Novel Combination Therapy Targeting Growth Factor Receptor Cross Talk with Epitranscriptomic Regulation in Glioblastoma
Abstract
Brain tumors represent severe challenges in clinical oncology. Among all brain tumors, glioblastomas are the most prevalent malignant brain tumor that originates in the brain itself. Despite decades of research, glioblastomas remain universally fatal, with current treatments offering only palliation. Veterans and members of the armed services with brain cancer suffer worse outcomes than the general population. We are dedicated to improving the outcomes of patients afflicted with brain tumors using novel scientific techniques, directions, and therapies. Precision Medicine, or Personalized Medicine, combines genetic testing with other patient and cancer data to direct optimal care. Our studies will inform the development of improved Precision Medicine approaches for glioblastoma patients: the right patient, the right drug, the right dose, the right route, and the right time. These efforts will provide the basis for the development of clinical trials to which patients, including members of the Armed Forces, which may improve the performance status and survival of brain tumor patients. We anticipate that these studies will also identify biomarkers, which allow for patients to be selected for specific therapies and monitor their efficacy. Biomarkers are essential for improved patient selection to avoid treating patients with ineffective drugs and identification of early treatment failure. Eventual downstream deliverables of our studies could be applied to noninvasive imaging and metabolic monitoring. Our proposed studies will focus on laying the foundation for clinical trials based on novel paradigms. Thus, the goals of this project are aligned with the fiscal year 2022 Peer Reviewed Cancer Research Program Overarching Challenges to: (1) Transform cancer treatment through the identification of new targets, especially for advanced disease. (2) Identify and elucidate the mechanisms behind cancer epigenetics/genetics and cancer development to improve treatment methods. Glioblastomas contain highly malignant tumor cells that replicate features of normal stem cells. These cancer stem cells contribute to the aggressiveness of brain tumors through their resistance to radiation and chemotherapy, ability to promote growth of new blood vessels to feed the tumor, evasion of the antitumor immune responses, and invasion into normal brain to prevent surgical removal. Designing new treatments that attack cancer stem cells, but not normal stem cells, could allow patients to survive longer and better. We generate cancer stem cells from the surgical biopsy samples from patients afflicted with glioblastoma. We are studying how the mechanisms by which these cancer stem cells are maintained. Cancer cells receive signals from their environment called growth factors. These growth factors and their receptors have served as targets for cancer therapies, but glioblastomas have been relatively resistant to these treatments. We find that these growth factor pathways regulate tumor cells through modifying RNA, which bridges DNA and proteins. As a result, cancer cells regulate their metabolism to survive stressful conditions. Using combinations of drugs against each of these targets, we predict that we will be able to specifically kill the cancer stem cells. Based on this background, we will extensively study these pathways and the dependency of cancer and normal cells to lay the foundation for clinical trials with brain cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310689
Entities
People
- Jeremy Rich
Organizations
- United States Army