A Novel Agent Targeting Microglial Activation Induced by Therapeutic Brain Irradiation
Abstract
The Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Topic Area(s) to be addressed by the research project. This proposal is focused on the evaluation of a new drug which suppresses inflammatory molecules that are produced by the body in response to radiation. The lead drug under development (referred to as CDD0-2P-Im, or 2P-Im) has been shown to improve the body s response to oxidative stress and injury. The immediate goal of this proposal is to show how oral administration of this drug in mice will block the brain tissue damage triggered by immune cell activation and inflammation following therapeutic irradiation (IR) of the brain. The use of IR is often essential in the context of treatment for both primary and metastatic cancer affecting the brain. However, the use of IR results in long-term neurocognitive deficits (such as loss of memory and reasoning skills) in both children and adults, adversely affecting their quality of life. Therefore, this proposal is highly relevant to several (FY21) PRCRP Topic Areas, including: brain cancer, pediatric brain tumors, pediatric, adolescent and young adult cancers, and metastatic cancers, specifically those affecting the brain and central nervous system. The Scientific Objective and Rationale for the Proposed Project: IR is an essential component in the standard of care for both children and adults diagnosed with brain tumors. However, the exposure to therapeutic doses of radiation is known to lead to devastating long-term complications for many patients, and particularly for survivors of childhood cancer. Many studies have documented these survivors experience significant intellectual deterioration, lower levels of educational attainment and social independence, and they are often dependent on caregivers for support. Similarly, adults undergoing therapeutic cranial radiation will lose brain function if large areas of the brain are in the radiation field. These survivors report memory loss, personality changes, and trouble concentrating and other symptoms that depend on the area of brain treated and how much radiation was given. There is now substantial evidence that these complications of IR are directly linked to the initiation of an inflammatory response in the brain within hours of radiation exposure that leads to long-term brain inflammation and loss of function. The therapeutic under development in this proposal has significant potential to prevent these complications or late effects triggered by the inflammatory response to IR. This new drug, 2P-Im, is representative of a novel class of molecules that are orally bioavailable, safe, non-toxic, and highly potent suppressors of the specific molecules known as chemokines that are responsible for recruiting immune cells into the radiation field. 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 Food and Drug Administration to acquire Investigational New Drug 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 the dose of 2P-Im required to prevent complications associated with brain radiation and provide a roadmap how 2P-Im can be administered to achieve clinical benefit. If successful, this new drug could be more broadly utilized to reduce radiation toxicity beyond the application in brain tumors. The FY21 PRCRP Overarching Challenge to be Addressed and How the Research Will Make an Impact: The proposed effort is designed specifically to develop a strategy that will mitigate risk for therapy-related toxicity in target populations that include individuals undergoing cranial IR for the treatment of primary brain tumors (both pediatric and adult) as well as metastatic cancers affecting the CNS.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210926
Entities
People
- John Letterio
Organizations
- Case Western Reserve University
- United States Army