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Principal Investigator: Gabrelle Lavender Hackman
Organization: UNIVERSITY OF TEXAS AT AUSTIN
Fiscal Year: 2024
Award: $39,539
Funding agency: National Cancer Institute
PROJECT SUMMARY
Broad Impact: Prostate cancer (PCa) is the most commonly diagnosed cancer in American men and in 2022
alone will result in the death of over 34,000 men. PCa mortality is typically caused by disease that has
advanced to the metastatic castration-resistant stage (mCRPC) and has spread to distant sites such as the
bone, brain, liver, and lymph nodes. Currently, there are no effective or curative therapeutic strategies for
mCRPC, which is in part due to high rates of acquired drug resistance to androgen deprivation therapy (ADT)
and the standard-of-care chemotherapy drug for mCRPC, docetaxel (DTX). Consequently, there is a critical
need for novel and effective therapeutic options for mCRPC. Recent findings have indicated glutamine and
related glutamate metabolism as significant drivers of the metabolic reprogramming of mCRPC that contributes
to drug resistance mechanisms. Indeed, a metabolic switch has been identified in PCa following ADT that
allows the cells to rely on the androgen-independent isoform of glutaminase (GLS1, the enzyme that converts
glutamine to glutamate) rather than the isoform that is inhibited by ADT, affording drug resistance. Efforts to
chemically inhibit GLS1 to overcome this issue have failed since there is a steady influx of glutamate via the
xCT transporter when there are physiologically-relevant levels of cystine. However, our preliminary data shows
that concurrently inhibiting GLS1 as well as glutamate dehydrogenase (GDH, the enzyme that converts
glutamate to the TCA cycle intermediate alpha-ketoglutarate) may be sufficient to overcome this resistance
mechanism across PCa subtypes including mCRPC. The overall goal of this project is to identify novel
combinatorial treatments for mCRPC that synergize with DTX to target metabolic vulnerabilities and overcome
drug resistance for improved treatment outcomes. Central hypothesis: Concurrent inhibition of GLS1 and GDH
in combination with DTX can circumvent drug resistance mechanisms and increase therapeutic efficacy
compared to SOC in mCRPC. Aim 1: Determine the metabolic role of GLS1 inhibition with CB-839 plus DTX
for the synergistic inhibition of PCa tumor growth in vivo. Aim 2: Elucidate the impact of concurrent GLS1 and
GDH inhibition plus DTX on PCa growth, proliferation, metabolism, aggressiveness, and invasiveness
compared to SOC in vitro. Aim 3: Evaluate whether combination treatment with a GLS1 inhibitor and a GDH
inhibitor plus DTX can synergistically inhibit PCa growth more effectively than SOC in vivo. Experimental
techniques including metabolomics, metabolic flux analysis using stable isotope tracers, in vitro and in vivo
modeling of mCRPC, and validation of drug treatment efficacy will be undertaken to achieve the research
goals. These findings will be used to inform novel treatment strategies to accompany docetaxel to prevent
cancer growth, proliferation, and aggressiveness in mCRPC for more effective treatments and improved
outcomes for patients with mCRPC.
Terms: <2-ketoglutarate><2-oxoglutarate><Allografting><American><Androgenic Agents><Androgenic Compounds><Androgens><Automobile Driving><Autoregulation><Biomass><Body Tissues><Brain><Brain Nervous System><Breast Cell Glutaminase><Bypass><Cancer Cause><Cancer Etiology><Cancers><Caring><Castration><Cell Body><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Proliferation><CellLine><Cells><Cellular Proliferation><Cessation of life><Chemicals><Chemoresistance><Citric Acid Cycle><Combined Modality Therapy><Cystine><DU-145><DU145><Data><Death><Development><Diagnosis><Disease><Disorder><Distant><Drug Synergism><Drug Therapy><Drug resistance><Drugs><EC 3.5.1.2><EGCG><EGCG cpd><Encephalon><Enzyme Gene><Enzymes><Epigallocatechin Gallate><Epigallocatechingallate><Essential Amino Acids><Event><Exhibits><Formulation><GA Protein><Generalized Growth><Generations><Gln><Glutamate Dehydrogenase><Glutamate Metabolism><Glutamate Metabolism Pathway><Glutamates><Glutaminase><Glutamine><Goals><Green Tea Extract><Green Tea Polyphenols><Growth><Homeostasis><In Vitro><Intermediary Metabolism><Isoforms><Kidney><Kidney Urinary System><Krebs Cycle><L glutamine amidohydrolase><L-Cystine><L-Glutamate><L-Glutamine><Liver><Liver Glutaminase><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Medication><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Neoplasm Metastasis><Nutrient><Oxidation-Reduction><PC-3><PC-3 cell line><PC3><PC3 cell line><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutical Preparations><Pharmacotherapy><Physiologic><Physiological><Physiological Homeostasis><Probability><Process><Production><Prognosis><Proliferating><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protein Isoforms><Q Levoglutamide><Q. Levoglutamide><Redox><Reporting><Research><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Signal Transduction Pathway><Site><Strains Cell Lines><Surgical Castration><Survival Rate><TCA cycle><Taxotere><Tea catechin><Techniques><Testing><Therapeutic><Therapeutic Agents><Therapeutic Androgen><Tissue Growth><Tissues><Tracer><Treatment Efficacy><Treatment outcome><Tricarboxylic Acid Cycle><Validation><Work><acquired drug resistance><advanced prostate cancer><alpha ketoglutarate><alpha-oxoglutarate><androgen ablation therapy><androgen blockade therapy><androgen dependent><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><androgen responsive><androgen sensitive><antiporter><bone><cancer cell><cancer diagnosis><cancer drug resistance><cancer metastasis><cancer sub-types><cancer subtypes><cancer type><carbon skeleton><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><combination therapy><combinatorial><combined modality treatment><combined treatment><common treatment><comparable efficacy><comparative efficacy><compare efficacy><cultured cell line><curative intervention><curative therapeutic><curative therapy><curative treatments><developmental><docetaxel><docetaxol><driving><drug resistant><drug treatment><drug/agent><druggable target><effective therapy><effective treatment><efficacy outcomes><epigallo-catechin gallate><epigallocatechin-3-gallate><experiment><experimental research><experimental study><experiments><glutamatergic><glutamic dehydrogenase><hepatic body system><hepatic organ system><hormone refractory prostate cancer><improved><improved outcome><in vivo><in vivo Model><inhibitor><insight><intervention efficacy><lymph gland><lymph nodes><lymphnodes><malignancy><men><metabolism measurement><metabolomics><metabonomics><meter><mortality><multi-modal therapy><multi-modal treatment><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><oxidation reduction reaction><pathway><patient oriented outcomes><prevent><preventing><prostate cancer cell line><prostate cancer progression><prostate cancer resistant to androgen><renal><resistance mechanism><resistance to Drug><resistance to cancer drugs><resistant><resistant mechanism><resistant to Drug><resistant to cancer drugs><social role><stable isotope><standard of care><synergism><therapeutic efficacy><therapeutically effective><therapy efficacy><treatment strategy><tumor cell metastasis><tumor growth><validations><α-ketoglutarate><α-oxoglutarate><αKG>