Human Oncology & Pathogenesis Program; Neurology
Memorial Sloan Kettering Cancer Center
As cancer cells spread throughout the body, or metastasize, they encounter environments vastly unlike those of the primary tumor. The membranes that contain the CSF and surround the brain and spinal cord, the leptomeninges, comprise a dedicated compartment that is anatomically isolated. Spread of cancer cells into the leptomeninges, or leptomeningeal metastasis, LM, is a bleak complication of cancer that is becoming more common. The mechanisms responsible for cancer cell entry into this space remain virtually unknown. As a result, current treatment strategies minimally alter the bleak clinical course. A hallmark of LM is a robust inflammatory infiltrate we hypothesize that cancer cells exploit innate immunity to gain entry into the leptomeningeal space. To address this hypothesis, we propose multi-modality iterative molecular profiling of patient samples to capture dynamic transcriptomal and microenvironmental changes coupled with hypothesis-driven mouse modeling to molecularly dissect the pathogenesis of LM. Our discovery process is rooted in clinical data, we uncover mechanism through mouse modeling and in vitro molecular biology. This approach leverages the strengths of each system to uncover clinically-relevant pathways that govern cancer cell entry into the leptomeninges. Our long-term research goal is to understand the molecular mechanisms that underlie cancer cell entry and growth within the leptomeningeal space, and interrupt these pharmacologically, to define novel, rational therapeutic strategies against LM.
Dr. Adrienne Boire is a physician-scientist at Memorial Sloan Kettering Cancer Center in New York. After undergraduate work in Biology at Macalester College, she earned a PhD in Biochemistry at Tufts University in 2004 and MD at the University of Chicago Pritzker School of Medicine in 2008. This was followed by residency in Neurology at Columbia Presbyterian Hospital and fellowship in Neuro-Oncology at Memorial Sloan Kettering Cancer Center. After post-doctoral fellowship under the guidance of Joan Massagué, she joined the Human Oncogenesis and Pathology Program at MSKCC as an assistant member in 2017. As a neuro-oncologist, Dr. Boire cares for patients with metastasis to the central nervous system (CNS) and conducts clinical trials targeting these tumors. As a scientist, she runs a laboratory-based research program focused on leptomeningeal metastasis. She has generated the first tractable mouse models of leptomeningeal metastasis, providing the first mechanistic insights into the molecular basis for leptomeningeal metastasis. Dr. Boire’s team identifies and targets cancer cell adaptations to the CNS microenvironment. Dr. Boire’s recent honors and awards include a Damon Runyon Clinical Investigator Award, a Vienna Medical Academy Award; she is also a Pew Biomedical Scholar.
Molecular Dissection of Innate Immunity in Leptomeningeal Metastasis
The spinal fluid surrounds and supports the brain and spinal cord. Leptomeningeal metastasis (LM), or spread of cancer cells into the spinal fluid, is a deadly complication of cancer. Little is understood about the mechanisms by which cancer cells gain entry into the spinal fluid. In the absence of cancer, there are few cells within this fluid. However, when cancer cells are present in the spinal fluid, many immune cells are also present. We hypothesize that cancer cells exploit these immune cells to unlock the gateway to the spinal fluid, a structure called the choroid plexus.
“The Pershing Square Sohn Prize will enable my team to uncover the molecular instructions that allow cancer cells to gain access to the spinal fluid. This information will enable us to zero in on this mechanism and inhibit leptomeningeal metastasis, a deadly complication of cancer.
More broadly, leptomeningeal metastasis has gone understudied for too long, because it was perceived to be an order-less product of end-stage cancer. The Pershing Square Sohn Prize represents hope in the face of this nihilism; it is a public declaration to patients with LM that the scientific community recognizes their plight, and is willing to take on this challenge.”
To discover the mechanism by which cancer cells might accomplish this, we will analyze spinal fluid collected from cancer patients during the course of diagnosis and treatment of LM. This analysis will enable us to identify key cells and molecules in this process. We will then turn to our mouse models of LM to determine how these key players work together to support cancer cell entry into the spinal fluid. The most important interactions will then be therapeutically targeted, to provide a novel approach for LM treatment.
“Innovation is intellectual courage: it is the creativity to see pattern where others see chaos, the boldness to follow one’s scientific intuition, and the audacity to change the discourse.”