Leptomeningeal Metastases of Breast Cancer: Toward New Therapies
Abstract
Leptomeningeal metastases (LM) are metastases on the linings of the brain and spinal cord or floating in the cerebrospinal fluid (CSF) that bathes them. At a recent Food and Drug Administration think tank on LM of breast cancer, I was struck by how much we don’t know and how devastating this disease is. We know that breast cancer is the largest source of solid tumor LM and that it is difficult to diagnose. We know that intrathecal (IT) chemotherapy with drugs rarely used in breast cancer (methotrexate, cytarabine) is the standard of care; and they produce an initial response that is short-lived and patients die rapidly from LM disease. Few clinical trials are open for LM. With a 10-year history in brain metastasis research, my lab is poised to make inroads. A robust research effort needs multiple mouse model systems of LM, which are scant in the literature. Preliminary data indicate that three of my brain metastasis models have LM. I will make other models that are LM-only by injecting tumor cells IT. With multiple LM models, I will go in two directions: First, the models will be profiled by RNA sequencing to identify what drives LM: Mutations? Over- or under-expression of a gene? An entire pathway? Model data will be supplemented with similarly analyzed human LM specimens. These data will permit us to perform functional experiments to determine what event or pathway actually causes LM progression. Moreover, we have access to the CSF that bathes the leptomeninges via Ommaya reservoirs in the human, modeled by IT delivery in the mouse. I hypothesize that IT delivery of drugs impacting the functional LM pathways can prevent or treat LM preclinically. I will set up prevention and treatment preclinical experiments using IT drug delivery. Second, I will use my models to explore immunology approaches to treating LM. The leptomeninges are infiltrated with immune cells at higher levels than the brain. My preclinical work has shown immune infiltration, mostly suppressive immune cells, into the brain and leptomeninges of brain metastatic mice. This work will be expanded to the LM models and human samples. I hypothesize that an immune checkpoint inhibitor, anti-PD-1/PD-L1, will have benefit in a LM prevention and/or treatment model systems when given both systemically and IT. If any of these preclinical experiments show a benefit, the National Cancer Institute is poised to open a new clinical trial based on the work. The Women’s Malignancies Branch is establishing a central nervous system (CNS) metastasis clinical program with a secondary brain metastasis trial open, and other prevention and treatment trials under development. A LM trial would fit into this portfolio of novel trials. Funding for the trials is available in the Intramural Program pending scientific and Institutional Review Board (IRB) approvals. Because of established agreements, we can also open trials at the Walter Reed National Military Medical Center, which has a young and racially diverse patient population. The time course of a trial would be limited by recruitment of patients, which are somewhat rare, but an estimate of 2-3 years would be reasonable. Depending on whether this is a prevention or treatment trial, the patient populations would differ; LM patients would be enrolled in a treatment trial while one could envision recurrent brain metastasis patients in a LM prevention trial. This trial aims to prevent or treat one very lethal aspect of it. There are interim outcomes that are also important. My lab has published five brain metastasis model systems and sent them out to >50 labs, jumpstarting the research field. I can do this again for LM. The RNA seq and immune databases will be publicly available for others to use for hypothesis development, again moving the field. The trial designs can be adapted elsewhere. This project addresses three aspects of the Breast Cancer Landscape: Identify why some breast cancers beco
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810737
Entities
People
- Patricia Steeg
Organizations
- National Cancer Institute
- United States Army