Predicting Response to Intense Neoadjuvant Androgen Deprivation Therapy Through Spatial Genomics and Imaging Heterogeneity
Abstract
Scientific Objective and Rationale: Although a large number of prostate cancer patients exhibit a non-aggressive (indolent) form of disease, among those with aggressive disease, treatment options include radiation therapy targeted to the pelvis or radical prostatectomy survey to remove the prostate. Given that newer agents such as abiraterone and enzalutamide have shown promise in the metastatic setting, there is increasing interest in treatment with hormone therapy (neoadjuvant androgen deprivation therapy followed by surgery) while definitive therapy may still be curative. Although several factors, including age, family history, PSA levels, and, increasingly, genetic or genomic test are considered before deciding on surgery, there is currently no clear indication of what can predict how a patient might respond to neoadjuvant therapy. The proposed study is intended to utilize samples collected during an ongoing clinical trial of neoadjuvant enzalutamide at the National Cancer Institute (NIH, Bethesda), in which men enrolled in the study receive multiparametric MRI (mpMRI) screening and undergo a pre-treatment targeted biopsy to regions identified on mpMRI. A second mpMRI is performed after treatment before surgery. Although these biopsies can produce discomfort, the targeted biopsy is an indispensable resource for understanding the state of disease before treatment, as our genetic and tissue analyses will add to the data generated by mpMRI. mpMRI is being considered as additional criteria for enrolling patients in future studies. Initial results from this study show that some men do indeed respond well to treatment. However, there are many men who show incomplete responses, and in some patients, one part of the tumor responds, but another part does not. The first objective of this study is to ask whether genetic features identified in a pre-treatment biopsy would indicate whether a tumor is likely to respond to treatment. The second objective is to use mpMRI imaging with tissue analysis to create a prostate cancer profile that would allow clinicians to better screen patients prior to treatment. Applicability of Research: This project is applicable to those patients with higher-grade primary disease for whom active surveillance is not an option and for whom decisions about surgery must be made. We are performing our correlative investigation in conjunction with a phase 2 clinical study at the NIH Clinical Center. Our project is testing the hypotheses that tumors that will not respond well to neoadjuvant androgen deprivation therapy could be distinguished from those prostate cancers that will respond well, and that cancer cells persisting after therapy achieve resistance by one or more recurrent and/or predictable mechanisms. If our immediate efforts are successful, it would substantiate efforts to reproduce our findings in larger, multi-institutional collaborative studies over the next 5-10 years to develop a panel of alterations that would inform decision-making prior to patients receiving neoadjuvant therapy. If successful, potential clinical benefits include receiving treatment that is more likely to have long-term or survival benefits. If successful, potential clinical risks include being advised of treatments (such as radiation therapy) that may be more likely palliative than curative. Career Goals: I am completing my postdoctoral fellowship in the laboratory of Dr. Adam Sowalsky at the National Cancer Institute to further my training as a cancer researcher, while preparing for a career as an independent academic prostate cancer scientist. This project will afford me the opportunity to more fully understand the genetics underlying prostate cancer development and progression, while also familiarizing myself with clinical and research perspectives of modern prostate cancer research, including diagnosis/pathology, treatment, and emerging perspectives into prevention and early detection. Published
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910712
Entities
People
- Scott Wilkinson
Organizations
- National Cancer Institute
- United States Army