Researchers at the Barbara Ann Karmanos Cancer Institute have seen pre-clinical activity of a cancer metabolism drug that has now entered Phase I clinical trials. This clinical trial will study the combination of chemoradiation to treat locally advanced and surgically inoperable pancreatic cancer.
The drug is called CPI-613® (devimistat), developed by Cornerstone Pharmaceuticals (Cranbury, New Jersey). Devimistat is a particular class of anti-mitochondrial drug that inhibits the tri-carboxylic acid cycle by working on enzymes involved with cancer cell energy metabolism. Devimistat can be given at lower doses and presents fewer side effects. In combination with gemcitabine and intensity-modulated radiation (Gem-RT) therapy, the ongoing Phase I will investigate the maximum dose of devimistat that can be safely given to pancreatic cancer patients. Currently, two patients are enrolled in this trial.
This open-label, dose-escalation study will be conducted at the Medical College of Wisconsin (MCW) in Milwaukee. The translation study done by researchers at Karmanos was in partnership with former Karmanos and Wayne State University (WSU) fellow Mandana Kamgar, M.D., principal investigator of the devimistat Phase I clinical trial.
“Pancreatic cancer is a deadly disease without effective drugs. Chemo and radioresistance continue to be an overwhelming obstacle to effective pancreatic cancer treatment,” explained Asfar Azmi, Ph.D., leader of the Molecular Therapeutics (MT) Research Program, director of the Pancreas Cancer Research Initiative at Karmanos and associate professor at Wayne State University School of Medicine.
“Emerging evidence supports the model that metabolic reprogramming and mitochondrial metabolism allow malignant cells to adapt to conventional therapies. Carbohydrates are a preferred energy source in tumor cells, and the tumor microenvironment generally favors glycolysis and oxidative phosphorylation (OXPHOS). A shift in mitochondrial energetics towards high OXPHOS has recently been shown to confer pancreatic cancer resistance to gemcitabine, a commonly used chemotherapy. Enhanced mitochondrial respiration modulates known radioresistance pathways, including cell-cycle checkpoint mechanisms, DNA repair processes and redox balance. These observations strongly suggest that selective inhibition of hyperactive mitochondrial metabolism can be used to potentiate current chemo and radio-based treatments against pancreatic cancer.”
“Our pre-clinical studies in cellular and 3D models demonstrate that devimistat can favorably re-wire the altered tumor metabolism to make pancreatic tumors sensitive to chemoradiation therapy. This combination is anticipated to enhance the efficacy of chemoradiation and improve survival outcomes of patients with deadly and by-far incurable pancreatic cancer,” concluded Dr. Azmi.
Team members at Karmanos who continue to work on this study are Dr. Husain Yar Khan, research scientist in the Department of Oncology at WSU School of Medicine, and Dr. Jessica Back, member of the Tumor Biology and Microenvironment Research Program at Karmanos, associate director of Molecular Imaging and Cytometry Core (MICR) and assistant professor of oncology, WSU School of Medicine. Pre-clinical metabolomic studies were supported by a collaboration with Dr. Jing Li, member of the MT Research Program, director of Pharmacology and Core at Karmanos Cancer Institute and professor of oncology at WSU School of Medicine.
Dr. Azmi’s team is leading the correlatives research on biopsies from the trials and hopes to obtain a federal grant to investigate further the future clinical use of devimistat and chemoradiation in pancreatic cancer.