Document text
Principal Investigator: John D Gordan
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $20,836
Funding agency: National Cancer Institute
ABSTRACT
Of the 6,500 known rare diseases, only about 5% have U.S. Food and Drug Administration-approved treatments.
In cancer, rare tumors account for approximately 20% of cancer incidence but often lack established therapeutic
regimens. Hence, gaining a molecular understanding of rare tumors is key for development of effective therapies.
This multi-investigator proposal investigates oncogenic mutations that activate protein kinase A (PKA) to promote
defective cell signaling in rare endocrine and hepatic tumors.
Targeted therapeutics have transformed care for patients with rare cancers by targeting oncogenic mutations in
protein kinases. PKAc-driven cancers are challenging to target in this way because this broad specificity kinase
controls myriad physiological processes. Consequently, selective PKAc inhibitors have been relegated to the
role of tool compounds rather than clinically viable drugs. Thus, alternative strategies must be developed to treat
PKAc-driven cancers. Our preliminary profiling of oncogenic PKAc mutants provide compelling evidence that
PKAc engages downstream protein kinase cascades that impact translation in adrenal and hepatic tumors. We
also observed increased mRNA translation as an emerging hallmark of these PKAc driven malignancies. These
findings have forged a working hypothesis that PKAc-driven cancers can be treated by targeting downstream
effectors such the RNA helicase eIF4A rather than globally blocking the catalytic activity of the kinase.
Three specific aims will test this transformative premise. 1) Proteomic and transcriptomic profiling of cells
expressing oncogenic PKAc variants that underlie Carney complex, Cushing’s adenoma and fibrolamellar
carcinoma will elucidate downstream signaling elements that impinge on mRNA translation. 2) Molecular
approaches will investigate new properties imparted by the DNAJ-PKAc-chimeric kinase in fibrolamellar
carcinoma that may confer resistance to chemically induced apoptosis. 3) Clinically relevant compounds and
novel bivalent inhibitors will dissect the mechanism of eIF4A dependence in PKAc-driven malignancies and
patient derived (PDX) models of fibrolamellar carcinoma. This proposal not only builds on a solid foundation of
PKAc research, but also affords an unparalleled opportunity to discover, develop and validate drug targets for a
group of patients in dire need.
Terms: <3'5'-cyclic ester of AMP><70-kD Heat-Shock Protein><A kinase anchoring protein><ACT2><AKAP><AT744.1><ATP-protein phosphotransferase><Act-2><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adrenal Gland Neoplasms><Adrenal Gland Tumor><Adrenal Tumor><Apoptosis><Apoptosis Pathway><Applications Grants><Atrial myxoma with lentigines><BAG2><BAG2 gene><BCL2-Associated Athanogene 2><Binding><Biochemical><Biogenesis><Biology><CCL4><CCL4 gene><Cancers><Caring><Carney Complex><Carney's Syndrome><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Chaperonin Family><Chemicals><Chemokine (C-C Motif) Ligand 4><Chemokine, CC Motif, Ligand 4><Clinical><Clinical Research><Clinical Study><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><DNA Helicases><DNA Unwinding Proteins><DNA unwinding enzyme><Dependence><Development><Diabetes Mellitus><Digestive Tract Tumor><Digestive Tumor><Disease Progression><DnaJ proteins><Drug Targeting><Drugs><Elements><Endocrine Gland Neoplasms><Endocrine System Neoplasm><Endocrine System Tumor><Endocrine Tumor><Fibrolamellar Hepatocellular Carcinoma><Food and Drug Administration><Foundations><GI Neoplasm><GI Tract Tumor><GI Tumor><Gastrointestinal Neoplasms><Gastrointestinal Tract Tumor><Gastrointestinal Tumor><Gene Targeting><Gene Transcription><Generalized Growth><Generations><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Grant Proposals><Growth><HSP 70><HSP40 protein family><HSP40 proteins><HSP70><Heart failure><Heat-Shock Proteins 70><Hepatic Neoplasms><Holoenzymes><Immune Activation 2><Incidence><Induction of Apoptosis><Initiation Factors><Intracellular Communication and Signaling><Intracellular Second Messenger><Investigators><Island><Kinase Family Gene><Kinases><L-Serine><Lentigines, Atrial Myxoma, Mucocutaneous Myoma, Blue Nevus Syndrome><Lesion><Link><Liver Cell Fibrolamellar Carcinoma><Liver neoplasms><Lung><Lung Neoplasms><Lung Respiratory System><Lung Tumor><MIP1B><MIP1B1><Macrophage Inflammatory Protein 1-Beta><Malignant Neoplasms><Malignant Tumor><Medication><Modeling><Molecular><Molecular Interaction><Mutation><NIH><National Institutes of Health><Neoplasm of the Digestive Tract><Neoplasm of the GI Tract><Neoplasm of the Gastrointestinal Tract><Nevi, Atrial Myxoma, Skin Myxoma, Ephelides Syndrome><Oncocytic Hepatocellular Tumor><Oncogenic><Oncology><Oncology Cancer><Organism-Level Process><Organismal Process><Origin of Life><Orphan Disease><Outcome><Output><Ovarian Tumor><Ovary Neoplasms><Ovary Tumor><PDX model><PKA><Pathway interactions><Patient Care><Patient Care Delivery><Patient derived xenograft><Patients><Peptide Initiation Factors><Pharmaceutical Preparations><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Physiologic><Physiologic Processes><Physiological><Physiological Processes><Polygonal Cell Type Hepatocellular Carcinoma with Fibrous Stroma><Production><Programmed Cell Death><Proliferating><Property><Protein Inhibition><Protein Kinase><Protein Kinase A><Protein Phosphorylation><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Proteins><Proteomics><Pulmonary Neoplasms><RNA Expression><RNA Helicase><Radial><Radius><Rare Diseases><Rare Disorder><Regimen><Regulation><Research><Research Personnel><Researchers><Resistance><Ribosomes><Role><SCYA4><Second Messenger Systems><Second Messengers><Serine><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Signal Transduction><Signal Transduction Systems><Signaling><Small Inducible Cytokine A4><Solid><Specificity><Strains Cell Lines><Testing><Therapeutic><Therapeutic Index><Threonine Kinase><Tissue Growth><Tissue Sample><Toxic effect><Toxicities><Transcription><Translation Initiation Factor><Translational Inhibition><Translational Initiation Factor><Translational Repression><Translations><Transphosphorylases><USFDA><United States Food and Drug Administration><United States National Institutes of Health><Variant><Variation><adenoma><adenosine 3'5' monophosphate><adrenal neoplasm><biological signal transduction><c myc><c-myc Genes><c-myc Proto-Oncogenes><cAMP><cAMP-Dependent Protein Kinases><cancers that are rare><cardiac failure><care for patients><care of patients><caring for patients><chaperonin><clinical relevance><clinically relevant><cmyc><cultured cell line><derepression><developmental><diabetes><digestive neoplasm><drug/agent><effective therapy><effective treatment><endocrine neoplasm><fibrolamellar carcinoma><forging><genome mutation><glycogen synthase a kinase><heat shock protein 40 family><heat-shock proteins 40><helicase><hepatic neoplasia><hepatic neoplasm><hepatic tumor><hsp70 Family><hydroxyalkyl protein kinase><in vivo><inhibit protein><inhibit proteins><inhibitor><kidney dysfunction><live cell image><live cell imaging><live cellular image><live cellular imaging><liver tumor><mRNA Translation><malignancy><mutant><nano><nano meter scale><nano meter sized><nanometer scale><nanometer sized><nanoscale><neoplasm/cancer><novel><ontogeny><orphan disorder><ovarian neoplasm><parent grant><pathway><patient derived xenograft model><pharmacologic><phosphorylase b kinase kinase><protein inhibitions><pulmonary><rare cancer><rare malignancy><rare tumor><recruit><renal dysfunction><resistant><response><signal transduction second messengers><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><tool><transcriptome profiling><transcriptomic profiling><translation><translational impact><tumor><tumor growth><v-myc Avian Myelocytomatosis Viral Oncogene Cellular 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