# Precision Neoadjuvant Therapy for High Risk Localized Prostate Cancer with PTEN Loss

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2024 · —

## Abstract

Project Background: Prostate cancer is the second leading cause of cancer deaths in men in the United
States. Prostate cancer treatment options fare historically based on clinical stage, prostate specific antigen
(PSA) blood test, and tumor grade. Recent advances in molecular research have shown that a common finding
in high-risk cancers prostate cancers that are surgically removed is loss of the phosphatase and tensin
homologue (PTEN) tumor suppressor gene, which leads to increased activity of the AKT signaling pathway.
PTEN loss is associated with higher rates of prostate cancer recurrence, metastasis, and cancer mortality. Pre-
clinical laboratory research has shown a reciprocal feedback regulation between the PTEN/AKT signaling axis
and the Androgen Receptor (AR) signaling axis. Manipulation of androgens and AR have been the focus of
prostate cancer systemic therapy for decades; however, PTEN loss is a lead mechanism for prostate cancer
resistance to AR directed therapy and development of castrate resistant prostate cancer.
Project Objectives: This study will change standard localized treatment (radical prostatectomy alone) by
conducting a single arm Phase II trial combining intensified androgen deprivation (abiraterone and leuprolide)
with an AKT inhibitor (capivasertib) prior to radical prostatectomy among high risk localized prostate cancers
with PTEN loss. The goal is that early precision treatment of aggressive disease will result minimal residual
cancer at the time of prostatectomy, and subsequently improved cancer outcomes. The response will be
compared to a historical control of neoadjuvant intensified androgen deprivation alone.
Project Methods This is an integral biomarker (biomarker required) treatment trial with integrated biomarker
discovery for mechanisms of resistance and response to therapy. Specific Aim1: Conduct a single arm phase
II study to determine efficacy and safety of neoadjuvant capivasertib combined with androgen receptor
pathway therapy (leuprolide + abiraterone) prior to radical prostatectomy among high risk localized PCa with
PTEN loss. The protocol will include an ADT+ abiraterone run-in (4 weeks) and addition of AKT inhibitor
therapy (16 weeks) prior to radical prostatectomy. Specific Aim 2: To investigate molecular signatures of
response and adaptive mechanisms of resistance to combined AKT and AR pathway therapies. Aim 2.1 We
will interrogate novel mechanisms of resistance and response using `omics profiles and molecular imaging
through integrated approaches. On treatment biopsy after abiraterone run-in and prostatectomy tissue will be
used to identify tumor adaptation and targetable mechanisms of resistance to therapies. Aim 2.2 Determine
the impact of ERG activation on resistance to therapy. We hypothesize that ERG activation will be associated
with lower response rates, and persistent activation of AR target genes. The results of the study will have
immediate implications for the feasibility of precision o...

## Key facts

- **NIH application ID:** 10486403
- **Project number:** 1I01CX002517-01
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Ryan Patrick Kopp
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10486403

## Citation

> US National Institutes of Health, RePORTER application 10486403, Precision Neoadjuvant Therapy for High Risk Localized Prostate Cancer with PTEN Loss (1I01CX002517-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10486403. Licensed CC0.

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