Novel peptide drug conjugates for the treatment of triple-negative breast cancers: Direct anti-tumor activity and immuno-oncology preclinical studies.

ABSTRACT Triple negative breast cancersTNBCsare 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 poorPrevious published studies show that LHRH receptor is detected inof biopsy specimens from patients with TNBC and could be used for delivery of cytotoxic agentsHerewe propose to conduct additional preclinical studies of our two novel LHRH based drug conjugates carrying tubulin destabilizing agents on TNBCOur preliminary studies showed that our drug conjugate OTS Pis stablesolublespecific and potent against TNBC cells in vitro and thatweekly injections of OTS Patmg kg caused atumor growth inhibition of orthotopic MDA MBTNBC without apparent toxicitiesmice had complete response andhad partial responseIn 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 activationIf fundedour proposed research will allow us to conduct additional efficacypharmacokineticbiodistributiontoxicology and immuno oncology studies of our conjugates as monotherapy or as combination therapy with anti PDimmune checkpoint inhibitor Pembrolizumab using humanized mice bearing MDA MBor BRpatient derived TNBC NARRATIVE 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 effectsOur new targeted drug conjugates are expected to be stablesolublesafer and highly potent in inhibiting triple negative breast cancers through direct antitumor and potential immuno stimulatory effects in vivo