In the largest group of results to date, researchers from Penn Medicine's Abramson Cancer Center and other institutions announced that they have shown in clinical trials that the malaria drug hydroxychloroquine (HCQ) blocked autophagy in a host of aggressive cancers—glioblastoma, melanoma, lymphoma and myeloma, renal and colon cancers—and in some cases helped stabilize disease. Autophagy—an essential process cancer cells need to fuel their growth—is a key troublemaker spurring tumor growth. According to the researchers, many preclinical studies suggest that blocking this pathway allows anti-cancer agents such as chemotherapy and radiation therapy to be able to do their job better.

Results of six trials—five in humans (with over 200 patients) and one in dogs—were all reported in the May online issue of Autophagy, and were presented at the Keystone Symposia on Autophagy in Austin, TX, by author Ravi K. Amaravadi, MD, Assistant Professor of Medicine in the division of Hematology/Oncology at the Perelman School of Medicine and co-leader of the Cancer Therapeutics Program at Penn Medicine's Abramson Cancer Center, who was the principal investigator on four of the six trials, which included a multi-disciplinary team of investigators at Penn Medicine and other institutions treating a wide range of cancers.

“There are currently over 40 clinical trials involving HCQ as a potential autophagy inhibitor worldwide, and the results of our trials are among the first to be published,” said Dr. Amaravadi. “These studies provide promising evidence that autophagy blockade can be achieved, and that combining autophagy inhibitors with other cancer therapies in very sick patients can be accomplished safely in most cases. We wanted to present the data for all of these trials at one time, because when presented side by side, a more comprehensive and synergistic understanding of the potential of blocking this pathway emerges.”

The Phase I and Phase I/II trials aimed to measure the safety of adding HCQ to either chemotherapy, radiation therapy or targeted therapies, its effectiveness at inhibiting autophagy,  and the potential clinical benefit of HCQ combination therapies.

In melanoma, researchers observed prolonged stable disease in 20 percent of the patients on temozolomide. While in another trial, researchers observed stable disease in 75 percent of patients with metastatic melanoma on temsirolimus. In the dog clinical trial, all 30 dogs with non-Hodgkin's lymphoma treated with HCQ and the standard chemotherapy doxorubicin had clinical benefit, and nine had complete remission.

Autophagy is a relatively new target in cancer, infectious disease and neurodegenerative disorders, and while advances in the fundamental understanding of autophagy are increasing at a breakneck speed, translation of these advances into clinical trials and clinical benefit has been lagging. More recently, HCQ has shown promise in treating pancreatic cancer patients in ongoing clinical trials; however, its tolerability and effectiveness to stop autophagy in humans with other cancers has not been shown before.