R01CA262555

Synergized Immune and Tumor Cell Bone Marrow Biomarkers to Predict Recurrence in Triple Negative Breast Cancer - Project Summary/Abstract

Triple Negative Breast Cancer (TNBC) is aggressive, and a large percentage of patients develop metastatic disease. Disseminated Tumor Cells (DTCs) found in the bone marrow (BM) of TNBC patients may be the intermediaries of the metastatic process. Data from our lab, as well as others, suggest that the immune landscape of BM may influence DTC latency, treatment resistance, and metastatic potential.

We have already defined and validated an 8-gene expression-based biomarker panel that can detect DTCs in the BM of treatment-naïve TNBC patients and predict the development of distant metastatic disease. Our recent data indicate that TNBC patients with DTC-positive BM have altered populations of immune cell precursors, and this is associated with recurrent disease development.

Based on these findings, we hypothesize that immune checkpoint inhibitors will facilitate the elimination of BM DTCs in TNBC patients by altering the immune microenvironment in patients with specific DTC and/or BM immune cell populations. Additionally, we believe that cell population-specific gene expression signatures can predict which patients will benefit most from aggressive immunotherapy to prevent metastatic disease relapse.

We will test this hypothesis using our extensive biorepository of BM specimens collected from TNBC patients who received conventional chemotherapy, as well as prospectively collected specimens from TNBC patients participating in an independently funded institutional Phase II immune checkpoint inhibitor (ICI) trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab.

Our goals are as follows:

1. To evaluate the ability of our 8-gene DTC gene panel to predict distant disease development in TNBC patients enrolled in our ICI therapeutic trial of carboplatin/paclitaxel/nivolumab with or without cabiralizumab.
2. To understand the specific subpopulations of BM DTCs in TNBC patients treated with conventional chemotherapy and ICI therapy that are resistant to therapy.
3. To understand alterations in specific T cell and conventional dendritic cell (CDC) populations in the BM when DTCs are present and how this is impacted by conventional and ICI therapy.

The results of this proposal will lead to a greater understanding of immune escape and heterogeneity of BM micrometastatic disease, as well as biomarkers for improving conventional and ICI therapy in TNBC patients.

Washington University

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER, TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS, AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Saint Louis, Missouri 631101010 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 406% from $629,761 to $3,185,429.