Enhancing Breast Cancer Therapy by Inhibiting the Adenosine Receptor and Oxygen Consumption
Abstract
Rationale, Objective, and Aims: Triple-negative breast cancer (TNBC) is an aggressive subset of breast cancer (BC), with a high risk of recurrence and poor survival. Patients who achieve a complete response to neoadjuvant (upfront) treatment have a higher cure rate. This study focuses on enhancing immune therapy (“checkpoint blockade”) because only about 20% of TNBC patients respond to current checkpoint blockade therapy. It focuses on maximizing checkpoint inhibition by: 1) introducing a novel double checkpoint blockade strategy and 2) enhancing efficacy of both checkpoints by decreasing tumor hypoxia. We hypothesize that the combination of double checkpoint blockade (adenosine and PD-L1) plus hypoxia reduction (Deferiprone or Metformin) will enhance neoadjuvant immune therapy efficacy leading to increased pCRs, a higher cure rate, and reduced metastases. We propose to decrease tumor hypoxia by decreasing tumor oxygen consumption. We expect significant “additive effect” (synergy) by combining inhibition of both the adenosine (A2aR) and PD-L1 receptors, with enhanced activation of the immune response against TNBC. The drugs in this study are in clinical use (or in clinical trials), have a low toxicity profile, and could be rapidly translated into clinical trials in TNBC patients. Describe the ultimate applicability of the research. This research applies to patients with newly diagnosed TNBC and those with more aggressive/widespread disease. The primary goal is to increase the likelihood of a complete pathologic response (pCR) rate to increase the TNBC cure rate and prevent/reduce metastases. Which overarching challenge(s)? Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival. What types of patients will it help and how will it help them? This therapy will benefit patients with TNBC, who are at high risk for metastatic disease and death. There is a need to increase the pCR rate with a novel, more effective adjuvant or neoadjuvant treatment to increase the cure rate. The combined treatment strategy will prevent recurrence by enhancing immune responses and killing micrometastatic tumor cells and will also be effective in treating metastatic disease. We hypothesize that all TNBC patients will benefit from this treatment. What are the potential clinical applications, benefits, and risks? Both newly diagnosed TNBC patients and patients with metastatic disease would benefit from this novel therapy. It is designed for patients with TNBC undergoing neoadjuvant treatment to increase pCRs and cure rate and prevent or significantly delay metastases. It also has potential benefit for patients with existing metastatic disease because it could treat and prevent further metastases. Treatment is expected to be safe and associated with “low toxicity” because DFP and MET have been administered safely to patients for many years with few complications. We selected DFP and MET for evaluation because they: 1) inhibit tumor and stromal cells; 2) have preclinical treatment efficacy, as single agents and in combination with standard drugs; and 3) have low toxicity profiles with protracted administration to patients. We expect that this study could be translated into a clinical trial rapidly, with low risks to patients. What is the projected time to achieve a patient-related outcome? Our preliminary data and literature studies show that DFP and MET are active as single agents, enhance immune effects, and enhance immune therapy. If successful, (we will have completed preclinical data in 2.5-3 years), a protocol could be presented to the regulatory agencies 6 months later. AZD4635 would be combined with a PD-1/PD-L1 “checkpoint” inhibitor initially; DFP or MET (FDA approved) would be added subsequently. What is the likely impact of this study on ending BC? This proposal is designed to significantly reduce mortality and morbidity of TNBC. Metastases are the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110102
Entities
People
- Taha Merghoub
Organizations
- Sloan-Kettering Institute
- United States Army