New study data indicate that VEGF inhibition suppressed angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system that has antitumor activity, in a mouse model of clear cell renal cell carcinoma (ccRCC). Furthermore, the addition of angiotensin-(1-7), a heptapeptide generated by ACE2 that is thought to be a mediator of this effect, to VEGF receptor tyrosine kinase inhibition (VEGFR-TKI) with or without immune checkpoint inhibition (ICI) was found to enhance the antitumor activity of these drugs in the model and improve survival outcomes. These findings were published in Science Translational Medicine.1

Attempts to understand the mechanisms of VEGFR-TKI resistance, which commonly occurs in patients with metastatic kidney cancer about a year after treatment initiation, have been a focus of RCC investigations aimed at finding new agents to enhance and prolong VEGF inhibition. Suppressing ACE2 “is probably one of several mechanisms of resistance,” said senior author of the study, Rupal S. Bhatt, MD, PhD, an associate professor at Harvard Medical School in Boston, Massachusetts.

Although the emergence of ICI therapy, whether administered in combination with VEGFR-TKI or as an ICI-ICI combination, has improved outcomes for patients with metastatic disease, many do not achieve long-term, durable responses. However, the new findings suggest that angiotensin-(1-7) in combination with VEGF inhibition “potentially prevents or delays resistance,” Dr Bhatt told Cancer Therapy Advisor.

Dr Bhatt and colleagues demonstrated ACE2’s antitumor activity in mice by showing that ACE2 overexpression in a human kidney cancer cell line called 786-O led to less tumor formation in mice injected with cells that overexpressed ACE2 compared with animals injected with cells that did not.1 The team’s interest in exploring the role of the ACE2 pathway in metastatic RCC stemmed from their previous finding that patients had improved overall survival on VEGFR-TKI if they were also treated with an ACE inhibitor to manage VEGFR-TKI-induced hypertension.2 ACE2 has been known to work in opposition to ACE in the renin-angiotensin system as a natural anti-tumor pathway, according to data from preclinical studies, Dr Bhatt explained.

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To determine the effect of VEGF inhibition on ACE2, the researchers treated mice with a xenograft derived from the A498 human kidney cancer cell line with sunitinib.1 They found lower levels of the ACE2 protein and the ACE2 product angiotensin-(1-7), or Ang-(1-7), in the mice that received sunitinib vs the mice that did not.