Repurposing Antiparasitic Drug Ivermectin for Combination Immunotherapy to Combat Metastatic Breast Cancer
Abstract
Overarching Challenges: The proposed research will address the following Overarching Challenges defined by the BCRP for FY2021: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival and Eliminate the mortality associated with metastatic breast cancer. Patients that can be helped by this proposal: This proposal is designed to test a cancer treatment strategy that can be applied to women diagnosed with triple-negative breast cancer (TNBC). The treatment strategy proposed is specifically designed to test a novel and safe approach to treat TNBC, but we anticipate that our findings can be generalized to treat other cancers, including other types of breast cancers. Objectives/Hypotheses/Aims: The objective of this proposal is to develop a new approach to treat TNBC by repurposing the anti-parasitic drug ivermectin (IVM) for combination treatment with immune checkpoint inhibitors (anti-PD1 antibodies), which are currently only effective in a small subset of patients. We hypothesize that IVM will synergize with anti-PD1 antibodies to treat TNBC more effectively and with less toxicity than current treatments. IVM is a commonly accessible, safe, and inexpensive drug that has been used by over 700 million people worldwide; therefore, it offers a promising, cost-effective agent that can be rapidly translated to the clinic. This project is motivated by our recent findings that the combination of IVM with checkpoint inhibitors kills TNBC cells in mice and protects these mice from developing new cancer cells. To build upon these results, we propose the following aims: Aim 1. To determine the optimal dosage and timing of neoadjuvant IVM + anti-PD1 combination therapy in an orthotopic mouse model of TNBC. Aim 2. To determine the optimal dosage and timing of IVM + anti-PD1 combination therapy in two mouse models of metastatic TNBC. Aim 3. To conduct correlative and pharmacokinetic studies to gain mechanistic insights and identify biomarkers to predict patient response to IVM + anti-PD1 treatment. Clinical Impact: This 3-year study will provide the necessary animal data to support testing of our combination treatment in patients. Because we are using mouse models, this proposal poses no clinical risks to humans. Additionally, IVM is well-tolerated in humans, inexpensive, and easily accessible. Thus, our study is potentially practice-changing and would offer a new treatment for breast, which we anticipate can also be generalized to other breast cancer subtypes. Applying the combination of IVM with anti-PD1 antibody as a treatment strategy against breast cancer may take several years, but because both drugs are already approved by the Food and Drug Administration and have a long track record of safe use in people, the combination can be ready for cancer treatment in humans much faster than other drugs. We anticipate that this project will lead seamlessly to a clinical study to explore the safety and efficacy of this novel combination in patients with TNBC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210031
Entities
People
- Peter P Lee
Organizations
- Beckman Research Institute of City of Hope
- United States Army