Harnessing Artificial Intelligence to Overcome Liver Immune Tolerance
Abstract
The proposed research project is important and directly relevant to the fiscal year 2022 Peer Reviewed Cancer Research Program (PRCRP) Overarching Challenge; transform cancer treatment by identifying new targets, especially for advanced disease and metastasis, and advance immunotherapy across the different PRCRP Topic Areas. Metastases are responsible for as much as 90% of cancer-associated deaths. This is because we continue to struggle with how to develop drugs for metastatic cancers. Metastatic cancers occur when cancer cells spread from their organ of origin (called the primary cancer site) to another organ (called the secondary or metastatic site). Metastasis is exceptionally dangerous as it usually affects essential organs such as the liver. The destruction of these organs by metastases results in rapid decline and failure. Unfortunately, drugs that are effective in treating localized cancer – that is, cancer that is contained within the primary cancer site – usually show little efficacy in thwarting the same cancer at the secondary site. That is because the behavior of cancer cells and their response to therapy are influenced by the specific environment surrounding them, the tumor microenvironment (TME). The TME varies significantly between the primary and secondary sites. Consequently, the 5-year relative survival rate for localized colorectal cancer is 91%, while the survival rate for distant metastatic colorectal cancer is only 14%. Our goal is to change the statistics by inventing a new way to discover drugs for metastatic cancers. The TME of cancer significantly impacts the drug response, including the response to immunotherapy. However, standard strategies for discovering, screening, and testing drug effects for novel cancer drugs use cancer cells in isolation, ignoring the important role of the TME. These Petri-dish models lack the complexities of the human tissue microenvironment and are not reliable predictors of the physiological drug response. As a result, about 95% of all oncology drugs currently being developed will not pass through the Food and Drug Administration (FDA) approval process. In preliminary data, we have taken a bold and risky approach past this hurdle: We developed a novel method combining human tissue microenvironment, artificial intelligence, and chemical tools to reliably predict candidate drugs and their combinations that significantly improve the response to immunotherapy. Using this innovative strategy, we identified cabozantinib, an FDA-approved drug that restores the response to immunotherapy in metastatic liver tissues. This Idea Development Award aims to build a robust preclinical package around cabozantinib and be backed by a solid experimental rationale. Specifically, we will confirm the efficacy of a combination of cabozantinib with immunotherapy in the liver metastases mouse model and in metastatic liver tissues from patients. The successful outcome of this proposal would accelerate the clinical development of cabozantinib and could provide new therapeutic and safer options for the treatment of metastatic liver cancer, offering unprecedented hope to the providers and patients who currently face this disease with severely limited alternatives.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310542
Entities
People
- Taran Gujral
Organizations
- Fred Hutchinson Cancer Center
- United States Army