Triple-negative breast cancers (TNBC) represent a significant challenge to basic scientists studying themolecular underpinnings of the disease and to patients and clinicians who deal directly with this most deadly andtherapy-resistant of breast cancers. Presently, targeted approaches toward the treatment of TNBC are lacking.This project directly addresses this critical unmet need. We have developed VDX-111, a novel drug that exertspotent pro-apoptotic action in TNBC cell lines but, interestingly, has little or no effect on the majority of non-TNBC and non-tumorigenic breast cells. In vivo, VDX-111 reduces tumor xenograft growth from TNBC cell linesand a TNBC patient-derived xenograft (PDX) model. To elucidate the mechanism of VDX-111action, we carriedout a genome-wide shRNA functional genomics screen designed to identify genes required for VDX-111 actionin TNBC and provide insight into potential resistance mechanisms. The highest-ranking hit from this screen wasthe gene, PTP4A3, encoding the oncogenic phosphatase, PRL-3. To evaluate the clinical significance of PRL-3in TNBC, we probed the TCGA database. PRL-3 is amplified in approximately 50% of invasive TNBCs. Wevalidated PRL-3 as a target of VDX-111. Knockdown of PRL-3 significantly impaired the ability of VDX-111 toinduce apoptosis. VDX-111 directly blocked the catalytic activity of purified PRL-3 and promotes the degradationof PRL-3. VDX-111 inhibited PRL-3-dependent TNBC cell migration and invasion. These findings indicate thatPRL-3 is a major target for VDX-111 in TNBC and is potentially a predictive biomarker for response to VDX-111.In TNBC cells, VDX-111 synergizes with standard of care drugs frequently administered to TNBC patients,highlighting its potential as a combinatorial therapeutic agent that could bolster efficacy while reducing the dosesof the chemotherapeutics. In Phase I we will extend our in vitro proof of concept studies of VDX-111 incombination with doxorubicin and paclitaxel in murine TNBC PDX tumor models. To develop thecommercialization potential of VDX-111, with the ultimate goal of moving it into clinical trials, IND-enablingstudies are proposed. In Phase II we will (i) complete development and validation of bioanalytical methods forclinical testing and (ii), complete IND-enabling safety, toxicity, and PK/PD testing in two species. Phase II studieswill position us for subsequent IND approval and the initiation of human trials. Moreover, accomplishing theproposed Phase II goals will empower the commercialization and investment required to bring VDX-111 to theclinic for use in TNBC. The expected outcomes of these studies will enable optimization of VDX-111 for improvedtherapeutic options for TNBC patients and determine the safety and PK/PD parameters required for a pre-INDmeeting with the FDA. These outcomes will establish an attractive investment opportunity to acquire the supportneeded to make VDX-111 an integral part of standard of care for patients with TNBC.
Public Health Relevance Statement: PROJECT NARRATIVE
Triple-negative breast cancer is the most aggressive of the major sub-types of breast cancer and is
overrepresented in young women and black women. The present proposal seeks to bring a novel therapeutic
agent, VDX-111, to a stage sufficiently mature to seek IND approval and to attract the investment required to
initiate human trials. Whether VDX-111 proves efficacious as a stand-alone therapy for triple-negative breast
cancer or improves outcome in combination with standard of care chemotherapy, the proposed project directly
impacts the mission of NIH to develop new therapies that will improve the capability to treat and/or prevent
disease.
Project Terms: Antineoplastic Agents ; Anti-Cancer Agents ; Antineoplastic Drugs ; Antineoplastics ; Cancer Drug ; Neoplastic Disease Chemotherapeutic Agents ; Tumor-Specific Treatment Agents ; anti-cancer drug ; anticancer agent ; anticancer drug ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Breast ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; cell motility ; Cell Locomotion ; Cell Migration ; Cell Movement ; Cellular Migration ; Cellular Motility ; Motility ; Cells ; Cell Body ; Clinical Trials ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Diagnosis ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Doxorubicin ; 14-Hydroxydaunomycin ; Adriamycine ; Doxorubicina ; Hydroxyl Daunorubicin ; Hydroxyldaunorubicin ; Drug Combinations ; Drug resistance ; drug resistant ; resistance to Drug ; resistant to Drug ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Patient Care ; Patient Care Delivery ; Genes ; Goals ; Growth ; Generalized Growth ; Tissue Growth ; ontogeny ; Human ; Modern Man ; In Vitro ; Investments ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Methods ; Mission ; Mus ; Mice ; Mice Mammals ; Murine ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Neoplasm Metastasis ; Metastasis ; Metastasize ; Metastatic Lesion ; Metastatic Mass ; Metastatic Neoplasm ; Metastatic Tumor ; Secondary Neoplasm ; Secondary Tumor ; cancer metastasis ; tumor cell metastasis ; Patients ; Phosphoric Monoester Hydrolases ; Phosphatases ; Phosphohydrolases ; Phosphomonoesterases ; Publishing ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research ; Safety ; Specificity ; Survival Rate ; Testing ; Tissues ; Body Tissues ; Translating ; Paclitaxel ; Anzatax ; Asotax ; Bristaxol ; Paclitaxel (Taxol) ; Praxel ; Taxol ; Taxol A ; Taxol Konzentrat ; TimeLine ; Apoptosis ; Apoptosis Pathway ; Programmed Cell Death ; base ; improved ; Acute ; Clinical ; Phase ; Active Sites ; Serum ; Blood Serum ; insight ; Databases ; Data Bases ; data base ; Therapeutic ; In-111 ; In111 isotope ; Indium-111 ; Therapeutic Agents ; Scientist ; Clinic ; Route ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; Risk-Benefit Assessment ; Outcome Study ; meetings ; Cell Growth in Number ; Cell Multiplication ; Cellular Proliferation ; Cell Proliferation ; experience ; tumor growth ; cell killing ; synergism ; Toxicities ; Toxic effect ; novel ; chemotherapeutic agent ; Position ; Positioning Attribute ; Modeling ; drug development ; functional genomics ; disease subgroups ; disease subtype ; disorder subtype ; Documentation ; Molecular Interaction ; Binding ; preventing ; prevent ; Address ; Dose ; Data ; Grant Proposals ; Applications Grants ; breast tumor cell ; Breast Cancer Cell ; in vivo ; Apoptotic ; research clinical testing ; Clinical Evaluation ; Clinical Testing ; clinical test ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Molecular ; resistance mechanism ; resistant mechanism ; Development ; developmental ; pre-clinical ; preclinical ; triple-negative invasive breast carcinoma ; TNBC ; triple-negative breast cancer ; therapy resistant ; resistance to therapy ; resistant to therapy ; therapeutic resistance ; treatment resistance ; knock-down ; knockdown ; design ; designing ; tumor xenograft ; Outcome ; Impairment ; small hairpin RNA ; shRNA ; short hairpin RNA ; Oncogenic ; combinatorial ; clinically significant ; clinical significance ; chemotherapy ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; commercialization ; tumor ; high risk ; new therapeutic target ; new drug target ; new druggable target ; new pharmacotherapy target ; new therapy target ; novel drug target ; novel druggable target ; novel pharmacotherapy target ; novel therapeutic target ; novel therapy target ; novel therapeutic intervention ; new therapeutic approach ; new therapeutic intervention ; new therapeutic strategies ; new therapy approaches ; novel therapeutic approach ; novel therapeutic strategies ; novel therapy approach ; standard of care ; genome-wide ; genome scale ; genomewide ; in vitro activity ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; The Cancer Genome Atlas ; TCGA ; young woman ; adolescent woman ; adolescent women ; Drug Targeting ; predictive marker ; predictive biomarkers ; predictive molecular biomarker ; targeted treatment ; targeted drug therapy ; targeted drug treatments ; targeted therapeutic ; targeted therapeutic agents ; targeted therapy ; Breast Cancer cell line ; Breast tumor cell line ; Breast Cancer Patient ; Breast Tumor Patient ; response biomarker ; response markers ; improved outcome ; Patient-derived xenograft models of breast cancer ; Breast PDX models ; breast cancer PDX ; breast cancer patient-derived xenograft ; relapse risk ; clinical development ; side effect ; pharmacokinetics and pharmacodynamics ; PK/PD ; in silico ; patient derived xenograft model ; PDX model ; Patient derived xenograft ; detection method ; detection procedure ; detection technique ; black women ; black female ;
