Background and Preliminary Data: Approximately 50% of late-stage HER2+ and triple-negative (TNBC) breast cancer patients experience brain metastasis, often linked to seizures and neurological impairment as well as decreased survival. Increased incidence of breast cancer brain metastasis might be explained in part by use of targeted therapies with low penetrance through the blood-brain barrier (BBB) and emergence of acquired resistance. Preclinical studies in mouse models have identified genes that mediate breast cancer metastasis to the brain. Unfortunately, therapies targeting these and other metastasis regulators have not translated into effective therapies against breast cancer brain metastasis. We have now uncovered a novel role for the ABL family kinases, ABL1 and ABL2, in promoting brain metastasis by breast cancer cells in mouse models. We found that a novel inhibitor of the ABL kinases crosses the BBB and markedly impairs the growth of brain metastasis by HER2+ breast cancer cells. Analysis of multiple databases showed that ABL upregulation is associated with decreased distant metastasis-free survival in basal-like and HER2-positive breast cancer patients. Our recent findings revealed that treatment of mice harboring metastatic breast cancer cells with ABL allosteric inhibitors markedly impaired the growth of HER2+ breast cancer cells in the brain. Further, we uncovered new mechanistic links between ABL and HER2 kinases that can be exploited to treat HER2+ tumors. Using a new mouse model expressing activated ABL2 in the mammary gland, we found that active ABL2 promotes mammary cell growth and therapy resistance. Moreover, we found that the ABL allosteric inhibitors sensitize breast cancer cells to growth inhibition by chemotherapy and targeted therapies.

Overarching Challenges: This proposal will address the following three overarching challenges: (1) Eliminate the mortality associated with metastatic breast cancer. (2) Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. (3) Identify why some breast cancers become metastatic.

Patient Benefits and Potential Clinical Applications: The proposed studies will benefit patients with metastatic triple-negative (basal) and HER2+ breast cancer subtypes. Specifically, we will identify pathways that promote breast cancer metastasis to the 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 HER2+ breast tumors in the brain. The proposed studies will evaluate whether pharmacological inhibition of the ABL kinases with novel selective inhibitors (now in clinical trials for the treatment of human leukemia) decreases brain metastasis by various breast cancer subtypes using preclinical models. The new ABL allosteric inhibitors have unique properties that make them superior to other compounds previously used to inhibit the activities of ABL and other related kinases. In the short term, results from this project are expected to identify ABL-dependent biomarkers for breast cancer subtypes with metastatic potential to brain and to repurpose available ABL allosteric inhibitors to treat brain metastatic breast cancer subtypes. In the long term, these studies will uncover novel signaling networks required for breast cancer progression, therapy resistance, and brain metastasis, leading to the identification of effective drug combinations for the treatment of brain metastatic and therapy-refractory breast cancer.

These studies are impactful because they will: (1) identify why some breast cancers become metastatic; (2) uncover new molecular mechanisms that direct breast cancer metastasis to the brain; (3) lead to the discovery of new pathways that can be targeted for the treatment of therapy-resistant breast cancer metastasis; and (4) repurpose currently available ABL allosteric inhibitors (used for the treatment of therapy-resistant leukemia) for the treatment of breast cancer brain metastasis. It is projected that these studies will lay the foundation for the design of clinical trials with combination therapies after 3 years.