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Principal Investigator: Mehdi Mollapour
Organization: SYRACUSE VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Over 79,000 people will develop kidney cancer, also known as renal cell carcinoma (RCC), and almost
14,000 patients will die from this disease in the US this year. Risk factors such as tobacco smoking, obesity
and exposure to organic solvents, heavy metals, herbicides, and petrochemicals, all play a major role in
the development of RCC. Members of the military and their families are at risk of developing RCC because
of exposure to these risk factors: 1) Cheap tobacco prices have been identified by enlisted personnel and
Department of Defense health policy experts as promoting a culture of tobacco use in the US Military.
Smoking doubles the risk of RCC in the members of the military; 2) Higher incidence of RCC in men versus
women (2:1 ratio); 3) Incidence of RCC in veterans of Operation Ranch Hand, the unit responsible for
aerially spraying herbicides in Vietnam. 4) Obesity among the non-active duty; 5) Military families are at
risk because of environmental exposures. In terms of treatment, traditional radiation and chemotherapies
are ineffective and ~50% of patients develop metastatic disease, for whom the 5-year survival rate is only
~10%. Such grim statistics point to an urgent need for deeper understanding of the RCC biology and also
for developing better therapeutic strategies. Clear Cell Renal Cell Carcinoma (ccRCC), the most common
type of renal cancer, is resistant to conventional radiotherapy and chemotherapy. This subtype of kidney
cancer uses aerobic glycolysis to convert glucose to pyruvate and then lactate, a phenomenon known as
the “Warburg effect”. Lactate dehydrogenase-A (LDHA) is the key enzyme in converting pyruvate to lactate
in order to speedily produce ATP. LDHA has Althouwith gh been shown to be an attractive target in ccRCC
therapy, LDHA inhibitors have yet to see meaningful clinical advancement. This is in part due to a lack of
LDH isoform selectivity. We have recently reported that the tumor suppressor FLCN function as an intra-
cellular specific inhibitor of LDHA but not LDHB. Our data has shown that a MAPK signaling pathway is
responsible for FLCN phosphorylation, inactivation and dissociation from LDHA. This is important for the
hyperactivity of LDHA and conversion of pyruvate to lactate. However, the detailed mechanism of this
process in ccRCC remains elusive. Additionally, we have created a cyclic decapeptide derived from the
FLCN which is protected from cellular proteases, but without losing its inhibitory activity towards LDHA.
This peptide readily enters cells, inhibit LDHA and cause apoptosis in ccRCC. The long-term goal of this
project is to improve outcomes for patients with ccRCC by developing therapeutic strategies that targets
LDHA. The overall objective is to determine the signaling networks involved in FLCN inactivation, disas-
sociation and hyperactivity of LDHA in ccRCC. The central hypothesis is that MAPK mediated phosphory-
lation of FLCN leads to its inactivation, disassociation and hyperactivity of LDHA. The rationale of this
proposal is that by dissecting these regulatory networks, we could design a strategy to specifically inhibit
LDHA. Biochemical, biophysical, cell-based assays, and patient derived ccRCC tumor xenograft model as
well and the ccRCC tissue array will be used to test the hypothesis in the following specific aims; Aim 1:
Determine the mechanism of MAPK mediated phosphorylation and inactivation of FLCN in ccRCC. Aim 2:
Determine the mechanism of MAPK activation by pyruvate stress in ccRCC. Aim 3: Evaluate the impact of
FLCN mediated inhibition of LDHA in ccRCC patient-derived xenograft model. We expect that data gener-
ated here will determine the molecular mechanism of the tumor suppressor FLCN inactivation and LDHA
hyperactivity and the Warburg effect in ccRCC. We also expect to demonstrate cyclic-FLCN decapeptide
as potent specific inhibitor of LDHA in ccRCC. The outcome of this research will allow us to design new
therapeutic strategies in treating Veterans with kidney cancer and potentially other cancers that experience
the Warburg effect.
Terms: <Acids><Active Sites><Apoptosis><Apoptosis Pathway><Armed Forces Personnel><Assay><Autoregulation><Binding><Bioassay><Biochemical><Biological Assay><Biology><Biophysics><Cancer Biology><Cancer cell line><Cancers><Carcinoma Cell><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clear cell renal cell carcinoma><Clinic><Clinical><Cyclicity><D-Glucose><Data><Department of Defense><Development><Dextrose><Disease><Disease Progression><Disorder><Dissociation><Environment><Environmental Exposure><Enzyme Gene><Enzymes><Esteroproteases><Exposure to><Family><Folliculin><Glucose><Glycolysis><Goals><Grawitz Tumor><Half-Life><Hand><Health Policy><Heavy Metals><Herbicides><Homeostasis><Human Resources><Hyperactivity><Hypernephroid Carcinoma><Hypernephroma><In Vitro><Incidence><Intermediary Metabolism><Intracellular Communication and Signaling><Isoforms><Kidney Cancer><Kidney Carcinoma><Kidney Neoplasms><Kidney Tumor><Knowledge><LDH-A><LDH-M><Lead><MAP kinase><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Tumor><Manpower><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Military><Military Personnel><Mitogen-Activated Protein Kinases><Molecular><Molecular Interaction><Movement><Murine><Mus><Nature><Nephroid Carcinoma><Normal Cell><O element><O2 element><Obesity><Organic Solvents><Organic solvent product><Outcomes Research><Oxygen><PDX model><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pb element><Peptidases><Peptide Hydrolases><Peptides><Periodicity><Persons><Phosphorylation><Physiological Homeostasis><Play><Price><Process><Production><Programmed Cell Death><Protease Gene><Proteases><Protein Isoforms><Protein Phosphorylation><Proteinases><Proteolytic Enzymes><Publishing><Pyruvate><Renal Adenocarcinoma><Renal Cancer><Renal Carcinoma><Renal Cell><Renal Cell Adenocarcinoma><Renal Cell Cancer><Renal Cell Carcinoma><Renal Neoplasms><Renal Tumor><Reporting><Resistance><Rhythmicity><Risk><Risk Factors><Role><Services><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Smoking><Speed><Stress><Survival Rate><Testing><Therapeutic><Thesaurismosis><Tissue Arrays><Tissue Chip><Tissue Microarray><Tobacco><Tobacco Consumption><Tobacco smoking><Tobacco smoking behavior><Tobacco use><Translating><Tumor Suppressor Proteins><Veterans><Viet Nam><Vietnam><Warburg Effect><Work><Xenograft Model><adiposity><aerobic glycolysis><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><body movement><ccRCC><chemo/radiation therapy><chemotherapy and radiotherapy><comparing females and males><comparing women and men><corpulence><design><designing><developmental><enzyme activity><experience><females compared to males><females compared with males><females versus males><females vs males><flexibility><flexible><glucose uptake><hands><health care policy><healthcare policy><heavy metal Pb><heavy metal lead><improved outcome><ineffective therapies><ineffective treatment><inhibitor><kidney adenocarcinoma><kidney cell><kidney development><lactate dehydrogenase A><malignancy><metabolism disorder><military family><military member><military population><military veteran><mortality><neoplasm/cancer><nephrogenesis><new approaches><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 approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><operation><operations><organic acid><pathway><patient derived xenograft model><patient oriented outcomes><personnel><prevent><preventing><pricing><radiation or chemotherapy><resistant><service member><social role><statistics><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tobacco product use><tumor growth><tumor suppressor><tumor xenograft><unpublished works><veteran population><women compared to men><women compared with men><women versus men><women vs men><xenograft transplant model><xenotransplant model>