Targeting Mechanisms Driving ErbB2 Activation in Subsets of CRPC
Abstract
The androgen receptor (AR) plays a central role in prostate cancer (PCa), and most patients with metastatic disease respond initially to androgen deprivation therapy (ADT), but they invariably relapse despite castrate-systemic androgen levels (castration-resistant prostate cancer [CRPC]), with tumors that express high levels of AR and AR-regulated genes. Studies from others and our own laboratory have shown that increased intratumoral androgen synthesis is a major mechanism driving AR in CRPC, and responses can be obtained by further suppression of androgen synthesis using agents such as abiraterone, which blocks CYP17A1, or more effective AR antagonists such as enzalutamide. Unfortunately, most of these patients relapse within a year, and AR appears to again be reactivated in most of these relapsed tumors. This reactivation is likely through diverse mechanisms including further AR gene amplification, AR mutations, AR splice variants, and activation of kinase pathways that directly or indirectly enhance AR protein stability and sensitivity to low androgen levels. Among these kinase pathways, studies in cell line and xenograft models have indicated that increased ErbB2 signaling can contribute to the restoration of AR activity and tumor growth in CRPC. ErbB2 (also termed HER2) is a growth factor receptor that is amplified and drives the growth of a subset of breast cancers. These breast cancers can be treated with drugs that inhibit ErbB2 (such as Herceptin and Lapatinib); however, ErbB2 is not amplified in PCa. Nonetheless, several studies have found increased ErbB2 expression or evidence of increased ErbB2 activity in CRPC clinical samples. Although previous clinical trials of ErbB2-targeted therapy have not shown significant activity, we hypothesize that this is because the ErbB2 pathway is a major driver of advanced PCa in only a minority of patients, and these patients may respond to more effective ErbB2-targeted therapies. Our preliminary data further suggest that expression of an ErbB2 splice variant may contribute to ErbB2 pathway activation and relative resistance to reversible ErbB2 inhibitors such as Lapatinib, and these tumors may respond to newer, more potent, irreversible ErbB2 inhibitors. Based on the above background, our overall hypothesis is that the ErbB2 pathway is driving a subset of advanced PCa, and these patients would respond to a therapy that effectively suppresses ErbB2 signaling. Our corresponding overall objective is to elucidate the functions of ErbB2 in advanced CRPC and develop reagents and methods that will allow us to identify the subset of patients who are most likely to respond to ErbB2 inhibition (predictive biomarkers). The overall goal is to generate the preclinical data needed to support a biomarker-driven clinical trial of an ErbB2 inhibitor in advanced CRPC. This proposal directly addresses the PCRP Overarching Challenge to “Develop effective treatments…for men with high-risk or metastatic PCa,” and the Precision Medicine, Therapy, and Tumor Biology Focus Areas. Although previous studies of agents targeting ErbB2 in PCa have not shown efficacy, based on our data, we propose that a subset of CRPC patients will be responsive and that efficacy will be enhanced by use of a more potent covalent ErbB2 antagonist (afatinib or dacomitinib). Our proposed preclinical studies will lay the foundation for a biomarker-driven clinical trial with the potential to benefit a substantial subset of men with CRPC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810379
Entities
People
- Steven P Balk
Organizations
- Beth Israel Deaconess Medical Center
- United States Army