Clinical Utility of Microfluidic Assay for Prognosis and Precision Medicine in Breast Cancer
Abstract
Rationale: Current breast cancer drug development and clinical detection rely on measurements of tumor growth, rather than focusing on the metastatic spread of tumor cells that leads to patient death. The Partnering PIs of this Breakthrough Award (Konstantopoulos, Martin) have developed a microfluidic device (MAqCI) that can rapidly identify the small subpopulation of breast tumor cells that is capable of migrating through the confined environments that are traversed during metastasis and initiate regrowth at distant sites. Objectives: This project will leverage a group of 30 patient-derived xenografts (PDX) from patients with triple-negative breast cancer (TNBC) to optimize MAqCI analysis and establish a streamlined clinical workflow. Since these 30 PDX (obtained from Baylor College of Medicine) also have detailed clinical outcome information, metrics identified with the MAqCI assay can be directly related to patient survival, metastatic progression and response to therapy. Through collaboration with Dr. Vered Stearns, the MAqCI device will also be used to analyze freshly isolated tumor cells from needle biopsies of 45 patients with TNBC. Both PDX and biopsy cells will be used for testing both established and experimental therapies for TNBC, to define a clinical workflow to identify the available drugs that most strongly reduce metastatic risk for individual patients. Since MAqCI can separate the migratory and non-migratory TNBC cells, we will also determine gene profiles that reflect metastatic risk and reveal new therapeutic opportunities. Specific Aims: Aim 1. Validate MAqCI using PDX and needle biopsy specimens from human TNBC patients. Aim 2. Evaluate the in vitro and in vivo translational efficacy of anti-metastatic drugs. Aim 3. Identify new therapeutic targets to combat TNBC metastasis through gene profiling of MAqCI captured metastasis-causing cells. Overarching Challenges: By rapidly identifying the rare metastasis-initiating tumor cells, the MAqCI device addresses the overarching challenge to Distinguish deadly from non-deadly breast cancers. Since MAqCI can test drug responses using tumor cells from individual patients, this technology can also help Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Patient Benefits and Clinical Applications: Chemotherapy given prior to surgery (neoadjuvant) helps some patients, but many do not benefit from neoadjuvant therapies. Emerging evidence now shows that neoadjuvant chemotherapy can also increase metastatic risk by scattering tumor cells into the circulation. The MAqCI device provides a unique opportunity to test both metastatic risk and drug response of tumor cells from needle biopsies within a rapid timeframe (72 hours h) that can identify optimal therapies on isolated tumor cells before the TNBC patient is ever given neoadjuvant chemotherapy. In this way, the MAqCI device allows both selection of the best therapy for an individual TNBC patient, and the avoidance of cancer drugs that could actually increase metastasis. Projected Time to Benefit Patients: Completion of this 3-year project will establish the clinical utility of the MAqCI test platform using 30 PDX and freshly isolated needle biopsy cells from 45 patients with TNBC. This combination of retrospective (PDX) and prospective (biopsy) studies will provide the essential information to immediately support clinical trials to integrate the MAqCI test into clinical decision-making. Breakthrough Provided: TNBC patients do not receive effective benefits from existing targeted therapies. Moreover, there is currently insufficient information to allow a rational selection of a specific neoadjuvant chemotherapy regimen for TNBC patients, which can expose patients to the risk of increased chemotherapy- induced metastasis. The MAqCI assay will provide a unique functional test of metastatic potential using nee
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210296
Entities
People
- Stuart Martin
Organizations
- United States Army
- University of Maryland, Baltimore