In their next experiments, the team administered chloroquine to several different pancreatic cancer cell cultures, and also tested its effects in three types of mouse models. In the laboratory cultures, they reported, the drug “markedly decreased” the growth of the tumor cells, showing that the cells were heavily dependent on autophagy to for continued growth.
In vivo testing involved three types of mouse models – human pancreatic cancer cells placed under the rodents’ skin (xenografts); human cells injected into the animals’ pancreases (orthotopic transplants); and a genetic model (mice bioengineered to develop native pancreatic tumors).
The response to chloroquine was “profound” in the xenograft models, Kimmelman said: All eight untreated mice died of their cancer within 140 days, while only one of eight treated mice had died by 180 days.
The drug’s effects were less dramatic but still impressive in the orthotopic and genetic mouse models, the researchers said. The tumors that developed in the genetically pancreatic cancer-prone mice were, like their equivalent in human patients, extremely resistant to all treatments. Among other properties, these tumors were embedded in tough, fibrous tissue that is difficult for drugs to penetrate.
Nevertheless, the scientists reported that chloroquine treatment as a single agent increased the rodents’ survival by 27 days compared with untreated control mice. This is encouraging, Kimmelman commented, because even the newest targeted drugs aimed at pancreatic cancer “don’t have much effect in this genetic mouse model.”
The Dana-Farber trial of hydroxychloroquine, led by Kimmelman and oncologist Brian Wolpin, MD, is designed to enroll 36 pancreatic cancer patients in whom first- or second-line treatments have failed. The drug is taken in pill form twice a day. Results won’t become available for at least a year, said Kimmelman.
Kimmelman said the next step will be to investigate the combination of hydroxychloroquine with radiation in patients with operable pancreatic cancer.
“This is a very interesting and promising approach, attacking the Achilles’ heel in pancreatic cancer’s defenses,” commented Robert Mayer, MD, of Dana-Farber’s Center for Gastrointestinal Oncology. “But it’s too early to say whether hydroxychloroquine should be added to chemotherapy, and what the risks and benefits might be, so we want to examine it in a clinical trial.”
Kimmelman’s lab is also investigating other forms of cancer that might be good candidates for inhibition of autophagy by the drug. He said that their work, as well as recent findings from other labs, suggests that those cancers may be ones that are primarily driven by the KRAS oncogene – as nearly all pancreatic tumors are.
Kimmelman, who also is an assistant professor of radiation oncology at Harvard Medical School, is the senior author of the publication. First author is Shenghong Yang, PhD, a member of the Kimmelman lab. Other authors are from Dana-Farber, Massachusetts General Hospital, Harvard Medical School, Boston University, and scientists from Italy and Germany.
Funding was provided by Dana-Farber, the Friends of Dana-Farber Cancer Institute, the Sidney Kimmel Foundation, and the AACR-Pancreatic Cancer Action Network.
Dana-Farber Cancer Institute (http://www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute. It provides adult cancer care with Brigham and Women’s Hospital as Dana-Farber/Brigham and Women’s Cancer Center and it provides pediatric care with Children’s Hospital Boston as Dana-Farber/Children’s Hospital Cancer Center. Dana-Farber is the top ranked cancer center in New England, according to U.S. News & World Report, and one of the largest recipients among independent hospitals of National Cancer Institute and National Institutes of Health grant funding.
Contact: Bill Schaller
Dana-Farber Cancer Institute