NEW YORK (Reuters Health) – Angiotensin-(1-7), a small peptide generated by angiotensin-converting enzyme 2 (ACE2), shows promise in combination with a programmed death-ligand 1 (PD-L1) pathway inhibitor and a vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) for patients with clear cell renal cell carcinoma (ccRCC), a preclinical study suggests.
Although the standard of care of metastatic RCC is combined VEGF/PD-1 pathway inhibition, “resistance is a key unmet need, and means to improve this could easily translate to clinical trials,” Drs. Thomas Walther of University College Cork, Ireland, and Rupal Bhatt of Beth Israel Deaconess Medical Center in Boston told Reuters Health in a joint email.
In a series of preclinical experiments in mouse models and tumor cells published in Science Translational Medicine, the team showed:
– ACE2 expression correlates strongly with overall survival in ccRCC patients.
– Higher ACE2 expression/activity leads to increased anti-tumor effects, reducing tumor formation and growth in two different mouse models of kidney cancer.
– VEGF receptor inhibitors such as sunitinib downregulate ACE2 expression in tumor cells in vitro and in tumors of ccRCC mouse models.
– ACE2 downregulation is likely the causative factor behind resistance to VEGF inhibition.
– – Ang-(1-7), generated by ACE2 by cleaving the eighth amino acid of Ang II, likely mediates the beneficial effects of ACE2 in ccRCC.
– Triple therapy with the VEGF pathway inhibitor axitinib and anti-PD-L1 and ang-(1-7) was superior to the standard treatment of VEGR and PD-1 pathway inhibition in a mouse ccRCC model.
“The beauty of Ang-(1-7) is that it is an endogenous peptide and has been already tested in other clinical trials, and thus the process of getting approval to perform clinical trials with kidney cancer patients is more simple and thus faster,” Drs. Walther and Bhatt said. “Having an industry partner or funding from governmental organizations could ensure a rapid testing in Phase II clinical trials, which could realistically start in less than a year.
“We plan to perform experiments in preclinical models of liver cancer to test our hypothesis that Ang-(1-7) is an ideal treatment option in all cancers where VEGF pathway inhibitors are used,” they concluded.
Dr. Bamidele Adesunloye, a medical oncologist at CTCA Atlanta with a focus on genitourinary cancers, commented in an email to Reuters Health. “It is quite intriguing that Ang-(1-7) not only improves disease control when added to a TKI (sunitinib) alone, it also inhibited tumor growth when added to a combination of a TKI (axitinib) and an anti-PD-L1 antibody. The ACE2/angiotensin-(1-7) axis is a promising therapeutic target and a potential game changer if these findings are replicated in clinical trials.”
“The investigators rightly stated one of the obvious limitations of the study – the lack of a biomarker to predict the likelihood of response to Ang-(1-7),” he said. “However, another challenge that may arise in clinical practice is whether Ang-(1-7) should be given concurrently during the initiation of a TKI or added only after the emergence of drug resistance. The risk/benefit ratio of a three-drug combination – i.e., TKI plus anti-PD-L1 plus Ang-(1-7) – versus a two-drug combination of TKI plus Ang-(1-7) will require a randomized controlled clinical trial.”
The study had no commercial funding, but the researchers have obtained patents, or filed patent applications, related to the research.
SOURCE: https://bit.ly/3ceooe4 Science Translational Medicine, online January 20, 2021