Targeted Synergistic Drug Combinations for Triple-Negative Breast Cancer Metastases Treatment

Abstract

Triple-negative breast cancer (TNBC) is a very aggressive disease and has the worst prognosis among the various breast cancer subtypes. The lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression disadvantages the patients from targeted therapies. The complex and heterogenic biology leads to a high incidence of relapse and metastasis that account for 40% of treatment failures. Insufficient drug exposure, overactivation of pathways of cancer proliferation, metastasis, DNA damage repair, and immunosuppressive tumor microenvironment (TME) contribute to tumor progression. To develop new therapeutic approaches for TNBC, our laboratory and others have recently focused on targeting the signaling pathways of the cluster of differentiation 44 (CD44), the receptor for hyaluronan mediated motility (RHAMM), and αvβ3 and αvβ5 integrins that are overexpressed on TNBC. In this thesis, oligomer hyaluronic acid (oHA) was explored as a therapeutic agent to impede the native HA/CD44/RHAMM axis-mediated cancer progression and metastasis and enhance the delivery and efficacy of doxorubicin (DOX). The internalizing cyclic peptide (CRGDRGPDC, iRGD) was selected to functionalize polymer-lipid hybrid nanoparticles (PLN) that were co-loaded with a synergistic combination of oHA and DOX (iRGD-DOX-oHA-PLN). The new nanoparticle system was successfully developed in aim one and demonstrated to reduce metastasis biomarkers and profoundly inhibit tumor growth and metastasis.The second aim was to evaluate the effects of iRGD-DOX-oHA-PLN on the oncogenic pathways relevant to the RHAMMA and DOX, and their associated chemoresistance, DNA repair and immune evasion. The iRGD-DOX-oHA-PLN inhibited biomarkers of DNA-double- and -single strand breaks repair pathways of homologous recombination (HR) and base excision repair (BER) of poly (ADP-ribose) polymerase (PARP1). It also reduced programmed death-ligand 1 (PD-L1) expression and secondary metastases to the lungs and liver compared to the PARP inhibitor olaparib in BRCA1 mutant and non-mutant TNBC tumor models. The third aim of this thesis was to investigate the effect of the iRGD-DOX-oHA-PLN on reversing immunosuppression of TME. Results showed increased innate and adaptive anti-tumor immune response facilitating the inhibition of the primary tumor growth and distal metastasis. The research findings suggest that the iRGD-DOX-oHA-PLN system is a promising multi-targeted nanomedicine for TNBC.