Targeting ENPP1 to Promote Immunity During PARP Inhibition in TNBC
Abstract
Inhibitors of PARP (poly ADP-ribose polymerase) are approved for use in HER2-negative breast cancer patients with germline mutations in BRCA1/2, which account for approximately 75% of patients with triple-negative breast cancer (TNBC). However, these inhibitors fail to improve overall survival, highlighting the fact that patients with BRCA-deficient TNBC currently lack effective treatment options. In preclinical models, it has been described that the first-generation PARP inhibitors (i.e., Olaparib, Talazoparib) function partially as activators of the immune response against cancer. This is thought to occur through reduced DNA repair in tumor cells, which results in the release of DNA into the cytoplasm and the production of the small molecule cGAMP. cGAMP is a potent activator of the immune system, and similar molecules are being explored as therapies directly injected into tumors. Despite this, PARP inhibitors fail to induce a profound immune response in patients. It has recently been shown that cGAMP can be degraded by an enzyme expressed on the surface of tumor cells, ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1). ENPP1 is expressed at higher levels in breast tumors than in normal tissue, and even at higher levels than in other types of solid tumors. These data suggest that the immune-stimulatory ability of PARP inhibitors may be blocked by the enzymatic activity of ENPP1. Blocking ENPP1 therefore represents a therapeutic opportunity to boost anti-tumor immunity during PARP inhibitor therapy in patients with TNBC. Here we propose to determine if ENPP1 expression regulates response to PARP inhibitors in preclinical models of TNBC. We will also develop monoclonal antibodies that block ENPP1 enzymatic activity in human and mouse. These antibodies will then be evaluated for efficacy in the preclinical models. As a result of these studies, we will understand if ENPP1 regulates anti-tumor immunity in TNBC, know whether ENPP1 can be therapeutically targeted with antibodies, and have agents that can potentially be moved forward into translational studies. We assert that the results from these studies have the potential to alter the landscape of breast cancer immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210406
Entities
People
- Brian Ruffell
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- United States Army