Development of Novel Molecularly Targeted Therapy to Secreted Frizzled-Related Protein 2 for Breast Cancer
Abstract
Rationale: In order for a new tumor to grow over a few millimeters in size, each increase in tumor growth must be preceded by new blood vessel growth, a process called angiogenesis. Tumor secreted growth factors stimulate the surrounding blood vessels to converge upon the tumor. Once this happens, the tumors can grow and metastasize. The DeMore laboratory has discovered in humans a novel growth factor secreted by tumors that stimulates blood vessel growth. This growth factor is called secreted frizzled-related protein 2. This protein is expressed by triple-negative, estrogen receptor-positive, and Her2-positive breast cancers. We initially made mouse monoclonal antibody to SFRP2 that we showed inhibits triple-negative breast cancer in mice. To move towards translation into humans, we have now generated a humanized monoclonal antibody to SFRP2 that our preliminary data show is effective against a metaplastic triple-negative carcinoma in mice. Our hypothesis is that a drug that blocks SFRP2 from binding to FZD5 will block new blood vessel growth to tumors. This in turn would halt breast tumors from growing and metastasizing. Because normal blood vessels are not rapidly dividing, this drug could potentially only block tumor vessels from growing and not normal vessels, suggesting that this therapy might not have serious toxicity. Objective: The objective of this application is to show that the humanized SFRP2 inhibits triple-negative breast cancer growth and that the effect is additive with chemotherapy, immunotherapy, and antiangiogenic therapy. We will also discover the mechanism of action of the antibody in mice. Specific Aim 1: To characterize the efficacy and toxicity of an hSFRP2 mAb in breast cancer in mice. Specific Aim 2: To elucidate the role of SFRP2 inhibition on immune system and NFAT activation in vivo. Specific Aim 3: Evaluate for additivity or synergy between hSFRP2 mAb and chemotherapy, antiangiogenic therapy, and anti- PD-1 therapy in breast cancer in vivo, and efficacy of single agent hSFRP2 mAb in drug-resistant cells. Overarching Challenges: This application will address two overarching challenges in BCRP’s vision: (1) Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic and (2) eliminate the mortality associated with metastatic breast cancer. Types of Patients This Could Help: SFRP2 has been shown to be expressed in 85% of triple-negative, estrogen receptor-positive, and Her2 neu-positive breast cancer, and therefore a small molecule drug that blocks this pathway could potentially be effective in the major subtypes of breast cancer. Because of the great need for novel agents in triple-negative breast cancer, the preclinical animal studies in this proposal will focus on this type of breast cancer. Potential Clinical Applications, Benefits and Risks: The goal of this preclinical study is to discover novel therapeutic agents for breast cancer. The next step, outside the scope of this study, will be to perform preclinical toxicology studies to identify any major risks, and then a Phase I clinical trial that will be designed to determine safety. Efficacy for improving survival would then be tested in a Phase II clinical trial. The potential long-term impact would be to prolong survival in women with metastatic breast cancer. Projected Time for Patient-Related Outcome: This project will involve 3 years of preclinical work. At the completion of this project, it will take 1 year to obtain Good Manufacturing Practices (GMP) material, preclinical toxicology studies, and Investigational New Drug (IND) filing to the Food and Drug Administration (FDA). It will then take 1 year for a Phase I trial. Therefore, it will be 5 years to a Phase II trial that will evaluate efficacy of the drug on survival in patients. Likely Impact of This Project Ending Breast Cancer: Our vision is to end death due to metastatic breast cancer, and our
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810008
Entities
People
- Ann-marie Broome
Organizations
- Medical University of South Carolina
- United States Army