The same biochemical triggers that spur a "fight or flight" response when we encounter threats may help tumor cells to thrive. A team of researchers from Roswell Park Comprehensive Cancer Center is looking at ways to disrupt that dynamic so that cancer treatments can be more effective. Their latest work, published today in Clinical Cancer Research, a journal of the American Association for Cancer Research, suggests that a drug widely prescribed to control blood pressure may improve patients' response to cancer immunotherapy.
The new publication reports results from the first prospective clinical trial to show that the beta-blocker propranolol is safe in combination with pembrolizumab, an immunotherapy also known as Keytruda that has become standard therapy for patients newly diagnosed with advanced or metastatic melanoma. The researchers also document preliminary evidence that these two drugs work together to engage the immune system against tumor cells.
We know that stress can have a significant negative effects on health, but the extent to which stress may impact the outcome of cancer therapy is not well understood at all. So building on the compelling preclinical work of our colleague Dr. Elizabeth Repasky documenting the role of adrenergic stress in the immune response to cancer, we set out to better understand this relationship and to explore its implications for cancer treatment."
Shipra Gandhi, MD, Assistant Professor of Oncology at Roswell Park and co-first author on the new study
In a small phase 1 study at Roswell Park, patients with newly diagnosed metastatic melanoma were given escalating doses of propranolol, which blocks the ability of stress hormones to interact with cells, in addition to standard treatment with the anti-PD-1 checkpoint inhibitor pembrolizumab. The team reports that this combination is safe and shows preliminary evidence of promising activity, demonstrating higher anticancer responses than expected with standard therapy alone.
The findings also suggest that stress reduction could be an important component to achieving optimal stimulation of a patient's immune system and reducing tumor growth.
"In repurposing propranolol, which has been in use for decades to treat or prevent conditions including migraine headache and various heart problems, for this study in melanoma, we've gained important insights on how to manage stress in people with cancer -; who can face dangerously elevated levels of mental and physical stress related to their diagnosis and treatment," says Manu Pandey, MBBS, Hematology-Oncology Fellow at Roswell Park and co-first author on the new publication.
The work was guided by two co-senior authors: Elizabeth Repasky, PhD, who is the Dr. William Huebsch Professor in Immunology and Co-Leader of the Cell Stress and Biophysical Therapies Program at Roswell Park, and Marc Ernstoff, MD, who was Chair of Medicine at Roswell Park when this study was conducted and now is ImmunoOncology Branch Chief with the National Cancer Institute (NCI) Division of Cancer Treatment and Diagnosis, Developmental Therapy Program.
Additional research is needed to confirm the team's findings. A larger study of this approach is under way at Roswell Park and three other cancer centers.
Gsndhi, S., et al. (2020) Phase I clinical trial of combination propranolol and pembrolizumab in locally advanced and metastatic melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clinical Cancer Research. doi.org/10.1158/1078-0432.CCR-20-2381.