A Novel Anti-Fibrotic Peptide Therapy for Metastatic Triple-Negative Breast Cancer

About This Grant

PROJECT SUMMARY This proposal focuses on developing a strategy to effectively treat metastatic triple-negative breast cancer (TNBC). In breast cancer, excess deposition of extracellular matrix (ECM) is considered prognostic of poor patient outcomes. The fibrotic ECM in primary and metastatic tumors is well-known for limiting chemotherapy penetration, excluding immune cell infiltration, and promoting immunosuppression and therapy resistance. Thus, developing an effective strategy to normalize the tumor ECM is an attractive therapeutic approach. Our proposal aims to address this unmet need with a novel peptide, FUD (Functional Upstream Domain), that targets and inhibits fibronectin (FN) assembly. Of the many ECM proteins in the tumor microenvironment, increased deposition of FN is prognostic of patient survival and known to directly contribute to tumor inflammation and fibrosis. Our pre-clinical studies demonstrate that PEGylating FUD (PEG-FUD) improves in vivo bioavailability and tumor-targeting compared to FUD and control peptides. Our recent data shows that therapeutic dosing with PEG-FUD significantly decreases insoluble (assembled) tumor FN, blocks adhesion signaling, and inhibits primary tumor growth without systemic blood or organ toxicity in two pre-clinical murine models of TNBC. Further, pretreating tumors with PEG-FUD enhanced the efficacy of the standard-ofcare, doxorubicin. Collectively, this data demonstrates the potential of PEG-FUD to normalize tumor FN and improve treatment efficacy. Despite the promise of PEG-FUD, the treatment did not mitigate the systemic toxicity of chemotherapy. Additionally, we have yet to establish how PEG-FUD alters the timing and function of tumorinfiltrating immune cells at the metastatic niche. These results point to the need to investigate PEG-FUD therapy in the clinically relevant setting of metastasis and test combinations with less toxic nano-drug formulations. Assessing toxicity and tumor immune response are aspects of developing PEG-FUD for breast cancer therapy that can only be accomplished in preclinical animal models. We hypothesize that targeting FN with PEG-FUD will normalize the ECM in the metastatic TNBC microenvironment, reducing mechanosignaling, inhibiting immune suppression, and improving the efficacy and toxicities of chemo- and immunotherapy. We will test this hypothesis by 1) defining how PEG-FUD modulates the physical properties of the metastatic TME to reduce TNBC burden, 2) testing the effect of PEG-FUD on the distribution, efficacy, and systemic toxicity of nano-chemotherapy in metastatic TNBC, and 3) investigating how PEG-FUD reduces immune suppression in the microenvironment of metastatic TNBC to improve response to immune checkpoint inhibitors (ICI). This proposal will provide pre-clinical evidence that targeting tumor ECM reduces the biophysical properties of the matrix to modulate the tumor immune response and improve the distribution and efficacy of chemo and immune therapy. Understanding these interactions will have a significant impact on treatment paradigms for metastatic TNBC and other breast cancers and will open the door for translation to other solid tumor types.