Posted February 10, 2023

Rahul Jandial, M.D., Ph.D., City of Hope Beckman Research Institute

Leptomeningeal carcinomatosis (LC) is an aggressive, life-threatening disease that develops when cancer cells spread to the cerebrospinal fluid-containing leptomeninges (tissues that surround the brain and spinal cord). Metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer remains the most common origin of this serious complication of cancer, and to date, clinically validated and effective treatments are scarce, causing HER2+ breast LC (HER2+ LC) to be deemed incurable. Dr. Rahul Jandial at the City of Hope Beckman Research Institute has developed novel HER2+ LC patient-derived cell lines (termed "Lepto" cell lines) and xenograft animal models to study this disease and identify potential therapeutic targets.

With support from a Fiscal Year 2018 Breast Cancer Research Program Breakthrough Award - Funding Level 2, Dr. Jandial and his team investigated the molecular mechanisms and interactions with various central nervous system cell types potentially involved in the development of LC using their uniquely developed in vitro and in vivo models of HER2+ LC. Cytokine analyses demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) is a significant promoter of Lepto cell growth through autocrine signaling (a secreted signal from a cell that binds to the same cell). Furthermore, animals co-implanted with Lepto cells and oligodendrocyte progenitor cells (OPC), which are abundant in white matter, had significantly diminished tumor growth and extended survival compared to the controls, due to OPC-induced apoptosis and decreased viability of the Lepto cells. His laboratory determined that the mechanism by which OPC inhibited Lepto cell growth was via the OPC-derived protein TPP1, which degrades GM-CSF and thus decreases its expression. Collectively, these findings suggest that targeting GM-CSF could represent a potential therapeutic strategy. To further investigate this, the team performed a compound screening, which identified a pan-Aurora kinase compound that inhibited Lepto cell viability and also induced apoptosis. Additionally, animals given combination treatment of the identified pan-Aurora kinase inhibitor and anti-GM-CSF neutralizing antibodies had significantly decreased tumor progression compared to the controls or those that received individual treatments, due to synergistic inhibition of GM-CSF.

Overall, the results presented in this study provide important insights into potential drivers behind the pathophysiology of this aggressive disease. Dr. Jandial and his team have demonstrated that the GM-CSF pathway may potentially be exploited for targeted therapy to inhibit growth of LC from HER2+ breast cancer. Ultimately, this work has potential to support the future development of treatments that could improve quality of life as well as survival for patients with LC from HER2+ breast cancer.

Publication:

Ansari K, Bhan A, Saotome M, et al. 2021. Autocrine GMCSF signaling contributes to growth of HER2+ breast leptomeningeal carcinomatosis. Cancer Research 81(18):4723-4735. doi: 10.1158/0008-5472.CAN-21-0259

Links:

Public and Technical Abstracts: Local GM-CSFR Blockade to Improve Outcome in Leptomeningeal Disease from Breast Cancer

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