Researchers uncover potentially promising therapeutic combination for renal cell carcinoma

January 20, 2021

Boston, Mass. -- Renal cell carcinoma (RCC) is the most common form of cancer of the kidney. In 2018, there were an estimated 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. Current treatments include inhibitors of the VEGF and PD-1 pathways. However, resistance to therapy occurs in most patients and new combination treatments are still needed to enhance the efficacy of these current approaches.

Now, investigators have demonstrated that ACE2 expression is a good prognostic factor in RCC, that loss of ACE2 mediates resistance to classical treatments, and that in preclinical models, treatment with a drug that is downstream of ACE2 can improve tumor responses in RCC and significantly prolong survival. The team, led by Beth Israel Deaconess Medical Center's (BIDMC) Rupal Bhatt, MD, PhD, and University College Cork, Ireland's Thomas Walther, PhD, published their findings in the journal Science Translational Medicine.

"Our team reported that ACE2 is a new protective molecule for RCC, and building on this finding, we show that angiotensin-(1-7), a small peptide generated by ACE2, can be used to control tumor growth in preclinical models," said co-corresponding Bhatt, a medical oncologist at BIDMC and associate professor of medicine at Harvard Medical School. "Our findings suggest that angiotensin-(1-7) could be developed in clinical trials as a promising therapeutic option in patients with RCC in combination with current standard of care treatments and has a strong potential to improve overall survival."

ACE2 is an enzyme that belongs to the renin-angiotensin system (RAS) and antagonizes the classical angiotensin II/AT1 receptor pathway. Interestingly, it is also the receptor for the SARS-CoV2 spike protein, and its downregulation by the virus leads to the often deadly progression of acute respiratory distress syndrome in COVID-19 patients.

Bhatt, Walther and colleagues show that higher ACE2 expression correlates with better overall survival in patients with RCC. They also demonstrated that VEGF receptor inhibitors such as sunitinib and axitinib down-regulate ACE2 expression in tumor cells in culture and in tumors in mouse models of RCC. Using novel and innovative methods and techniques, the authors generated multiple lines of evidence that this ACE2 down-regulation can be causative for the resistance to VEGF pathway inhibition, the inevitable consequence of this approved used class of drugs.

The authors also report that angiotensin-(1-7) is the likely mediator of this effect. The authors also showed that triple therapy of VEGF pathway inhibitors and anti-PD-L1 with angiotensin-(1-7) is superior to the actual standard treatment with VEGR and PD-1 pathway inhibition.

"Our work shows that angiotensin-(1-7) could provide a promising therapeutic option in patients with RCC in combination with VEGF-pathway inhibitors," said co-corresponding author Walther, Professor in Pharmacology at the University College Cork. "Resistance to VEGF-pathway inhibitors is a general problem in cancer treatment and therefore our findings have broader implications for VEGF-pathway inhibitor therapies that beyond RCC could be extended to other types of cancers."
Co-authors included Prateek Khanna, Chun-Hau Chen, Ruchi Saxena, Manoj Bhasin, Seema Amin and Patrick Neset Joslin of BIDMC, Hong Jie Soh, Maura Naughton, Andrew Moore and Carol O'Callaghan of the University College Cork, Ziad Bakouny, Paul Catalano, Rana McKay, Toni K. Choueiri and Sabina Signoretti of 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-inventor of the patent "Use of an Ang-(1-7) receptor agonist in acute lung injury" (application no. 08016142.5-2107). Walther is also a scientific advisor of Constant Pharmaceuticals LTD (Boston, USA). A patent by Bhatt and BIDMC was filed on 16 April 2017 for the "Combination therapy for cancer" outlining combination of VEGFR inhibition with angiotensin pathway molecules. Bhatt also has a patent pending for the use of Ang-(1-7) and VEGFR-TKI therapy in RCC.

For a full list of support and disclosures, please refer to the manuscript.

Beth Israel Deaconess Medical Center

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to