Development of a Novel, CNS-Penetrant Synthetic Oleanane Triterpenoid for DIPG
Abstract
The FY22 PRCRP Topic Areas to be addressed by the research project. This proposal is focused on evaluation of a newly identified interaction between a novel drug candidate (known as 2P-Im) and an enzyme known as Cathepsin B, which plays a critical role in cancer progression and therapy resistance. This discovery is highly relevant to several FY22 PRCRP Topic Areas as Cathepsin B is now known to be activated in normal immune cells in patients exposed to radiation therapy (RT) and chemotherapy. The activation of Cathepsin B in normal cells contributes to treatment resistance and also underlies the complications of cancer therapy. Currently, RT is the only therapy approved by the Food and Drug Administration (FDA) for a rare childhood brain tumor known as Diffuse Intrinsic Pontine Glioma (DIPG, a FY22 PRCRP Topic Area). RT is also the standard of care for many other brain tumors, metastatic brain cancer, and other solid tumors, such as head and neck cancer (all of which are FY22 PRCRP Topic Areas). The scientific objective and rationale for the proposed project. There currently is no FDA-approved therapy that directly targets the Cathepsin B enzyme. We have made the serendipitous observation that a newly developed synthetic oleanane triterpenoid (SOT), known as 2P-Im, binds to the active site of Cathepsin B. Exposure to RT leads to induction of Cathepsin B activity in immune cells known as myeloid cells in the tumor microenvironment (TME). Thus, we propose to demonstrate the capacity of 2P-Im to directly inhibit Cathepsin B activity induced by RT, specifically in myeloid cell populations in the TME, and to determine whether this effect has the capacity to both enhance the response to RT and to reduce the risk for cancer recurrence following RT. We pursue these studies in models of DIPG, a childhood cancer for which resistance to radiation therapy is a significant challenge. How the results of this research will benefit patients and advance the field of cancer research. The drug (2P- Im) is now entering studies that are required by the FDA to acquire Investigational New Drug (IND) status, which will be an important step to create opportunities for patients including Veterans affected by cancer to participate in clinical trials. The data generated by this study will provide important information regarding both the mechanism of action of 2P-Im and the capacity of 2P-Im to overcome radiation resistance in a rare childhood brain tumor, DIPG. Given Cathepsin B has been linked to radiation toxicity, a successful effort will position 2P-Im for potential use in strategies to reduce adverse effects of radiation. The FY22 PRCRP Overarching Challenge to be addressed and how the research will make an impact. The objectives of this effort are highly relevant to two of the topic categories identified in the FY22 PRCRP Overarching Challenges: Therapeutics and Behavioral Science. 2P-Im has a unique potential to disrupt the activity of an enzyme or protein, known as Cathepsin B, which is turned on in non-cancer cells following exposure to radiation. These bystander cells, principally immune cells known as macrophages, may be chronically induced to produce Cathepsin B and other inflammatory proteins, which together increase the risk for cancer recurrence and treatment-related toxicity. This is of particular importance to the community of patients affected by brain tumors, for whom the exposure to RT leads to impairment of cognitive function and overall performance due to therapy-related neurotoxicity. A successful effort will advance a new drug with capacity to significantly improve quality of life by reducing effects of radiation on normal brain health while mitigating the risk for cancer recurrence. This proposal directly addresses the FY22 PRCRP Military Health Focus Area Gaps in cancer research that may affect mission readiness. Specifically, the proposed research is focused on development of a novel drug des
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310946
Entities
People
- John Letterio
Organizations
- Case Western Reserve University
- United States Army