Iron Chelation Enhances TAM and Triple-Negative Breast Cancer Cell Death
Abstract
Rationale, Objective, and Aims: The goal of this study is to complete preclinical testing of Deferiprone (DFP), an iron chelator in clinical use for non-oncologic diseases. We propose to demonstrate the sensitivity of TNBC to DFP as a single agent and in combination with immune modulation therapy (checkpoint inhibitors) and chemotherapy (paclitaxel). The novelty of this proposal is the enhanced benefit of DFP with standard and immune-based therapies. Ultimate Applicability of the Research: The ultimate goal/applicability of this project is to prevent and treat breast cancer metastases by treating both tumor and stromal “supporting” cells. This research is applicable to patients with newly diagnosed triple-negative breast cancer (TNBC) and those with more aggressive/widespread disease. The goal is to increase the complete response (CR) rate, prevent/reduce metastases, and increase TNBC cure rate. Which overarching challenge(s) does this research address? Eliminate (or reduce) mortality from breast cancer; replace drug treatments with severe (often life-threatening) toxicities with safer and more effective interventions. What types of patients will it help and how will it help them? This therapy will primarily benefit TNBC patients who are at risk for metastatic disease and death, by increasing the CR rate, with a novel, more effective adjuvant or neoadjuvant treatment to prevent recurrence by attacking both tumor and stromal cells. Patients who achieve a CR in TNBC have a superior survival. This treatment could also be used to treat patients with metastatic disease. Thus, we hypothesize that all patients with TNBC will be able to benefit from this treatment. What are the potential clinical applications, benefits, and risks? It is expected that both newly diagnosed patients with TNBC and patients with metastatic disease would benefit from this novel metabolic therapy. It is viewed as an adjuvant or neoadjuvant therapy (to be combined with current drugs) for patients with TNBC to increase the CR rate, which has been shown to increase the cure rate and prevent or significantly delay metastases. The potential benefit to patients with existing metastatic disease is that it could treat and prevent further metastases. The therapy is expected to be safe and associated with “acceptable toxicity,” since DFP has been administered to patients for as long as 15 years. We selected DFP for evaluation as an iron chelator because: (1) it inhibits multiple targets (tumor and stroma); (2) we have preliminary data demonstrating treatment efficacy, both as a single agent and in enhancing responses in combination with standard drugs; and (3) its acceptable toxicity profile in protracted administration to patients with different (including normal iron background) nononcologic diseases. Thus, it is likely that this proposal could be translated into a clinical trial very rapidly. What is the projected time it may take to achieve a patient-related outcome? We have promising preliminary data showing: (1) TNBC tumors are sensitive to DFP (both in vitro and in vivo); (2) DFP decreases M2 (“bad”) and increases M1 (“good”) macrophages; (3) DFP enhances (~200% to >1000%) the efficacy of paclitaxel (a drug that is widely used in patients with TNBC); and (4) DFP enhances the efficacy of immune modulation therapy (checkpoint blockade). If this study is successful (we will have preclinical data in 2.5-3 years), DFP could then be put into clinical trials. A dose with therapeutic efficacy used in either thalassemia (75 mg/kg) or Friedreich Ataxia (30 mg/kg) could be used initially in a Phase I study. What is the likely impact of this study on ending breast cancer? This proposal is designed to end or significantly reduce the mortality and morbidity of TNBC and more aggressive forms of breast cancer. Since metastases are the primary cause of death in breast cancer (in addition to a significant decrease in quality of life)
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710526
Entities
People
- Ronald Blasberg
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army