Pancreatic cancer is highly lethal, and surgical removal of tumor tissue is currently the only potential cure for most patients. Once the cancer has spread beyond the pancreas, treatment options are limited.
- By MGH NEWS and PUBLIC AFFAIRS
A recent phase 2 clinical trial led by Harvard Medical School researchers at Massachusetts General Hospital identified a promising combination treatment regimen for patients with locally advanced pancreatic cancer, meaning that their cancer had spread, but only to nearby tissue.
The trial's investigators have now identified potential mechanisms behind the treatment's beneficial effects.
The combination therapy - losartan+FFX+CRT - includes the blood pressure drug losartan plus a chemotherapy cocktail called FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin), followed by chemoradiation.
The therapy is meant to combat as much of the cancer as possible before a patient has surgery to remove any remaining tumor in the pancreas. A 2019 report on a phase 2 clinical trial demonstrated that this therapy is effective in doing so.
In this latest work, published in Clinical Cancer Research, investigators analyzed blood and tissue samples from patients undergoing this and other treatments for locally advanced pancreatic cancer.
The team found that FFX+CRT improved the expression of genes linked to normalization of blood vessels and migration and maturation of various immune cells.
Losartan+FFX+CRT inhibited immunosuppression and reduced the expression of genes that promote the invasion of tumor cells into normal tissue.
Also, losartan induced changes in the blood levels of various molecules involved in blood-vessel health and the immune response.
Lastly, tumor tissue from patients in the group treated with losartan+FFX+CRT had a lower number of cells that suppress the immune response and a higher number of immune cells important for killing cancerous or virally infected cells.
"Our findings suggest that losartan may potentiate the benefit of FFX+CRT by reducing tumor invasion and immunosuppression," said senior author Rakesh Jain, the Andrew Werk Cook Professor of Radiation Oncology at HMS and director of the E.L. Steele Laboratories for Tumor Biology at Mass General.
"Thus, our results are important because they would not only reveal how losartan may synergize with emerging cytotoxic regimens, but also provide valuable information for overcoming resistance to immunotherapy - such as immune checkpoint blockers - that can occur in pancreatic cancer," Jain said.
Jain and his colleagues found that blood levels of a molecule called soluble Tie2 increased over time in patients treated with losartan+FFX+CRT and who experienced only a partial or poor response.
Therefore, an increase in soluble Tie2, which is involved in new blood vessel formation, could be an indication of tumor progression.
"Inspired by our published studies on the benefit of adding losartan, several clinical trials in patients with pancreatic cancer are currently evaluating the effectiveness of adding losartan to different cytotoxic treatment regimens or cytotoxics plus immunotherapy," said Jain.
"When completed, these clinical trials will indicate whether losartan, when combined with different therapies, can improve the treatment response and long-term survival of patients with pancreatic cancer," he said.
Authorship, funding, disclosures
Co-authors on the study included co-corresponding author Yves Boucher; co-first authors Jessica M. Posada, Sonu Subudhi, and Ashwin S. Kumar; Spencer R. Rosario, Liqun Gu, Heena Kumra, Mari Mino-Kenudson, Nilesh P. Talele, Dan G. Duda, Dai Fukumura, Jennifer Y. Wo, Jeffrey W. Clark, David P. Ryan, Carlos Fernandez-Del Castillo, Theodore S. Hong, and Mikael J. Pittet.
This work was supported by the National Institutes of Health, the U.S. Department of Defense, Jane's Trust Foundation, Ludwig Cancer Center at Harvard, National Foundation for Cancer Research, and Nile Albright Research Foundation.
