ABL-Regulated Transcriptional and Epigenetic Networks Promote Outgrowth of Breast Cancer Metastases, Revealing Novel Therapeutic Targets
Abstract
Rationale, Objectives, and Aims: Existing therapies to treat breast cancer metastasis to the bone and brain have proven ineffective due to variable, transient, and/or incomplete responses. Bone metastases occur in up to 70% of breast patients with advanced disease, and approximately 50% of late-stage HER2+ and triple-negative (TNBC) breast cancer patients experience brain metastasis, often linked to seizures, neurological impairment, and decreased survival. Lack of effective therapies to treat brain and bone metastasis is due in part to limited knowledge of actionable targets to inhibit metastatic seeding and colonization. Thus, there is a critical need to identify actionable signaling networks that might be targeted to treat breast cancer metastasis to brain and bone. The proposal builds upon our exciting and breakthrough discovery that ABL kinases are required for breast cancer metastasis to bone and brain, and the finding that a novel allosteric inhibitor of the ABL kinases (currently in clinical trials to treat therapy-resistant leukemia patients) markedly impairs the growth of both bone and brain metastasis by breast cancer cells in preclinical mouse models. Notably, we have identified ABL-regulated transcription factors required for brain metastasis by breast cancer cells and found that ABL allosteric inhibitors sensitize breast cancer cells to growth inhibition by therapies targeting epigenetic modulators. The goal of the proposal is to dissect the mechanisms employed by ABL kinases to promote colonization and outgrowth of metastatic breast cancer through the activation of transcriptional and epigenetic programs, as well as to evaluate whether inhibition of ABL kinases impairs metastatic colonization to bone and brain, and sensitizes breast cancer cells with hyper-activation of ABL signaling to therapies targeting diverse epigenetic modulators. An innovative feature of this proposal is that it utilizes state-of-the-art spatial transcriptomic techniques, as well as the integration of transcriptional and epigenetic profiling of breast cancer subtypes that metastasize to brain or bone, revealing novel biomarkers and actionable targets for the treatment. The proposed studies will provide (1) new insights into transcriptional and epigenetic landscapes of breast cancer metastasis to brain vs. bone; (2) reveal whether the aggressive triple-negative (basal) breast cancer subtype exhibits unique and common gene expression profiles upon colonization to brain or bone; (3) identify changes in the transcriptional and epigenetic profiles induced by ABL allosteric inhibitors in mouse models of metastasis to brain and bone; and (4) generate unique datasets with integrated gene expression profiles and chromatin accessibility landscapes of breast cancer subtypes that will be disseminated to the research community at large. Overarching Challenges: This proposal will address the following overarching challenges: (1) Eliminate the mortality associated with metastatic breast cancer. (2) Identify what drives breast cancer growth; determine how to stop it. (3) Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. (4) Identify why some breast cancers become metastatic. Patient Benefits and Potential Clinical Applications: The proposed studies will benefit patients with breast cancer metastatic to bone and brain. Specifically, the proposed research will identify pathways that promote breast cancer metastasis to the bone and brain. The potential clinical applications of this project are high, as we showed that currently available ABL kinase small molecule inhibitors are markedly effective in decreasing the growth of metastatic breast cancer tumors not only in the bone but also in the brain. The proposed studies will evaluate whether pharmacological inhibition of the ABL kinases with novel selective inhibitors, alone or in combination with drugs targeting factors that reg
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210034
Entities
People
- Carey Anders
Organizations
- Duke University
- United States Army