Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor 2) and AR (androgen receptor), is the breast cancer subtype with the worst prognosis, and QNBC disproportionately afflicts African Americans. It has no standard-of-care treatment targets and thus efficacious and safe treatments must be urgently sought for this unmet medical need, and to address the disparity in breast cancer outcomes. The current proposal is motivated by data showing elevated expression of proteasome subunit RPN13 is associated with both African American race and lower survival in QNBC patients, that RPN13 targeted by our Up284 inhibitor, a strong ongoing collaboration with Dr. Karanam (TU), and the guidance of Dr. Yates (TU) in health disparity research and Dr. Davis (Weill Cornell) in breast cancer subtypes. Both triple negative breast cancer and QNBC cell lines show evidence of greater vulnerability to proteasome inhibitors. However, licensed 20S proteasome inhibitors, e.g. bortezomib, have proven ineffective against solid tumors, with emergence of resistance, and dose limiting toxicities including thrombocytopenia and neutropenia. Up284 has a target and structure designed to overcome the limitations of the licensed drugs with respect to drug resistance (Up284 blocks substrate recognition and deubiquitination rather than just one of the three 20S catalytic activities), poor activity against solid tumors (Up284 has a novel spiro structure with evidence of improved drug access to tumor as compared to peptide-based 20S inhibitors), key toxicities of thrombocytopenia and neutropenia (unlike 20S inhibitors, Up284 does not target the immunoproteasome expressed by hematopoietic cells and does not show these toxicities). Up284 shows broad anticancer activity in vitro, including against QNBC lines with a robust therapeutic index, a promising safety profile and pharmacodynamics, and the ability to control xenograft tumor. This promising data reflects our extensive medicinal chemistry effort to achieve drug-like properties and a patent has been filed globally to cover the novel backbone and lead compounds. By inhibiting proteasome ubiquitin receptor RPN13 function and its associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight polyubiquinated protein aggregates than is induced by 20S inhibitors. These toxic misfolded protein aggregates produce an unresolved ER stress, activate the canonical Unfolded Protein Response (UPR) signaling cascade and more rapidly triggers apoptosis than 20S inhibitor. The safety parameters and promising efficacy of Up284 against breast cancer lines encourages us to validate Up284 efficacy in more QNBC lines and xenografts, and examine key mechanistic and drug pharmacologic questions. This proposal will address questions critical for the development of QNBC as the lead indication for our iRPN13, Up284, and to support a pre-IND application to FDA. Public Health Relevance Statement Quadruple Negative Breast Cancer (QNBC) is a particularly aggressive form of breast cancer that disproportionately afflicts African Americans. Although the licensed peptide-based proteasome inhibitors are effective against multiple myeloma, unfortunately they have not proven useful to treat solid tumors (e.g. QNBC). Up Therapeutics is developing a novel drug with a structure designed to improve uptake into solid tumor, and targeting a different component of the proteasome (RPN13), as candidates to better treat QNBC.
Project Terms: Aftercare ; After Care ; After-Treatment ; post treatment ; inhibitor/antagonist ; inhibitor ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biopsy ; Breast ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cells ; Cell Body ; Pharmaceutical Chemistry ; Medicinal Chemistry ; Pharmaceutic Chemistry ; Cisplatin ; CDDP ; Cis-diammine-dichloroplatinum ; Cis-diamminedichloridoplatinum ; Cis-diamminedichloro Platinum (II) ; Cis-dichloroammine Platinum (II) ; Cis-platinous Diamine Dichloride ; Cis-platinum II ; Cis-platinum II Diamine Dichloride ; Cisplatina ; Cisplatinum ; Cysplatyna ; Dichlorodiammineplatinum ; Peyrone's Chloride ; Peyrone's Salt ; Platinum Diamminodichloride ; cis dichlorodiammineplatinum ; cis platinum compound ; cis-Diaminedichloroplatinum ; cis-Diamminedichloroplatinum ; cis-Diamminedichloroplatinum(II) ; cis-Dichlorodiammineplatinum(II) ; cis-Platinum ; Drug resistance ; drug resistant ; resistance to Drug ; resistant to Drug ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Exhibits ; Female ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Human ; Modern Man ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Molecular Weight ; Morbidity - disease rate ; Morbidity ; mortality ; Multiple Myeloma ; Plasma-Cell Myeloma ; myeloma ; myelomatosis ; Mus ; Mice ; Mice Mammals ; Murine ; Neutropenia ; Organoids ; Legal patent ; Patents ; Patients ; Peptides ; Pharmacology ; Proteins ; Race ; Racial Group ; Racial Stocks ; Androgen Receptor ; Epidermal Growth Factor Receptor ; EGF Receptor ; EGFR ; ERBB Protein ; Epidermal Growth Factor Receptor Kinase ; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase ; Epidermal Growth Factor-Urogastrone Receptors ; HER1 ; TGF-alpha Receptor ; Transforming Growth Factor alpha Receptor ; Urogastrone Receptor ; c-erbB-1 ; c-erbB-1 Protein ; erbB-1 ; erbB-1 Proto-Oncogene Protein ; erbBl ; proto-oncogene protein c-erbB-1 ; Estrogen Receptors ; Progesterone Receptors ; Progestin Receptors ; Research ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Vertebral column ; Spinal Column ; Spine ; backbone ; Stress ; Testing ; Thrombocytopenia ; Thrombopenia ; Time ; Ubiquitin ; APF-1 ; ATP-Dependent Proteolysis Factor 1 ; HMG-20 ; High Mobility Protein 20 ; Weight ; Measures ; SCID Mice ; Severe Combined Immunodeficient Mice ; African American ; Afro American ; Afroamerican ; Black Populations ; black American ; Paclitaxel ; Anzatax ; Asotax ; Bristaxol ; Paclitaxel (Taxol) ; Praxel ; Taxol ; Taxol A ; Taxol Konzentrat ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; base ; sensor ; improved ; Ovarian ; Solid ; Medical ; Series ; multicatalytic endopeptidase complex ; 20S Catalytic Proteasome ; 20S Core Proteasome ; 20S Proteasome ; 20S Proteosome ; Macropain ; Macroxyproteinase ; Multicatalytic Proteinase ; Prosome ; Proteasome ; Proteasome Endopeptidase Complex ; Proteosome ; Chemical Structure ; Hematopoietic ; hemopoietic ; drug sensitivity ; ERBB2 gene ; ERBB2 ; HER -2 ; HER-2 ; HER2 ; HER2 Genes ; HER2/neu ; NEU Oncogene ; NEU protein ; Oncogene ErbB2 ; TKR1 ; c-erbB-2 ; c-erbB-2 Genes ; c-erbB-2 Proto-Oncogenes ; erbB-2 Genes ; herstatin ; neu Genes ; uptake ; Solid Neoplasm ; Solid Tumor ; Collaborations ; Therapeutic ; Malignant Cell ; cancer cell ; Dependence ; Protocol ; Protocols documentation ; subdermal ; subcutaneous ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; particle ; Receptor Protein ; receptor ; receptor expression ; synergism ; Toxicities ; Toxic effect ; complete response ; In complete remission ; Stable Disease ; Structure ; Therapeutic Index ; novel ; Pharmacodynamics ; Modeling ; Property ; response ; Deubiquitination ; Molecular Interaction ; Binding ; disparity in health ; health disparity ; Bortezomib ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; Normal Cell ; Address ; Proteasome Inhibitor ; Data ; Dose-Limiting ; Proteasome Inhibition ; in vivo ; Nucleosome Core Particle ; Core Particle ; Nucleosome Core ; Tumor-Derived ; Xenograft Model ; xenograft transplant model ; xenotransplant model ; partial response ; Development ; developmental ; Image ; imaging ; triple-negative invasive breast carcinoma ; TNBC ; triple-negative breast cancer ; design ; designing ; protein aggregation ; insoluble aggregate ; protein aggregate ; tumor xenograft ; Outcome ; anticancer activity ; anti-cancer activity ; cancer type ; Resistance ; resistant ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; prototype ; tumor ; standard of care ; effective therapy ; effective treatment ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; in vitro activity ; Drug Targeting ; Breast Cancer cell line ; Breast tumor cell line ; Breast Cancer Patient ; Breast Tumor Patient ; invention ; small molecule inhibitor ; cancer subtypes ; cancer sub-types ; misfolded protein ; proteotoxic protein ; proteotoxin ; experimental study ; experiment ; experimental research ; Prognosis ;
