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Principal Investigator: Nitai Hait
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2024
Award: $86,750
Funding agency: National Cancer Institute
ABSTRACT Sphingolipid metabolites and their metabolic enzymes, often dysregulated in cancer, may present
a novel but exploitable target for therapeutics against aggressive diseases such as triple -negative breast cancer
(TNBC) and epidermal growth factor receptor 2 (HER2+) breast cancers, where new therapy is desperately
needed. A growing body of evidence implicates the cellular bioactive sphingolipid metabolite, ceramide -1-
phosphate (C1P), and ceramide kinase (CERK), the only mammalian enzyme known to produce cellul ar C1P,
as essential signaling mediators of inflammation and cancer progression. However, the function of C1P and
CERK remains enigmatic. Nevertheless, CERK is prominently associated with cancer, including lung
adenocarcinoma, pancreatic cancer, and breast cancer. Excessive tumor CERK expression correlates with
greater aggressiveness and poorer clinical outcome. A Cancer CERK is linked with activation of Ras/ERK,
PI3K/AKT/mTOR, and resistance to chemotherapy. It is commonly thought that Golgi-resident CERK generates
C1P that is released into the extracellular milieu and that signals through unknowncell surface G -protein coupled
receptors to regulate inflammation and cancer cell survival, migration and wound healing. Challenging the notion
of Golgi-resident CERK, our Preliminary Results showed enzymatically active CERK is enriched in the nucleus
of normal breast epithelial cells and highly overexpressed in aggressive breast cancer cells. The presence of
nuclear CERK and intracellular C1P implicate an undocumented underlying mechanism in aggressive breast
cancer. Moreover, our Preliminary Data point to a previously uncharacterized role of CERK in aggressive
diseases. 1.) Analysis of breast cancer metastases cohort (GSE2034, n=286) data revealed higher expression
levels of CERK mRNA are linked to poor relapse-free survival (RFS). 2.) Our RNA-Seq data showed that CERK
expression is elevated in primary breast tumors in patients with a history of breast cancer bone metastasis. 3.)
As a proof-of-principle, an existing CERK inhibitor, NVP-231, drastically reduced the 3D invasive growth of
aggressive breast cancer cells. 4.) NVP-231 also reduces aggressive type tumor progression and metastasis in
mouse models. The overarching hypothesis is that CERK and C1P in the nucleus play a key role in aggressive
breast cancer progression and metastasis. The immediate goal of this proposal is to gather more robust
preliminary data to understand the functions, a) clinical utility and significance, and b) characterization of CERK
and C1P in aggressive breast cancers. Two Specific Aims are proposed, 1) Clinical significance of ceramide
kinase and C1P and 2) Functional role of ceramide kinase and C1P in aggressive breast cancers. The scope of
the proposed work explores a previously unknown novel mechanism by which CERK and C1P function in the
nucleus. This work will demonstrate whether nuclear C1P and CERK are critical for aggressive diseases for
developing novel therapeutics, which can be tested for R01/DoD grant application.
Terms: <3-D><3-Dimensional><3D><Applications Grants><Attention><Biological Markers><Bone Metastasis><Bone cancer metastatic><Bony metastasis><Brain><Brain Nervous System><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Epithelial Cells><Breast Metastasis><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cell Survival><Cell Viability><Cell surface><Cessation of life><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Development><Disease><Disease Progression><Disorder><Distant Cancer><Distant Metastasis><EGF Receptor><EGFR><ERBB Protein><ERBB2><ERBB2 gene><Encephalon><Environmental Factor><Environmental Risk Factor><Enzyme Gene><Enzymes><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Freezing><Funding Mechanisms><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Gene Transcription><Generalized Growth><Genetic Transcription><Genetic mutation><Goals><Golgi><Golgi Apparatus><Golgi Complex><Grant Proposals><Growth><HER -2><HER-2><HER1><HER2><HER2 Genes><HER2/neu><History><Inflammation><Inflammation Mediators><Intermediary Metabolism><Intracellular Communication and Signaling><Knowledge><Link><Lipids><Liver><Lung><Lung Adenocarcinoma><Lung Respiratory System><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mammary Cancer><Mammary Neoplasms><Mechanistic Target of Rapamycin><Mediating><Messenger RNA><Metabolic><Metabolic Processes><Metabolism><Metastasis><Metastasis to bone><Metastasize><Metastatic Cancer to the Bone><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Bone><Metastatic Tumor><Metastatic Tumor to the Bone><Metastatic malignant neoplasm to bone><Modeling><NEU Oncogene><NEU protein><Neoplasm Metastasis><Nuclear><Nucleus><Oncogene ErbB2><Organoids><Osseous metastasis><Outcome><PI-3K/AKT><PI3K/AKT><Pancreas Cancer><Pancreatic Cancer><Patients><Play><Primary Neoplasm><Primary Tumor><R-Series Research Projects><R01 Mechanism><R01 Program><RAFT1><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Recording of previous events><Relapse><Research Grants><Research Project Grants><Research Projects><Research Specimen><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Secondary cancer of bone><Secondary malignancy of bone><Secondary malignant neoplasm of bone><Sequence Alteration><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal metastasis><Specimen><Sphingolipids><Surface><TGF-alpha Receptor><TKR1><TNBC><Testing><Tissue Growth><Transcription><Transforming Growth Factor alpha Receptor><Tumor Tissue><Urogastrone Receptor><Work><Wound Repair><aggressive breast cancer><bio-markers><biologic marker><biological signal transduction><biomarker><bone><bone neoplasm secondary><breast cancer metastasis><breast cancer progression><breast tumor cell><c-erbB-1><c-erbB-1 Protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer metastasis><cancer progression><ceramide 1-phosphate><ceramide kinase><chemotherapy><clinical significance><clinically significant><cohort><developmental><environmental risk><erbB-1><erbB-1 Proto-Oncogene Protein><erbB-2 Genes><erbBl><extracellular><fat metabolism><genetic approach><genetic strategy><genomic alteration><hepatic body system><hepatic organ system><herstatin><histories><inflammatory mediator><kinase inhibitor><lipid metabolism><mRNA><mTOR><malignancy><malignant breast tumor><mammalian target of rapamycin><mammary epithelial cells><mammary tumor><migration><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic progression><neu Genes><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><ontogeny><overexpress><overexpression><pancreatic malignancy><pharmacologic><power analysis><predictive biomarkers><predictive marker><predictive molecular biomarker><progression biomarker><progression marker><protein expression><proto-oncogene protein c-erbB-1><pulmonary><resistant><response><social role><sphingosine 1-phosphate><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><three dimensional><transcriptome sequencing><transcriptomic sequencing><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor progression><wound healing><wound recovery><wound resolution>