Targeting TNBC Brain Metastases Using a Brain-Penetrable KDM1A Inhibitor
Abstract
Breast cancer is the most common malignancy of women. Among the breast cancer subtypes, triple negative breast cancer (TNBC) makes up to 15%-24% of all breast cancers. TNBC is a highly aggressive disease with a poor prognosis, a high rate of recurrence despite treatment, and is linked with the shortest overall survival. The incidence rates of brain metastasis occur more commonly for TNBC compared to other breast cancer subtypes, and advanced TNBC constitutes approximately 46% of brain metastases. Standard treatment for patients with brain metastatic TNBC (TNBC-BM) consists of surgery followed by whole-brain radiation or stereotaxic radiosurgery. Despite heavy investment in new therapies, median survival of patients with TNBC-BM is only 4.9 months. There is an urgent need for new therapies to treat TNBC-BM. Although changes to DNA in the form of alterations to important genes such as BRCA1/2 have been linked with breast cancer, reversible changes to molecules that closely associate to DNA can change gene expression that may contribute to cancer. These reversible changes, known as epigenetic alterations, have been shown to play a pivotal role in TNBC-BM development and disease progression. The enzyme lysine-specific histone demethylase 1A (KDM1A) plays a part in these epigenetic alterations. In particular, KDM1A is highly expressed in TNBC and is associated with worse survival. However, the role of KDM1A in TNBC-BM progression remains unknown. Additionally, oxygen deficiency within tumors, known as hypoxia, occurs more frequently in TNBC-BM. These hypoxic conditions seem to selectively support proliferation of breast cancer cells in the brain, thereby modulating aggressive tumor cell behavior. Recent studies support the involvement of KDM1A in hypoxia, though whether KDM1A plays a part in TNBC-BM hypoxia-mediated responses requires further study. Since KDM1A is highly expressed in several human cancers, there is significant interest in development of KDM1A inhibitor drugs, some of which are currently being tested in clinical trials for leukemia and lung cancer. However, these inhibitors are not suitable for TNBC-BM because they cannot cross the blood brain barrier to access the brain. We developed a new KDM1A-specific inhibitor, NCD38, that efficiently reaches the brain and demonstrates minimal toxicity. Preliminary studies show promising results, namely, that NCD38 reduces tumor growth of TNBC-BM and enhances survival of tumor-bearing mice. In this proposal, we will test the usefulness of KDM1A inhibitor NCD38 to treat TNBC-BM and determine the method by which it is able to accomplish this. This proposal aims to address two overarching Department of Defense challenges: (1) revolutionize treatment regimens by replacing them with more effective and less toxic alternatives that positively impact patient health and survival; and thus to (2) reduce the mortality associated with metastatic breast cancer. The objective of this proposal is to determine the functional role of KDM1A in TNBC-BM and develop a possible new clinical strategy to target TNBC-BM by employing KDM1A-specific inhibitor NCD38. The central hypothesis of this study is to demonstrate that KDM1A is essential for TNBC-BM cell survival and proliferation, that KDM1A plays a key role in TNBC-BM hypoxic responses, and that inhibiting KDM1A using NCD38 can promote cancer cell death, attenuate hypoxic responses, and thus lead to a decrease in TNBC-BM growth. We will test this hypothesis using two aims. In Aim 1, we will test the efficacy of KDM1A inhibitor NCD38 in killing TNBC-BM cells and evaluate its therapeutic efficacy alone or in combination with radiation therapy to reduce TNBC-BM progression. In Aim 2, we will define the mechanism by which KDM1A inhibitor NCD38 exerts antitumor effects on TNBC-BM cells using global gene expression and protein analysis of cancer cells, and determine the role of KDM1A in promoting hypoxia-mediated respon
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210013
Entities
People
- Gangadhara Reddy Sareddy
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio