Study Finds Potentially Promising Therapeutic Combination for Renal Cell Carcinoma

Investigators have demonstrated that angiotensin-converting enzyme inhibitor 2 (ACE2) expression is a good prognostic factor in renal cell carcinoma (RCC) and loss of ACE2 mediates resistance to classical treatments, according to research published in the journal Science Translational Medicine.

Preclinical models have also shown that treatment with a drug that is downstream of ACE2 can improve tumor responses in RCC and significantly prolong survival, according to the study authors.

RCC is the most common form of cancer of the kidney, with the 5-year survival rate for patients with metastatic RCC at only approximately 12%. Current treatments include inhibitors of the vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1) pathways, but resistance to therapy occurs in most patients and new combination treatments are still needed to enhance the efficacy of these current approaches, according to the study authors.

"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 researcher Rupal Bhatt, PhD, in a press release. "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 and antagonizes the classical angiotensin 2/AT1 receptor pathway. Further, it is also the receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, and its downregulation by the virus leads to deadly progression of acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19).

The study authors noted that higher ACE2 expression correlates with better overall survival in patients with RCC and demonstrates 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. In addition, multiple lines of evidence that this ACE2 down-regulation can be causative for the resistance to VEGF pathway inhibition, which is the consequence of the approved used class of drugs, according to the study.

Angiotensin-(1-7) is the likely mediator of this effect, and triple therapy of VEGF pathway inhibitors and anti-PD-L1 with angiotensin-(1-7) is superior to the actual standard treatment with VEGF and PD-1 pathway inhibition, according to the study authors.

"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 study author Thomas Walther, PhD, in a press release. "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."

REFERENCE

Researchers uncover potentially promising therapeutic combination for renal cell carcinoma. EurekAlert! https://www.eurekalert.org/pub_releases/2021-01/bidm-rup011521.php. Published January 20, 2021. Accessed January 25, 2021.