexandra M; Brogi, Edi et al. (2016) Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism. JCI Insight 1:|
|Danila, Daniel C; Samoila, Aliaksandra; Patel, Chintan et al. (2016) Clinical Validity of Detecting Circulating Tumor Cells by AdnaTest Assay Compared With Direct Detection of Tumor mRNA in Stabilized Whole Blood, as a Biomarker Predicting Overall Survival for Metastatic Castration-Resistant Prostate Cancer Patients. Cancer J 22:315-320|
|Braun, Katharina; Sjoberg, Daniel D; Vickers, Andrew J et al. (2016) A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort. Eur Urol 69:505-11|
|Preston, Mark A; Batista, Julie L; Wilson, Kathryn M et al. (2016) Baseline Prostate-Specific Antigen Levels in Midlife Predict Lethal Prostate Cancer. J Clin Oncol 34:2705-11|
Showing the most recent 10 out of 424 publications