Targeting SLC7A11-induced nutrient dependency in cancer: mechanisms and preclinical translation

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Boyi  Gan
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $404,602
Funding agency: National Cancer Institute

Project Summary
 Specific genetic alterations in cancer cells may reprogram their metabolic networks and render them highly
dependent on particular nutrients for survival. A mechanistic understanding of nutrient dependency in cancer
cells has important implications for cancer treatment because drugs that impair nutrient metabolism may be
effective for killing cancer cells that depend on specific nutrients for survival while sparing normal cells. While
targeting nutrient dependency has been successful in leukemia, to date there has been limited success in
targeting nutrient dependency in solid tumors. Therefore, there is a significant need to understand the
mechanisms of action of anti-neoplastic agents that target nutrient dependency in cancer cells. SLC7A11 is an
amino acid transporter that enables cystine uptake and its subsequent conversion to cysteine, which is critical
for maintaining redox balance and cell survival. SLC7A11 is frequently overexpressed in human cancers,
including KEAP1-mutant lung cancers. This application aims to determine the roles and mechanisms of
SLC7A11 in regulating nutrient dependency and to therapeutically target nutrient dependency in cancers with
aberrant expression of SLC7A11. Our specific aims are: Specific Aim 1: To determine the metabolic mechanisms
underlying SLC7A11-induced glucose dependency in cancer cells. Specific Aim 2: To determine the therapeutic
potential of inhibiting GLUTs or the PPP in treating tumors with aberrant SLC7A11 expression. The rationale for
the proposed research is that studying the roles of SLC7A11 in regulating glucose dependency will not only
advance our mechanistic understanding of nutrient dependency in cancer cells but also provide important
insights into the development of novel therapeutic strategies to target metabolic vulnerabilities in SLC7A11-
overexpressing tumors. Our proposed studies will have significant impact on both our understanding of the
fundamental mechanisms of nutrient dependency and our ability to therapeutically target nutrient dependency in
cancer treatment.

Terms: <Amino Acid Channel><Amino Acid Transport Systems><Amino Acid Transporter><Anti-Cancer Agents><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Autoregulation><Biochemical Pathway><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancer Drug><Cancer Treatment><Cancers><Cell Body><Cell Death><Cell Death Induction><Cell Line><Cell Survival><Cell Viability><CellLine><Cells><Coenzyme II><Cysteine><Cystine><D-Glucose><Data><Dependence><Development><Dextrose><Disulfides><Drugs><Equilibrium><Exhibits><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Glucose><Glucose Binding Protein><Glucose Transport Protein><Glucose Transporter><Glucosephosphates><Goals><Half-Cystine><Heterograft><Heterologous Transplantation><Hexose Monophosphate Shunt><Homeostasis><Human><Immune system><Impairment><Intermediary Metabolism><L-Cysteine><L-Cystine><Link><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Medication><Metabolic><Metabolic Networks><Metabolic Processes><Metabolism><Modern Man><Mutation><NAD phosphate><NAD(H) phosphate><NADH phosphate><NADP><NADPH><Nature><Neoplastic Disease Chemotherapeutic Agents><Nicotinamide-Adenine Dinucleotide Phosphate><Normal Cell><Nutrient><Outcome><Oxidation-Reduction><PDX model><Pathway interactions><Patient derived xenograft><Pentose Phosphate Pathway><Pentose Phosphate Shunt><Pentose Shunt><Pentosephosphate Pathway><Pentosephosphate Shunt><Pharmaceutical Preparations><Phosphates><Physiological Homeostasis><Pre-Clinical Model><Preclinical Models><Pulmonary Cancer><Pulmonary malignant Neoplasm><Radiation therapy><Radiotherapeutics><Radiotherapy><Redox><Research><Role><Solid Neoplasm><Solid Tumor><Starvation><Strains Cell Lines><Testing><Therapeutic><Translations><Triphosphopyridine Nucleotide><Tumor-Specific Treatment Agents><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer drug><anti-cancer therapy><antiporter><balance><balance function><cancer cell><cancer therapy><cancer-directed therapy><clinical care><clustered regularly interspaced short palindromic repeats screen><cultured cell line><developmental><drug/agent><genome mutation><glucose phosphate><inhibitor><innovate><innovation><innovative><inorganic phosphate><insight><leukemia><lung cancer><lung cancer cell><malignancy><mutant><necrocytosis><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><nutrient metabolism><overexpress><overexpression><oxidation reduction reaction><pathway><patient derived xenograft model><pre-clinical><preclinical><programs><radiation treatment><small molecule><social role><standard of care><success><targeted agent><therapeutic target><translation><treatment with radiation><tumor><uptake><xeno-transplant><xeno-transplantation>