New data describes how an experimental drug can stop the debilitating and life-threatening adverse effect cachexia commonly associated with advanced cancers and restore muscle health. The experimental agent, currently known as AR-42, was developed and tested in preclinical studies, the results of which were described in the Journal of the National Cancer Institute (doi:10.1093/jnci/djv274).
AR-42 is an histone deacetylase (HDAC) inhibitor, a class of drugs designed to block proteins that play a key role in mediating skeletal muscle breakdown. In patients with cancer, HDAC proteins also tend to drive pathways in cancer cells that lead to aggressive disease. AR-42 is unique among HDAC inhibitors because it appears to have beneficial effects on muscle health and function, according to this new research from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
In this preclinical study, Tanios Bekaii-Saab, MD, and colleagues report data illustrating that orally administered AR-42 can significantly preserve body weight and prolong survival while simultaneously preventing loss of muscle and fat tissue mass and preserving the health/strength of muscle.
Bekaii-Saab explained that most patients with advanced cancer experience significant loss of muscle mass as a result of their disease at some point during treatment, a condition clinically known as cachexia. The condition most commonly occurs with pancreatic and gastrointestinal cancers. Cachexia is severe enough to impact patients’ ability to tolerate treatment in up to 80% of cases. The molecular mechanisms behind why this occurs are not well understood, therefore, good intervention strategies to reverse its effects are not currently available.
Approximately one-third of patients with pancreatic cancer die from the effects of cachexia, not their cancer. “Finding better intervention strategies for the condition is critical so we can keep our patients strong enough to tolerate the cancer treatments necessary to give them the best chances of eradicating their cancer,” said Bekaii-Saab, GI-oncology section chief.
AR-42 was developed in the laboratory of Ching-Shih Chen, PhD, a professor and scientist with the OSUCCC – James Molecular Carcinogenesis and Chemoprevention research program.
For this study, researchers evaluated AR-42 against 2 other HDAC inhibitors, vorinostat and romidepsin, to determine each agent’s ability to prevent cachexia. The researchers used metabolomic profiling to evaluate the pathways involved in muscle changes that lead to cachexia as well as other advanced molecular testing. AR-42 was the only agent shown to have a strong protective effect against tumor-associated muscle wasting. These findings were confirmed in a second preclinical model.
“These new findings show that AR-42 can preserve muscle and every aspect of its functionality, which is an important step in refining potential methods of stopping cancer cachexia,” said Chen.
Researchers expect to begin evaluating AR-42 in human pancreatic cancer clinical trials within a year. Funding support for this work comes from the Lucius A. Wing Endowed Chair Fund, Cure for Pancreatic Cancer Philanthropic Fund, and a pancreatic cancer research grant from The Ohio State University Wexner Medical Center and OSUCCC – James.