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Principal Investigator: Deliang Guo
Organization: OHIO STATE UNIVERSITY
Fiscal Year: 2024
Award: $418,800
Funding agency: National Cancer Institute
ABSTRACT
Glioblastoma (GBM) is the most common primary brain tumor and one of the most lethal of all cancers. The main
challenge in treating GBM is the quickly developing resistance to all kinds of treatments by tumor cells. Whereas
our partial understanding of GBM biology is a major roadblock to elucidate the underlying resistance
mechanisms. Our laboratory recently uncovered that GBM greatly alters lipid metabolism to gain sufficient lipids
for its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master
transcription factor that controls fatty acid synthesis, is highly expressed in GBM and is essential for tumor
growth. Our findings were recently validated by multiple groups showing that SREBP-1 is also elevated in various
other cancers. However, whether the dramatically altered lipid metabolism facilitates tumor resistance is
completely unknown. Moreover, the mechanism that upregulates SREBP-1 expression in cancer cells remains
elusive. Interestingly, we recently found that all-trans retinoic acid (ATRA) and 13-cis-RA could significantly
reduce the expression of SREBP-1 and lipogenic enzymes in a dose-dependent manner in GBM cells. These
retinoic acids are effective drugs in treating acute promyelocytic leukemia and have also been used to treat GBM
and other solid tumors, but tumor resistance has been very challenging. To date, both their antitumor and
resistance mechanisms remain poorly understood. We examined the expression of their binding partner, retinoic
acid nuclear receptor α (RARα) in GBM patient tissues and found it to be highly expressed in tumor tissues and
positively correlated with SREBP-1 expression, while inversely associated with poor patient survival.
Interestingly, our data further show that 13-cis-RA and ATRA treatment significantly increased the expression of
carnitine palmitoyltransferase 1A (CPT1A), a key enzyme shuttling fatty acids into mitochondria for β-oxidation
and energy production. Pharmacological inhibition of CPT1A combined with retinoic acid treatment resulted in
marked GBM cell death. Together, these novel preliminary data strongly support the hypothesis that 13-cis-RA
or ATRA can significantly alter lipid metabolism in GBM and promote fatty acid oxidation to support tumor cell
survival and resistance. We further hypothesize that retinoic acid treatment in combination with suppression of
SREBP-1 activation or fatty acid oxidation will effectively inhibit GBM growth and overcome tumor resistance.
The goal of this study is to identify the previously unreported roles and mechanisms of retinoic acids and RARα
in lipid metabolism regulation and GBM growth (Aim 1), and to develop effective combination approaches to
target GBM (Aim 2). Completion of this study will uncover the underlying mechanism upregulating SREBP-1
expression and lipogenesis in GBM, provide great insights into understanding the antitumor and resistance
mechanisms of retinoic acids, and identify novel strategies to target GBM and overcome retinoic acid resistance.
Terms: <13 cis retinoate><13-cRA><13-cis-Retinoic Acid><13-cis-Vitamin A Acid><21+ years old><ATRA><Acute Promyelocytic Leukemia><Adult><Adult Human><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Binding><Biology><Body Tissues><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CPT 1><Cancers><Carnitine Acyltransferase I><Carnitine O-Palmitoyltransferase><Carnitine Palmitoyltransferase><Carnitine Palmitoyltransferase I><Cell Body><Cell Death><Cell Survival><Cell Viability><Cells><Ceramides><Cholesterol><Clinical><Clinical Research><Clinical Study><Combined Modality Therapy><Data><Dose><Down-Regulation><Drugs><ER stress><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><Fatty Acids><Foundations><Gene Alteration><Gene Expression><Gene Mutation><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genus Hippocampus><Glioblastoma><Glycolysis><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Homeostasis><In Vitro><Isotretinoin><Isotretinoinum><Laboratories><Lipids><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Medication><Mitochondria><Molecular><Molecular Interaction><Multimodal Therapy><Multimodal Treatment><Myeloid Leukemia, Acute, M3><Nuclear Receptors><Outcome><Palmitoylcarnitine Transferase><Palmitylcarnitine Acyltransferase><Patients><Pharmaceutical Preparations><Phosphatides><Phospholipids><Physiological Homeostasis><Play><Primary Brain Neoplasms><Primary Brain Tumors><Production><Prognosis><Progranulocytic Leukemia><Regulation><Reporting><Resistance><Resistance development><Resistant development><Retinoic Acid><Retinoicacid-13-cis><Role><SRE-1 binding protein><SREBP-1><Sampling><Seahorse><Solid Neoplasm><Solid Tumor><Testing><Tissue Growth><Tissues><Trans Vitamin A Acid><Transcription Factor Proto-Oncogene><Transcription factor genes><Tretinoin><Tretinoinum><Tumor Cell><Tumor Promotion><Tumor Tissue><Vitamin A Acid><adipogenesis><adulthood><all-trans-Retinoic Acid><all-trans-Vitamin A acid><cancer cell><carnitine palmitoyltransferase 1><cis-Retinoic Acid><clinical relevance><clinically relevant><cohort><combination therapy><combined modality treatment><combined treatment><determine efficacy><developing resistance><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endoplasmic reticulum stress><evaluate efficacy><examine efficacy><fat metabolism><fatty acid oxidation><gene synthesis><glioblastoma multiforme><improved><in vivo><insight><lipid biosynthesis><lipid metabolism><lipidomics><lipogenesis><malignancy><metabolism measurement><metabolomics><metabonomics><mitochondrial><multi-modal therapy><multi-modal treatment><necrocytosis><neoplasm/cancer><neoplastic cell><new approaches><novel><novel approaches><novel strategies><novel strategy><ontogeny><oxidation><pharmacologic><promyelocytic leukemia><rapid growth><resistance mechanism><resistant><resistant mechanism><response><screening><screenings><social role><spongioblastoma multiforme><sterol regulatory element-binding protein 1><synergism><trans-Retinoic Acid><transcription factor><tumor><tumor growth><tumors in the brain><uptake>