ACE2 Pathway Stimulation Enhances VEGF Inhibition in ccRCC, May Help Overcome VEGF Resistance

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.

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.

Following a series of experiments suggesting that ACE2 mediates its antitumor effects via its cleavage product Ang-(1-7) peptide, the researchers gave mice with A498 or 786-O tumors the peptide either alone or in combination with sunitinib. Although Ang-(1-7) alone did not reduce tumor size as much as sunitinib, combination Ang-(1-7) and sunitinib led to a greater reduction in tumor growth than either single agent. Adding Ang-(1-7) to the combination of VEGFR-TKI axitinib and an anti-PD-L1 antibody—simulating the axitinib-avelumab doublet therapy approved on May 14, 2019 as a first-line intervention for patients with advanced RCC³—drove down tumor growth more than the axitinib-PD-L1 inhibitor combination.¹

Based on the study data, “it sounds like [ACE2] could be a pathway in kidney cancer that needs to be investigated further,” said Yousef Zakharia, MD, an associate professor of medicine at the University of Iowa who was not involved in the research. Further, the study raises several questions, Dr Zakharia told Cancer Therapy Advisor, such as whether the findings might complement the story about the potential benefits of ACE inhibitors in RCC⁴.

If other research groups can validate their findings and if Dr Bhatt and colleagues can find a partner in clinical development, Bhatt hopes that it would be possible to start phase 1 clinical trials testing Ang-(1-7) in advanced ccRCC patients in combination with VEGF inhibition or together with VEGF and PD-1/PD-L1 inhibition. She is optimistic about the safety of the peptide because it has been tested in phase 1/2 clinical trials as a treatment for nonmalignant conditions and was found to be well tolerated in these earlier examinations.⁵

The researchers are now interested in studying whether treatment with a VEGF inhibitor induced changes in ACE2 activity or Ang-(1-7) levels in patients with RCC. Dr Bhatt noted that her colleague, a co-author of the study, Thomas Walther, PhD, a professor at the University College Cork in Ireland, has been leading many of the ACE2-focused studies.

They are also exploring whether stimulating ACE2 activity could make VEGF inhibition a therapy option for more cancer types. “It has not really, I think, fulfilled the promise we thought it had. We are hoping we can make it work better” Dr Bhatt said.

References

1. Khanna P, Soh HJ, Chen C-H, et al. ACE2 abrogates tumor resistance to VEGFR inhibitors suggesting angiotensin-(1-7) as a therapy for clear cell renal cell carcinoma. Sci. Transl Med. Published online January 20, 2021. doi:10.1126/scitranslmed.abc0170
2. McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21(11):2471-2479. doi:10.1158/1078-0432.CCR-14-2332
3. Bavencio [package insert]. Rockland, MA: EMD Serono, Inc.; 2019.
4. Pinter M, Jain RK. Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci Transl Med. 2017;9(410):eaan5616. doi:10.1126/scitranslmed.aan5616
5. Rodgers KE, Espinoza T, Roda N, et al. Accelerated hematopoietic recovery with angiotensin-(1-7) after total body radiation. Int J Radiat Biol. 2012;88(6):466-476. doi:10.3109/09553002.2012.676228

This article originally appeared on Cancer Therapy Advisor