Research
New Methods to protect cancer patients' hearing
Dr. Mukherjea files patents for two methods
It’s tough to ask cancer patients to choose between shrinking cancer tumors and keeping their hearing. Cisplatin, a widely used cancer drug, kills the cancer cells but also damages normal cells, leading to common side effects that include ototoxicity (hearing loss) as well as nephrotoxicity (kidney damage) and peripheral neuropathy (loss of touch sensation). Currently, no FDA approved therapies exist to treat the hearing loss.
Debashree Mukherjea, Ph.D., Research Assistant professor, Department of Surgery, Division of Otolaryngology, has been studying the biochemical basis of chemotherapeutic drugs and noise-induced hearing loss. She received a two-year NIH grant from the National Institute on Deafness and other Communication Diseases for her project “Amelioration of Cisplatin Ototoxicity by Transplatin.”
Transplatin is a trans isomer (an inactive isomer) of cisplatin, considered clinically inactive against tumors and relatively non-toxic. In a landmark finding, Dr. Mukherjea has found that transplatin actually protects hearing from cisplatin ototoxicity when injected directly into the ear drum immediately prior to cisplatin chemotherapy. Dr. Mukherjea has also found that systemic injection of transplatin with cisplatin has protective effects on kidney damage. Ongoing testing for systemic use is being evaluated to ensure that co-administration of transplatin will not interfere with the ability of cisplatin to destroy cancer cells.
In a second novel finding, Dr. Mukherjea has found that injecting short interfering siRNA (a class of double-stranded RNA molecules) directly into the ear drum can also prevent cisplatininduced hearing loss. Specific custom-made siRNA sequences silence genes like NOX3 (cochlear specific ROS generating NADPH oxidase enzyme) and the transient receptor potential vanilloid 1 (TRPV1) channel (responsible for increase in Calcium release, ROS generation and cisplatin entry) respectively. Increasing one or both of these molecules causes generation of free radicals at toxic levels in the ear. As such, cisplatin increases both NOX3 and TRPV1 significantly. Stopping the generation of free radicals by siRNA treatment decreases the hearing loss caused by cisplatin. This method could also be applied to other platinum-containing anti-tumor drugs, aminoglycoside antibiotics, and perhaps even noise-induced hearing loss.
Patents have been filed for both methods, and clinical trials are being planned. Dr. Mukherjea hopes to help all cancer survivors, especially the pediatric population 6-18 months old. For these babies already battling cancer, hearing loss is especially traumatic, affecting speech, social, and cognitive development. These novel methods may mean that patients may be able to increase their dosage of cisplatin to wipe out cancer without the dose-limiting side effects.