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Principal Investigator: JUNG-MO AHN
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $283,533
Funding agency: National Cancer Institute
Project Summary/Abstract
Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Despite initial response to
chemotherapy, most OCa patients become resistant and progress to metastatic disease. Long-term prognosis of
OCa is dismal, and new therapeutic strategies are desperately needed to improve OCa patient survival. The rapidly
proliferative OCa cells have a high demand for de novo protein synthesis, which results in an enhanced basal level
of endoplasmic reticulum (ER) stress. Indeed ER-stress associated proteins GRP78, PERK, and ATF6 are
overexpressed in OCa compared to normal tissues. ER stress triggers the compensatory unfolded protein response
(UPR), which can either restore homeostasis or activate cell death. We reasoned that the high basal level of ER
stress in OCa represents a critical vulnerability, and drugs that further aggravate this already engaged system in
OCa may exhaust its protective features and contribute to apoptosis induction. Towards that end, we have identified
a first-in-class compound, the oligobenzamide ERX-208, which enhances ER stress in OCa cells but not in
primary epithelial cells. ERX-208 significantly reduced the growth of OCa xenografts, patient-derived explant, and
patient-derived xenografts. Unbiased CRISPR knockdown screens identified the lysosomal acid lipase A (LIPA)
protein as the critical target of ERX-208: knockdown of LIPA abrogates response to ERX-208, while reconstitution
of LIPA restores ERX-208 response. We have shown that the binding of LIPA to ERX-208 is critical for the ability
of ERX-208 to induce ERS and subsequently apoptosis in OCa cells. The objective of this proposal is to conduct
mechanistic studies to identify the precise mechanism of action of ERX-208 in OCa, to optimize the “lead” ERX-
208 analog with improved pharmacologic and pharmacokinetic features and to validate that ERX-208 can
overcome the heterogeneity of OCa. Our overarching hypothesis is that the binding of ERX-208 to LIPA
enhances ERS and induces apoptosis in OCa and targets a critical vulnerability in OCa. Aim1 studies will establish
molecular correlates of ERX-208 in OCa cells using unbiased transcriptomics and proteomics, define
ultrastructurally how ERX-208 binding to LIPA causes ERS/UPR, define specific interactions between ERX-208
and LIPA with unbiased mutagenesis and define LIPA binding partners disrupted by ERX-208 and their effect on
ERS/UPR pathways. Aim 2 studies will use medicinal chemistry approaches to generate few ERX-208 analogs for
enhanced specificity for LIPA, define the maximum tolerated dose, dose-ranging studies for ERX-208, and
determine PK, PD, and toxicity to therapeutic ratios. Aim 3 studies will test the efficacy of ERX-208 in blocking
OCa progression in vivo using clinically relevant orthotopic xenograft, syngeneic mouse models, patient-derived
explant, organoids and patient-derived xenograft models. We believe that our studies will establish a novel
therapeutic strategy (enhancing ERS), novel therapeutic target (LIPA), novel therapeutic agents (ERX-
208/analogs) and the preclinical rationale for further clinical translation for patients with advanced OCa.
Terms: <ATF6><ATF6 gene><Acid Lipase><Activating Transcription Factor 6><Apoptosis><Apoptosis Pathway><Autoregulation><BiP gene><BiP protein><Binding><Biodistribution><Biological><CRISPR><CRISPR/Cas system><Cancer Cause><Cancer Etiology><Cancer Model><Cancer Patient><Cancer cell line><CancerModel><Cell Death><Cell Line><CellLine><Chemicals><Chemistry><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Disease><Disorder><Dose><Drug Kinetics><Drugs><EIF-2 alpha><EIF-2alpha><EIF-2α><ER stress><Epithelial Cells><Face><Female Reproductive Cancer><GRP78><GRP78 gene><Generalized Growth><Genetics-Mutagenesis><Glucose-Regulated Protein, 78-kD><Growth><Gynecologic Cancer><Gynecological Cancer><HSPA5><Heat-Shock 70-kD Protein 5><Heterogeneity><Heterograft><Heterologous Transplantation><Homeostasis><In Vitro><Induction of Apoptosis><Inter-tumoral heterogeneity><Intratumoral heterogeneity><Libraries><Lipase><Malignant Cell><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor of the Female Reproductive System><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medication><Medicinal Chemistry><Modeling><Molecular><Molecular Interaction><Mutagenesis><Mutagenesis Molecular Biology><Normal Cell><Normal Tissue><Normal tissue morphology><Organoids><Outcome><Ovary Cancer><PDX model><Pathway interactions><Patient derived xenograft><Patients><Pharmaceutic Chemistry><Pharmaceutical Chemistry><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Physiological Homeostasis><Prognosis><Programmed Cell Death><Protein Biosynthesis><Proteins><Proteomics><Resistance><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Signal Pathway><Somatic Mutation><Specificity><Strains Cell Lines><System><Testing><Therapeutic><Therapeutic Agents><Tissue Growth><Toxic effect><Toxicities><Treatment Efficacy><Triacylglycerol Hydrolase><Triacylglycerol Lipase><Triacylglycerol acylhydrolase><Tributyrinase><Triglyceridase><Triglyceride Lipase><Triolean Hydrolase><Tumor Cell><United States><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><aberrant folded protein><aberrant folded proteins><abnormal folded protein><abnormal folded proteins><alpha Subunit Eukaryotic Initiation Factor 2><analog><biologic><cancer cell><cancer progression><chemotherapy><clinical relevance><clinical translation><clinically relevant><clinically translatable><cofactor><cultured cell line><drug/agent><efficacy testing><endoplasmic reticulum stress><exhaust><expression subtypes><faces><facial><gynecologic malignancy><gynecological malignancy><heterogeneity in tumors><immunoglobulin heavy chain-binding protein><improved><in vivo><indexing><intertumoral heterogeneity><intervention efficacy><intra-tumoral heterogeneity><intratumor heterogeneity><knock-down><knockdown><lead optimization><misfolded protein><misfolded proteins><molecular sub-types><molecular subsets><molecular subtypes><mouse model><murine model><necrocytosis><neoplasm progression><neoplastic cell><neoplastic progression><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><ontogeny><ovarian cancer><overexpress><overexpression><pathway><patient derived xenograft model><pharmacologic><potential biological marker><potential biomarker><pre-clinical><preclinical><protein synthesis><proteotoxic protein><proteotoxin><rational design><reconstitute><reconstitution><resistant><response><response biomarker><response markers><somatic variant><survival outcome><therapeutic efficacy><therapy efficacy><transcriptomics><translational study><tributyrase><tumor><tumor heterogeneity><tumor progression><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model>