Targeting Creatine Kinase Brain Isoform (CKB) to Inhibit Brain and Bone Metastasis
Abstract
Overarching Challenges: This Breakthrough Funding Level 2 proposal will: (1) identify why some breast cancers become metastatic, (2) eliminate mortality associated with metastatic breast cancer (MBC), and (3) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. Rationale: The overall survival (OS) rate of patients diagnosed with MBC remains dismal. Breast cancer deaths are due to spread (metastasis), then growth, of tumor cells that left the breast to seed and grow in distant organs. Therefore, to improve survival rates, cancer researchers must refocus our efforts on finding safe, effective and specific targeted drug therapies to block the pathways in the tumor that drive metastasis and to stop metastatic tumor cells from surviving and/or growing. Researchers must also strive to test promising new therapies in the most appropriate animal (preclinical) models available, using only those breast tumor models in the laboratory setting that consistently spread to, then grow in, the same organs in mice as in patients. Rigorously proving anticancer efficacy in animals that develop relevant sites of metastasis is needed before initiating new clinical trials and enrolling breast cancer patients, in order to improve likelihood of drug success and ultimately, U.S. Food and Drug Administration (FDA) approval. Types of Patients, or At-Risk Individuals, Research Will Help: • Patients with triple-negative breast cancer (TNBC), who have limited treatment options except general cell killing (cytotoxic) chemotherapies, such as Taxol or Adriamycin (doxorubicin). Patients developing resistance to these drugs is common; different strategies are needed to stop cancer growth again. • Patients with metastasis to brain and to bone since anti-creatine kinase pathway targeting drugs, like cyclocreatine (older generation agent), and like RGX-202-01 (a new agent, made by Inspirna), cross the blood-brain barrier and cyclocreatine can prevent bone loss in rodents in the non-cancer setting. The bone data suggest that creatine kinase inhibitors could attack bone-destroying breast cancer cells, helping patients with osteolytic breast cancer. • All patients with breast tumors that express the biomarker (creatine kinase CK, brain isoform, or CK brain isoform CKB). • Cancer patients diagnosed with other cancer types that also express CKB (glioma, colon cancer, pancreatic cancer, ovarian cancer, prostate cancer). Potential Clinical Applications, Benefits and Risks, and Potential Breakthroughs Relevant to Mission of Ending Breast Cancer: • Efficacy of anti-creatine kinase agents (like cCr and RGX-202-01) appears to be most potent for blocking metastasis, which is the stage of cancer that kills breast cancer patients, although these drugs also prevent primary tumor cell growth. • RGX-202-01 is made for pill form, and is already in early clinical trials, to be taken by mouth twice per day. • RGX-202-01 is reported to be well-tolerated in early phase clinical trials, and since RGX-202-01 is made into pill form, this dosing route avoids the need for intravenous (IV) infusion in a clinic. These features lower the risks of treatment-induced adverse reactions for patients. • Combination of an anti-CK agent, like RGX-202-01, with conventional chemotherapies, like Taxol or doxorubicin, seems to be more effective in breast cancer cells than either drug alone, potentially allowing the dose of Taxol or doxorubicin to be lowered. These two drugs have known adverse side effects and also require IV infusion (Taxol: dose-dependent risk of peripheral neuropathy, or nerve numbness/burning/pain; and doxorubicin: dose-limiting cardiotoxicity, or the risk of future heart failure). • Understanding how CKB and anti-creatine kinase pathway drugs work to inhibit metastasis (i.e., which genes/proteins predict if a CKB+ tumor will respond well to therapy) may be useful to identify those patient
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310091
Entities
People
- Tiffany N Seagroves
Organizations
- United States Army
- University of Tennessee Health Science Center