Interdisciplinary Initiatives Program Round 11 - 2022
Project Investigators:
Julien Sage, Pediatrics (Hematology/Oncology) and Genetics
Anca Pasca, Pediatrics (Neonatology)
Jon Park, Neurosurgery
Abstract:
Metastases are a major cause of death in cancer patients. In particular, an estimated 30-40% of all cancer patients in the United States develop brain metastases, often from primary lung or breast tumors. These brain metastases are a major cause of morbidity and mortality. Here we propose to investigate brain metastasis using small cell lung cancer (SCLC) as a model. SCLC is a subtype of lung cancer that causes ~250,000 deaths worldwide each year. SCLC grows quickly and is highly metastatic, with ~70% of patients presenting with metastatic disease at the time of first diagnosis. Metastatic SCLC is managed with conventional chemotherapy along with immunotherapy, but most patients relapse rapidly and survival rates for metastatic SCLC have remained virtually unchanged for the past 30 years, with a 5-year overall survival below 2%. ~15-20% of the patients with SCLC have detectable brain metastases at the time of first diagnosis, and the incidence of such metastases increases to 40-70% during the course of the disease. These metastases have debilitating effects and fatal consequences, but the only treatment thus far is prophylactic brain irradiation, which also has strong side effects in patients.
In general, the lack of pre-clinical models for brain metastasis and, in many cases, the exclusion of patients with brain metastases from clinical trials, have impaired our understanding of the process of brain metastasis and have limited the development of better therapies. Here, we propose a new collaborative effort between three groups to develop new pre-clinical models to investigate the molecular and cellular underpinnings of the striking ability of cancer cells to form brain metastases. First, we will create 3-dimensional human “mini-brains” to determine how cancer cells functionally interact with human brain cells. These “mini-brains” (also known as “organoids”) resemble a normal developing human brain but are grown in tissue culture plates from stem cells; they have been used to study developmental brain disorders mostly, but we will repurpose them to study brain metastasis. We will also develop new mouse models to identify in vivo mechanisms of brain metastasis, including by direct injection of cancer cells in the carotid artery so they can directly go to the brain of recipient mice. Finally, we will engineer a model of the blood-brain barrier on microchips. The blood-brain barrier normally prevents unwanted cells from penetrating the brain; this process is disrupted in cancer but has been difficult to study, and we will use this new engineered platform to investigate how SCLC cells enter the brain. These new preclinical models for brain metastasis will allow us to test candidate mechanisms, which hopefully will result in the development of new strategies to block the formation of brain metastases and inhibit the growth of brain metastases that are already present in the brain of patients.
