Toward the Dual Targeting of HER2 and Androgen Receptor in Patients with High-Risk, Hormone-Naive Prostate Cancer with Curative Intent
Abstract
Scientific Objective and Rationale: Approximately three out of every 20 men diagnosed with prostate cancer are considered high risk for disease reoccurrence after standard treatment. For some of these patients, early clinical intervention with aggressive, pre-operative systemic treatment with androgen withdrawal and second-generation anti-androgen neoadjuvant therapy have been promising compared to surgery alone. However, up to 70% of these neoadjuvant-treated tumors are considered nonresponders with poorly understood etiology. In our recent clinical trial conducted at the National Cancer Institute (NCI, Bethesda), we examined the gene expression profiles of biopsies acquired prior to treatment and compared the tumors that responded to therapy to tumors that did not. We found the expression of genes indicating the activation of HER2, a commonly altered protein in breast cancer, were strongly increased in tumors that did not respond to treatment, prior to therapy. The uncovering of the link between HER2 activation and treatment resistance can potentially offer a new way of treating these high-risk patients using drugs already approved by the Food and Drug Administration for breast cancer. Interestingly, in the patients with high levels of HER2 activation, we find very low levels of androgen receptor activity, indicating that there may be a link between poor response to anti-androgen therapy and HER2 activity. Ultimate Applicability of the Research: This project aims to address the PCRP Overarching Challenges to define the biology of lethal prostate cancer to reduce death and develop treatments that improve outcomes for men with lethal prostate cancer. The high-risk patients with elevated HER2 activity share strong similarity to the tumors of patients with newly diagnosed metastatic prostate cancer, indicating that these are likely the same type of aggressive disease. Our goal in this project is to confirm the biology underlying our findings with sufficient rigor to enable new clinical trials. In order to facilitate the translation of HER2/AR therapy, we propose testing our hypotheses using prostate cancer cell and organoid models that recapitulate the hormone sensitivity of high-risk localized prostate cancer. In addition, the heterogeneous nature of prostate tumors can impact treatment response and will require investigation into how different cell types in the prostate may lead to HER2 activity. To accomplish that goal, we will analyze genomic information on a single cell level in both responding and nonresponding tumors, using state-of-the-art histology and sequencing technologies. This project is applicable to patients at high risk of tumor progressing to metastatic disease that have yet received any systemic androgen deprivation. For this subset of patients, standard treatment by androgen deprivation or radical prostatectomy will likely only provide short-term relief, if any, as the tumor will continue to grow or have already developed micrometastases and will progress. We have developed and published a classifier based on tumor genomic information that can identify these patients prior to therapy. If combination treatment with FDA-approved HER2 inhibitors are effective, it is plausible to resensitize the tumor towards intense androgen deprivation and evoke better responses. Thus, the short-term goal of this study is to determine feasibility (within 2-3 years) and, if successful, move rapidly into clinical trials within 5 years. While many of these FDA-approved drugs targeting HER2 are considered safe, toxicity profiles will be carefully evaluated (especially if administered in conjunction with intense anti-androgen therapy) as part of any clinical trial. Career Goals: I am undertaking postdoctoral training in the laboratory of Dr. Adam Sowalsky at the National Cancer Institute (NIH, Bethesda) to further my training as a cancer researcher, with the goal of becoming an independent prostate
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210067
Entities
People
- Anson Ku
Organizations
- National Cancer Institute
- United States Army