Disruption of the Tumor Microenvironment in Her2+ Breast to Brain Metastasis
Abstract
Which overarching challenge(s) does this research address? This study will address two overarching challenges: (1) identify why Her2+ breast cancers become life-threatening brain metastasis by studying the tumor and brain microenvironment and (2) eliminate the mortality associated with breast to brain metastasis. What types of patients will it help and how will it help them? It is often unrecognized that 90% of deaths from cancer occur because of metastasis, and the most dangerous areas to which cancer can spread is the brain. This is particularly relevant for women with breast cancer with Her2+ subtypes in whom nearly 40% of women will develop this dreaded and life-threatening complication. What are the potential clinical applications, benefits, and risks? Worryingly, breast-to-brain metastases are increasingly a first site of relapse even while their extra-cranial disease is under control. While patients are living longer from the success of new systemic therapies, a new frontier has been unmasked, which is breast cancer spread to the brain. This clinical scenario is terrifying and worsened by the fact that we have no good treatment options to offer other than brain surgery and radiation. Improving upon this clinical problem for women with advanced breast cancer will affect both how long they live and how well they live from a quality of life perspective. The brain is the most complex biological system, which poses unique obstacles but also harbors opportunities for discovery. Much of what we know about the brain microenvironment comes from neuroscience. We hypothesize that the cellular responses in neurodevelopment and neuronal connectivity may guide us towards new perspectives in understanding how Her2+ breast cancer cells communicate with brain cells to form metastases and drug resistance. Our previous research established that the physiologic microenvironment of the brain must become a tumor-favorable microenvironment for successful metastatic colonization by breast cancer cells. We further show breast to brain metastases display similar characteristics to brain cells and then can utilize the molecule GABA as a biological fuel for energy. Among these characteristics, a brain protein, Reelin, was found to have direct association with Her2 on breast to brain metastatic cells. Our current results, utilizing Reelin-deficient mice, show that breast cancer cells do not metastasize to the brain. Furthermore, when patient-derived Her2+ breast to brain metastatic cells are given Reelin, they have an increase resistance to Her2 directed agents, e.g., Herceptin. Therefore, it may be during this critical time period when tumor cells will likely "hijack" the brain s milieu and form communicative dialogue with endogenous brain cells in order to gain proliferative advantage and resistance. Therefore, successful future therapy for brain metastases should target both the breast cancer cells and the microenvironment that facilitates tumor cell growth and resistances. Accordingly, this proposal will be clinical beneficial by developing a targeted therapy that crosses the blood-brain barrier to inhibit the mutual interaction of Her2 on breast cancer cells and brain-derived Reelin, thus reducing limiting the risk or off-target effects for breast cancer patient treatment. What is the projected time it may take to achieve a patient-related outcome? Through the preclinical studies we will conduct, we will lay the foundation to motive and guide a Phase I clinical trial for a small molecule inhibitor targeting Reelin-Her2 interaction. This milestone of completing the preclinical work will be completed during the tenure of this grant (3 years). What is the likely impact of this study on ending breast cancer? Breast cancer cells that successfully metastasize to the brain may represent a subpopulation of tumor cells that best mimic brain cells and adapt to the resources available in the brain s microenvironment
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510426
Entities
People
- Yousha Neman
Organizations
- United States Army
- University of Southern California