Overcoming Radiation Resistance in DIPG: A Novel Therapy to Block Macrophage Activation
Abstract
The Scientific Objective and Rationale for the Proposed Project: The objective of this project is to test a new drug, known as 2P-Im, that has been designed specifically to improve the response to cancer therapy by targeting immune cells often found growing with cancer cells. More specifically, the drug under development is a very potent suppressor of a population of immune cells known as myeloid cells, and a specific type known as macrophages. These cell populations, which exist in normal brain tissue and are also recruited from bone marrow, are known to promote the growth of brain cancer cells and to protect them from the effects of radiation. This application is focused on a particularly lethal subtype of high grade glioma (HGG) that primarily affects children. This HGG, known as diffuse intrinsic pontine glioma (DIPG), affects less than 300 patients annually, but is uniformly fatal. Macrophages are abundant in DIPG and are known to limit the ability of radiation to cure this cancer. We aim to prove that administration of 2P-Im as a dietary supplement will enhance the radiation response of DIPG through mechanisms that include suppression of macrophage recruitment into the DIPG environment. The Fiscal Year 2021 (FY21) Rare Cancers Research Program (RCRP) Focus Area(s) the Project Addresses: This proposal addresses two of the three FY21 RCRP Focus Areas, including Biology and Etiology and Therapy, with a main emphasis on determining the therapeutic benefit of a novel strategy for targeting a population of immune cells that contribute to treatment resistance in brain tumors in general, but specifically in the rare childhood cancer known as DIPG. These immune cells, known as myeloid cells, become very abundant within brain tumors after they are exposed to radiation, which is an important part of the therapy for every brain tumor. If successful, this effort will reveal a potential new strategy to block these immune cells and improve the response to radiation therapy. The Ultimate Applicability of the Research The types of patients will this research help and how it will help them. An important outcome of this work will be the identification of a new therapy for the treatment of a rare childhood brain cancer known as DIPG. The only known therapy for this disease is radiation therapy, but the response to radiation if limited. A new therapy that enhances response to radiation can significantly improve survival, not only for children with DIPG, but for many other patients affected by brain tumors, the majority of whom will receive radiation as part of their therapy. The potential clinical applications, interim outcomes expected and their applicability to the field. It is now widely accepted that certain immune cells, known as macrophages, populate many tumors and may complicate the response to cancer therapy. In particular, macrophages and the factors they produce are responsible for both therapy resistance and therapy-related toxicity. This is particularly true for radiation therapy. Therefore, any new drug that has the ability to block the accumulation and activity of macrophages may enhance the response to radiation and reduce the harmful effects of radiation on normal tissue. Such a benefit will not only improve the lives of children receiving radiation treatment for cancer, but will also be useful for adult patients who require radiation to cure their disease. The immediate outcome of this work will be a demonstration that 2P-Im can directly impact the growth of the rare pediatric brain tumor known as DIPG and block the accumulation of macrophages in the brains of mice undergoing radiation treatment. The projected time anticipated to achieve a clinically relevant outcome. There is a potential for accelerated clinical development of 2P-Im, particularly as an earlier generation of this class of drugs has already advanced successfully through large, multi-center clinical trials for non-cancer ind
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210787
Entities
People
- John Letterio
Organizations
- Case Western Reserve University
- United States Army