Document text
Principal Investigator: Brian K. Law
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $165,076
Funding agency: National Cancer Institute
Breast cancer remains a major killer of women due to the ineffectiveness of current drugs against
metastatic and drug-resistant cancers. Additionally, African American (AA) women suffer
disproportionately from breast cancer mortality in part because they develop the aggressive Triple-
Negative Breast Cancer (TNBC) subtype more frequently than other ethnic groups. Thus, agents
effective against drug-resistant and metastatic cancers and TNBCs may improve the survival of
breast cancer patients. These aggressive cancers evade cell death through a variety of mechanisms
including overactivation of the pro-survival HER-family of Receptor Tyrosine Kinases (RTKs),
including EGFR/HER1, HER2, and HER3 (HER1-3), and inactivation of pro-apoptotic signaling.
Tumors expressing HER1-3 are difficult to treat due to the partial redundancy among these receptors,
their oncogenic signaling as heterodimers, and their ability to aberrantly heterodimerize with non-HER
RTKs such as MET and IGF1R. Thus, resistance to current HER-targeted agents is a significant
clinical problem. Defective cancer cell apoptosis can result from inactivation of the TNF Receptor
Apoptosis Inducing Ligand (TRAIL)/Death Receptor 4/5 (DR4/5) pathway, which selectively kills
cancer cells, while not affecting normal cells. Tumor resistance to TRAIL and other DR4/5 agonists
results primarily from poor pharmacological properties of the agonists and the ability of cancer cells to
downregulate DR4/5. Consequently, agents that could inactivate the EGFR/HER2/HER3 signaling
axis and upregulate and activate DR4/5 independently of the TRAIL ligand may be efficacious against
breast cancers unresponsive to current medicines. Disulfide bond Disrupting Agents (DDAs) are a
new class of anti-cancer agents that induce regression of primary tumors and metastatic lesions of
drug-resistant patient-derived tumors in animal models. In addition to the structural uniqueness of
DDAs, recent studies indicate that DDAs are the first identified active site inhibitors of the Protein
Disulfide Isomerases (PDIs) ERp44 and AGR2. Further, DDA inhibition of the PDIs ERp44, AGR2,
and PDIA1 alters the disulfide bonding of HER1-3 and DR4/5, resulting in HER1-3 downregulation,
DR5 upregulation, and disulfide bond-mediated oligomerization and activation of DR4/5. The
objective of the current project is to move DDAs toward clinical trials. The two Specific Aims proposed
to achieve this objective are to 1) optimize DDA pharmacological properties and dosing for future
IND-enabling studies, and 2) validate biomarkers to predict tumor sensitivity to DDAs and to monitor
target engagement, and thoroughly evaluate any adverse effects of DDAs on normal tissues or
animal health. Based on their unique mechanisms of action and preclinical efficacy, we expect DDAs
to benefit breast cancer patients with treatment-refractory breast cancers.
Terms: <AG2><AGR2><AGR2 gene><APO2><Active Sites><Advanced Cancer><Advanced Malignant Neoplasm><Adverse effects><Affect><African American Females><African American Women><Agonist><American><Animal Model><Animal Models and Related Studies><Animals><Anterior Gradient 2 Homolog><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Gene Caspase 8><Apoptotic><Apoptotic Cysteine Protease Gene><Apoptotic Protease MCH-5 Gene><Autopsy><Binding><Biological Markers><Blood Cell Count><Blood Cell Number><Blood Plasma><Breast><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Tumor Patient><CAP4><CAP4 protease><CASP8><CASP8 Protein><CASP8 gene><Cachectin Receptors><Cancer Drug><Cancer Induction><Cancers><Caspase-8 Gene><Caspase-8/Flice><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell surface><Cessation of life><Chemicals><Client><Clinical><Clinical Trials><Cytotoxic TRAIL Receptor-2><DR4><DR5><DR5 protein><Death><Death Receptor 4><Death Receptor 5><Dependence><Disseminated Malignant Neoplasm><Disulfide Interchange Enzyme><Disulfide Isomerase><Disulfides><Dose><Down-Regulation><Drug Kinetics><Drug resistance><Drugs><EGF Receptor><EGF Receptor 3 Gene><EGFR><ERBB Protein><ERBB2><ERBB2 gene><ERBB3><ERBB3 gene><ERp59 PDI><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Erp59><Ethnic Group><Ethnic People><Ethnic Population><Ethnic individual><Ethnicity People><Ethnicity Population><Exhibits><FADD-Homologous ICE/CED3-Like Protease Gene><FADD-Like ICE><FADD-Like ICE Gene><FADD-homologous ICE/CED3-Like Protease><FLICE><FLICE protein><Family><Fas-Like Protein Precursor><Formulation><Future><GOB-4><GSBP><Glycosylation Site-Binding Protein><HAG-2><HAG-2 Gene><HER -2><HER-2><HER1><HER2><HER2 Genes><HER2/neu><HER3><Health><Heterodimerization><Histologic><Histologically><Human><ICE-Like Apoptotic Protease 5 Gene><IGF1R><IGF1R gene><Induction of Apoptosis><Insulin-Like Growth Factor 1 Receptor Gene><Intermediary Metabolism><Intracellular Communication and Signaling><KILLER/DR5><Kidney><Kidney Urinary System><Knock-out><Knockout><Ligands><Link><Liver><MACH protein><MACH-Alpha-1/2/3 Protein Gene><MACH-Beta-1/2/3/4 Protein Gene><MCH5><MCH5 Isoform Alpha Gene><MGC9365><MORT1-Associated CED-3 Homolog Gene><MORT1-Associated CED3 Homolog Gene><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mch5 protease><Mediating><Medication><Medicine><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Monitor><Murine><Mus><Muscle><Muscle Tissue><NEU Oncogene><NEU protein><Needle biopsy procedure><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Normal Cell><Normal Tissue><Normal tissue morphology><Oncogene ErbB2><Oncogene Products><Oncogene Proteins><Oncogenic><Oncoproteins><PK/PD><PTK Receptors><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacokinetics><Plasma><Plasma Serum><Preparation><Primary Neoplasm><Primary Tumor><Programmed Cell Death><Property><Protein Disulfide Isomerase><Protein Inhibition><Proteins><Publishing><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Refractory><Resistance><Reticuloendothelial System, Serum, Plasma><Role><Route><S-S rearrangase><Safety><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Sulfhydryl-Disulfide Interchange Enzyme><TGF-alpha Receptor><TKR1><TNBC><TNF Receptor Family Protein><TNF Receptor Ligands><TNF Receptor Superfamily><TNF Receptors><TNF-Related Apoptosis Inducing Ligand Receptor 1><TNF-related apoptosis-inducing ligand receptor 1><TNFR><TNFRSF10A><TNFRSF10A gene><TNFRSF10B><TNFRSF10B gene><TRAIL Receptor 1><TRAIL Receptor 2><TRAIL-R2><TRAIL-R4><TRAILR-1><TRAILR1><TRAILR2><TRICK2><TRICK2A><TRICK2B><TRICKB><Therapeutic><Thiol-Disulfide Transhydrogenase><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Transmembrane Receptor Protein Tyrosine Kinase><Trypanothione-Glutathione Thioltransferase><Tumor Escape><Tumor Immune Escape><Tumor Necrosis Factor Family Protein><Tumor Necrosis Factor Receptor><Tumor Necrosis Factor Receptor Family><Tumor Necrosis Factor Receptor Superfamily><Tumor Necrosis Factor Receptor Superfamily, Member 10A><Tumor Necrosis Factor Receptor-Like Protein ZTNFR9><Tumor Necrosis Factors><Tumor-Specific Treatment Agents><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Up-Regulation><Upregulation><Urogastrone Receptor><Woman><Work><XAG-2><XAG-2 Gene><ZTNFR9><advanced breast cancer><advanced stage breast cancer><anti-cancer><anti-cancer drug><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker validation><breast cancer survival><breast tumor cell><c-erbB-1><c-erbB-1 Protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer metastasis><cancer sub-types><cancer subtypes><cancer survival><carcinogenesis><caspase-8><clinical relevance><clinically relevant><death receptor-4><disulfide bond><dosage><drug resistant><drug/agent><dsbA Gene Product><dsbA Protein><dsbC Gene Product><dsbD Gene Product><erbB-1><erbB-1 Proto-Oncogene Protein><erbB-2 Genes><erbBl><ethnic subgroup><ethnicity group><hepatic body system><hepatic organ system><herstatin><improved><in vivo><inhibit protein><inhibit proteins><inhibitor><malignancy><malignant breast tumor><marker validation><model of animal><mortality><muscular><necrocytosis><necropsy><needle biopsy><neoplasm/cancer><neu Genes><overexpress><overexpression><pathway><patient stratification><pharmacokinetics and pharmacodynamics><pharmacologic><postmortem><pre-clinical efficacy><pre-clinical study><preclinical efficacy><preclinical study><predictive biomarkers><predictive marker><predictive molecular biomarker><preparations><prevent><preventing><protein folding><protein inhibitions><proto-oncogene protein c-erbB-1><receptor><receptor TRAIL-4><refractory cancer><renal><resistance to Drug><resistance to therapy><resistant><resistant cancer><resistant to Drug><resistant to therapy><response><social role><stratified patient><targeted agent><therapeutic resistance><therapeutically effective><therapy resistant><treatment effect><treatment resistance><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor evasion><tumor immune evasion><tumor necrosis factor receptor superfamily member 10A><xprA Gene Product>