Triple-negative breast cancers (TNBCs) are clinically very aggressive tumors with standard chemotherapy the only therapeutic option for patients with such cancers but the response rates are low and the prognosis remains poor. Previous published studies show that LHRH receptor is detected in 49-73.8% of biopsy specimens from patients with TNBC and could be used for delivery of cytotoxic agents. Here, we propose to conduct additional preclinical studies of our two novel LHRH-based drug conjugates carrying tubulin destabilizing agents on TNBC. Our preliminary studies showed that our drug conjugate OTS-P19 is stable, soluble, specific and potent against TNBC cells in-vitro and that 3 weekly injections of OTS-P19 at 1.6 mg/kg caused a 92.8% tumor growth inhibition of orthotopic MDA-MB-231 TNBC without apparent toxicities (7/10 mice had complete response and 3/10 had partial response). In addition to their direct anti-tumor activities our two drug conjugates are expected to have immuno-stimulatory activities through dendritic cell maturation and T cell activation. If funded, our proposed research will allow us to conduct additional efficacy, pharmacokinetic, biodistribution, toxicology and immuno-oncology studies of our conjugates as monotherapy or as combination therapy with anti-PD1 immune checkpoint inhibitor Pembrolizumab using humanized mice bearing MDA-MB-231 or BR1126 patient-derived TNBC.
The long term outcome of prolonged use of standard chemotherapy for triple-negative breast cancer patients is disappointing due to drug resistance and serious toxic effects. Our new targeted drug conjugates are expected to be stable, soluble, safer and highly potent in inhibiting triple negative breast cancers through direct anti- tumor and potential immuno-stimulatory effects in-vivo.
