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Principal Investigator: Shunqiang Li
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $602,262
Funding agency: National Cancer Institute
Project Summary
Cyclin-dependent kinase CDK4/6 inhibitor (CDK4/6i) in combination with aromatase inhibitors is the first-line
treatment for ER+ advanced or metastatic breast cancer. Despite CDK4/6 inhibitors significantly improve
overall survival of such patients, not all patients respond to these drugs and most patients whose tumors
initially respond to CDK4/6i eventually develop acquired resistance. Although many efforts have been invested
into the studying mechanism of resistance, CDK4/6i resistance remains a big challenge for HR+ breast cancer.
Thus, it is urgent to develop new approaches to overcome resistance in CDK4/6i resistant breast cancer
(CRBC). O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is one type of glycosylation that occurs when a
monosaccharide, O-GlcNAc, is added onto serine or threonine residues of proteins by O-GlcNAc transferase
(OGT). O-GlcNAcylation is involved in a range of cellular activities and aberrant O-GlcNAcylation has been
implicated in a host of diseases including cancer. However, the role of O-GlcNAcylation in cancer drug
resistance remains largely unknown.
Through an innovative quantitative high throughput combination screen (qHTCS) and follow-up
extensive preliminary studies using cellular and molecular approaches, we identified a novel OGT-mediated
mechanism regulating the resistance to CDK4/6i in ER+ breast cancer. The major objective of this proposal is
to determine the role of OGT-mediated pathway in the regulation of CDK4/6i resistance in CRBC cells.
Specifically, we will (1) investigate the molecular mechanism of how OGT-mediated pathway regulates
CDK4/6i resistance in CRBC cells, (2) evaluate the effects of newly identified drug combinational treatments on
palbociclib resistance using resistant PDX and syngeneic models, (3) conduct clinical study to further evaluate
the correlation between OGT-mediated pathway and CDK4/6i resistance in tumors from patients. The
completion of proposed studies will not only elucidate a novel mechanism regulating CDK4/6i resistance in
ER+ breast cancer, but also provide an innovative therapeutic strategy to treat CRBC patients.
Terms: <Active Follow-up><Affect><Androstenedione Aromatase Inhibitor><Aromatase Inhibitors><Atovoquone><Basal Transcription Factor><Basal transcription factor genes><Breast Cancer><Breast Cancer Cell><Breast Cancer Patient><Breast Tumor Patient><CDK4><CDK4 gene><Cancer Biology><Cancers><Cell Communication and Signaling><Cell Division Kinase 4><Cell Nucleus><Cell Signaling><Clinical Oncology><Clinical Research><Clinical Study><Combined Modality Therapy><Cyclin-Dependent Kinase 4><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><Cytoplasm><Data><Development><Disease><Disorder><Drug Combinations><Drug Screening><Drug Therapy><Drug resistance><Drugs><ER Positive><ER+><Estrogen Synthase Inhibitor><Estrogen Synthetase Inhibitor><Estrogen receptor positive><FDA approved><Gene Expression><General Transcription Factor Gene><General Transcription Factors><In Vitro><Intracellular Communication and Signaling><Investments><Isoforms><L-Serine><L-Threonine><Link><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Melanoma Cell><Mepron><Metabolic Glycosylation><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Modeling><Molecular><Monosaccharides><Multimodal Therapy><Multimodal Treatment><Neoplasm Metastasis><Nuclear Translocation><Nucleus><O-GlcNAc Transferase gene><O-GlcNAc transferase><PSK-J3><Pathway interactions><Patients><Pharmaceutical Preparations><Pharmacotherapy><Physiologic><Physiological><Proliferating><Protein Conformation><Protein Isoforms><Proteins><Regulation><Regulatory Pathway><Resistance><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Serine><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Testing><Therapeutic><Threonine><Transcription Factor Proto-Oncogene><Transcription factor genes><Wellvone><active followup><atovaquone><biological signal transduction><breast tumor cell><cancer cell><cancer drug resistance><cancer metastasis><cdk Proteins><clinical applicability><clinical application><combination therapy><combined modality treatment><combined treatment><developmental><drug discovery><drug resistant><drug treatment><drug/agent><follow up><follow-up><followed up><followup><glycosylation><improved><in vivo><inhibitor><innovate><innovation><innovative><malignancy><malignant breast tumor><melanocyte><migration><mouse model><multi-modal therapy><multi-modal treatment><multidisciplinary><murine model><neoplasm/cancer><new approaches><new drug combination><new pharmacotherapy combination><novel><novel approaches><novel drug combination><novel pharmacotherapy combination><novel strategies><novel strategy><pathway><prevent><preventing><protein function><resistance mechanism><resistance to Drug><resistance to cancer drugs><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to cancer drugs><resistant to therapy><response><senescence><senescent><social role><therapeutic resistance><therapy resistant><tool><transcription factor><treatment resistance><treatment strategy><tumor><tumor cell metastasis><virtual>