Boston, Mass. – Renal cell carcinoma (RCC) is the most common form of kidney cancer. In 2018, there were approximately 403,000 new cases of RCC and 175,000 deaths due to kidney cancer worldwide. Currently, the 5-year survival rate for patients with metastatic RCC is only about 12 percent. Conventional therapies include blockers of the VEGF and PD-1 pathways. However, resistance to treatment occurs in the majority of patients and new combination therapies are still needed to strengthen the effectiveness of these conventional therapies.
Now, researchers have confirmed that ACE2 expression is a good prognostic factor in RCC, that ACE2 loss is contraindicated in classical therapies, and in preclinical models, treatment with a downstream drug can of ACE2 improve tumor responses in RCC and significantly extend survival. The team, led by Beth Israel Deaconess Medical Center (BIDMC) Rupal Bhatt, MD, PhD, and University College Cork, Thomas Walther, PhD in Ireland, published their findings in the journal Science Translational Medicine.
“Our team reported that ACE2 is a new immune molecule for RCC, and building on this finding, we show that angiotensin- (1-7), a small peptide can be formed with ACE2, used to control tumor growth in preclinical models, ”said Bhatt Correspondent, a medical oncologist at BIDMC and an associate professor of medicine at Harvard Medical School. “Our findings suggest that angiotensin- (1–7) may be developed in clinical trials as a promising therapeutic option in patients with RCC in combination with the standard regimen of care therapies and is its strong ability to promote overall survival. “
ACE2 is an enzyme belonging to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin II / AT1 receptor pathway. Interestingly, it is also the receptor for SARS-CoV2 spike protein, and the reduction by the virus often leads to a fatal progression in respiratory distress syndrome in COVID-19 patients.
Bhatt, Walther and colleagues show that higher ACE2 expression is associated with improved overall survival in patients with RCC. They also showed that VEGF receptor blockers such as sunitinib and axitinib regulate ACE2 expression in tumor cells in culture and in tumors in mouse models of RCC. Using new and innovative methods and techniques, the authors generated several lines of evidence that this ACE2 pretreatment may be a factor in counteracting VEGF pathway inhibition, the inevitable outcome of the class. this permitted drug.
The authors also report that angiotensin- (1-7) is the most likely mediator of this effect. The authors also showed that triple treatment of VEGF and anti-PD-L1 pathway inhibitors with angiotensin- (1-7) is superior to the true conventional treatment with VEGR and PD-1 pathway inhibition.
“Our work demonstrates that angiotensin- (1-7) may provide a promising therapeutic option in patients with RCC in combination with VEGF pathway protectors,” said co-author Walther , Professor of Pharmacology at University College Cork. “Opposition to VEGF pathway inhibitors is a common problem in cancer treatment and therefore our decisions for VEGF inhibitor therapies have broader implications -path that may extend beyond RCC to other types of cancer. ”
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Co-authors included Prateek Khanna, Chun-Hau Chen, Ruchi Saxena, Manoj Bhasin, Seema Amin and Patrick Neset Joslin from BIDMC, Hong Jie Soh, Maura Naughton, Andrew Moore and Carol O’Callaghan from University College Cork, Ziad Bakouny, Paul Catalano, Rana McKay, Toni K. Choueiri and Sabina Signoretti from the Dana-Farber Cancer Institute.
This work was supported by grants from the National Institutes of Health Funding (R01 CA196996, R01 NS105910-01, and P50 CA101942-12) and Science Foundation Ireland (1R01HL150145-01).
Together with Kuebler, Walther is a co-engineer on the patent “Use of Ang-receptor agonist (1-7) in severe lung injury” (application number 08016142.5-2107). Walther is also a scientific advisor of Constant Pharmaceuticals LTD (Boston, USA). A patent by Bhatt and BIDMC was filed on April 16, 2017 for the “Combination therapy for cancer” producing a combination of VEGFR inhibition with angiotensin pathway molecules. Bhatt also holds a patent pending use of Ang- (1-7) and VEGFR-TKI therapy in RCC.
For a full list of support and publications, please refer to the manuscript.
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