In Vivo PARP-1 Expression as a Predictive and Pharmacodynamic Tool
Abstract
As the daughter of a Stage IIIB breast cancer survivor – a pianist whose career was ended due to side effects from ineffective neoadjuvant chemotherapy – Dr. McDonald is committed to finding clinically relevant decision tools to help select patients for appropriate treatment. Our study involves using an imaging tool for this purpose: to both identify who will most likely benefit from therapy and monitor response. Historically, most breast cancers were treated with similar chemotherapeutic regimens, adding endocrine and HER2 directed therapy, depending on the receptor status. More recently, a multitude of therapies directed at individual tumor characteristics have been introduced. While promising, the pace of drug development has exceeded development of methods for identifying patients who will benefit most from these new therapies. Most targeted therapy trials do not include a way to identify patients who have the specific drug target or measure the impact of the cancer drug on the tumor. As a result, interpreting mixed responses within a single patient or between different patients can be difficult. Also, patients may receive a drug for months before a decision can be made about whether the therapy is working. In cases of new or newly progressed metastatic disease, this time is especially critical, and lost ground can be difficult to recover. In January 2018, the first biologically targeted drug for metastatic triple-negative breast cancer (TNBC) was approved by the Food and Drug Administration (FDA), the PARP protein inhibitor (PARPi) olaparib. This approval represents a significant step forward in treatment of a disease that has had historically inferior outcomes and in which standard treatments are limited largely to cytotoxic chemotherapy. While some patients derive significant survival benefit from this drug, others do not benefit, even in the population with germline BRCA1/2 mutations, where the drug was originally tested and approved. Pathologic tests have not been able to reliably predict patient response, possibly because they are not representative of the entire tumor. Only a small fraction of the tumor is sampled during a biopsy and breast cancer is invariably biologically mixed. We propose an evidence-based approach to molecular therapy that includes directly measuring the effect of the drug on the target of interest using functional imaging. Imaging allows simultaneous assessment of different tumors in the same patient, especially important for metastatic disease. Imaging also provides a non-invasive approach to repeat assessment of the tumor during therapy to monitor response. In this project, we are proposing to use a unique tracer agent that can detect PARP expression at a molecular level as a tool to select both patients for PARPi therapy and drugs used in the neoadjuvant setting. Funding this application will allow us to take the first step toward validating a tool for personalized therapy. If successful, this trial could lead to a new way to functionally characterize breast cancer, identify appropriate patients for chemotherapy, and expand the population of patients who are candidates for PARPi treatment, reducing the possibility that a patient will receive this drug without benefit. Thus, our research has high translational impact by better selecting patients for therapy and potentially increasing the numbers of patients who will benefit from a new targeted drug.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010025
Entities
People
- Elizabeth Mcdonald
Organizations
- United States Army
- University of Pennsylvania