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.


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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 carcinomaSci. 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