Angiotensin-(1-7) as a Novel Therapeutic Target for Renal Cancer
Abstract
Renal cell carcinoma (RCC) can lead to significant illness and death in patients. Despite the fact that approved therapies such as pazopanib and sunitinib, which target the vascular endothelial growth factor (VEGF) pathway, and therapies that target the immune system, such as nivolumab and atezolizumab, can help patients with metastatic RCC, we still see disease progression in the majority of patients. Immune therapies have increased options for patients in recent years. However, the dependence of RCC on VEGF has maintained this as a critical target in RCC. Thus, ways to improve VEGF-targeted approaches could lead to an increased number of options for patients either before or after checkpoint inhibition. Agents that target VEGF can slow disease progression in a significant number of patients. However, only about a third of patients who receive these agents respond to treatment. Moreover, the majority of patients develop resistance to treatment within about one year. We have been committed to understanding why patients stop responding to VEGF-targeted agents and have spent the past year accumulating new and exciting preliminary data to answer this question. One of our main findings was that when tumors develop resistance to VEGF inhibitors, levels of ACE2, an enzyme that generates a small beneficial peptide, Ang-(1-7), which decreases blood pressure and reduces tumor growth, is down modulated. Ang-(1-7) has also very recently been shown to have anti-cancer properties in other cancers. Tying these observations together, we hypothesize that repleting Ang-(1-7) could directly prevent tumor growth in RCC and could be a very promising treatment strategy to prevent resistance to VEGF inhibitors such as sunitinib or pazopanib alone or when used in combination with immune check point inhibitors. While many have tried to identify molecules, which could prevent the resistance, we propose a very promising new approach to this critical clinical problem. We will test our hypotheses in established mouse models of resistance to identify how best to combine these approaches. We will use several models to ensure that we test our hypotheses rigorously. We are very optimistic that these experiments will pave the way for a clinical trial in the near future. One key strength of this proposal is the collaboration between a kidney cancer expert (Dr. Bhatt) and an expert in ACE2/Ang-(1-7) biology (Dr. Walther). We will use several mouse models and cell studies to understand the exact mechanisms by which resistance to VEGF inhibitors is overcome with Ang-(1-7). We will evaluate two different forms of Ang-(1-7) which could be subsequently tested in patients: one formulation that is given intravenously and an oral formulation to test the efficacy of using Ang-(1-7) in combination with existing therapies to increase antitumor efficacy. If we are successful, by the end of the grant we will have identified several potential pathways that control tumor growth in RCC and cause resistance to VEGF targeted therapy. We will have promptly tested the new combinations in mouse models to build the ground for an immediate launching of clinical trials. Thus, it is likely that we would be able to design trials for patients within 1-2 years of completion of this proposal. If successful, we will increase the effectiveness of VEGF-targeted agents in patients with RCC. We are excited to develop new treatments for patients with metastatic RCC. If we could improve current therapy, we would increase the number of options for our patients, improve their quality of life, and help them enjoy life longer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110708
Entities
People
- Rupal Bhatt
Organizations
- Beth Israel Deaconess Medical Center
- United States Army