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.
Project Terms: Affinity; Aftercare; Amides; Amino Acids; Animals; anti-PD1 antibodies; Apoptosis; aqueous; base; Biochemical; Biodistribution; Biological Assay; biophysical properties; Biopsy Specimen; Blood specimen; Brain; Breast; Breast Cancer Cell; Breast Cancer Patient; Cancer cell line; CD8-Positive T-Lymphocytes; Cell Culture Techniques; cell immortalization; Cell Maturation; Cells; Chemistry; chemotherapy; Clinical; Combined Modality Therapy; cytotoxic; Cytotoxic agent; Data; Dendritic Cells; Dose; Drug Kinetics; Drug resistance; efficacy study; Endothelial Cells; Epithelial; experimental study; Female; Fibroblasts; Formalin; Funding; Generations; Gonadotropin-Releasing Hormone Receptor; Heart; Hematoxylin and Eosin Staining Method; High Pressure Liquid Chromatography; Hour; Human; humanized mouse; Immune checkpoint inhibitor; Immunooncology; In complete remission; In Vitro; in vivo; Injections; Kidney; light scattering; Liver; Liver Microsomes; Lung; Malignant neoplasm of ovary; Malignant Neoplasms; Mass Spectrum Analysis; MDA MB 231; MDA-MB-468; Mesenchymal; Methods; Molecular Sieve Chromatography; Mus; new therapeutic target; novel; Organ; Outcome; outcome forecast; Pancreas; partial response; Patients; peptide drug; Peptides; Pharmaceutical Preparations; Pituitary Gland; preclinical study; Publishing; radioligand; receptor; receptor binding; Regulatory T-Lymphocyte; Research; response; S Phase; Saline; SCID Mice; Serum; SKOV3 cells; Solid; Solubility; stable plasma protein solution; Stains; T-Cell Activation; Testing; Therapeutic; Toxic effect; Toxicology; Toxin; triple-negative invasive breast carcinoma; Tubulin; tumor; tumor growth; Tumor Volume; Tumor Weights; Water; Weight; Weights and Measures; Western Blotting; White Blood Cell Count procedure;
