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Principal Investigator: Song Li
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2021
Award: $428,652
Funding agency: National Cancer Institute
The amplification of Estrogen, Progesterone and Human Epidermal Growth Factor receptors (i.e. ER, PR and HER2) serve as prognostic markers in breast cancer. The prognosis of ER+ breast cancer is relatively better due to availability of several drugs that essentially block ER-signaling. However, HER2+ breast cancer has limited options and is treated either by using humanized antibodies, Trastuzumab (Herceptin) or Pertuzumab or tyrosine kinase inhibitor, Lapatinib. The initial responses to anti-HER2 therapies are favorable, however, the tumors subsequently acquire resistance and relapse to form metastatic tumors. Therefore, there is a need to identify novel target and develop new therapeutics that can overcome anti-HER2 therapies resistance and perhaps can be used as an alternative to the existing anti-HER2 agents. Interestingly, it is well recognized that HER family-mediated signaling primarily impinge on PI3K-AKT pathway and is reported to be a main source of either, de novo or acquired resistance. Therefore several inhibitors of PI3K or AKT have been in clinical trials, however the outcome of these trials are dismal due to unacceptable toxicities. Furthermore, it is also reported that ER and IGF1R are co-amplified in HER2 positive tumors, treated with anti-HER2 therapies, leading to resistance. Both of these receptors are known to activate PI3K-AKT and is considered to be initiating anti-HER2 therapies resistance. Collectively these results suggest that PI3K-AKT is one of the main nodal point of resistance in HER2+ tumors. Therefore, any therapeutic(s) that can block PI3K-AKT signaling pathway and congruently also activate the downstream pro-apoptotic molecule will be a drug of choice to treat both HER2 therapy sensitive and resistant tumors. We reported previously that a member of Mixed Lineage Kinase (MLK) family, MLK3 was inhibited by ER, IGF1R and HER2 pathways and this inhibition was mediated via direct phosphorylation of MLK3 by AKT. We also reported that ceramide, a bioactive lipid was able to activate MLK3 and was necessary for MLK3-mediated cell death. It is reported that ceramides inactivate PI3K-AKT pathway and therefore we hypothesize that delivery of ceramides into HER2-resistant and sensitive cells might cause cell death and tumor regression. Our preliminary data clearly showed that indeed ceramide nanoparticles were able to cause cell cycle arrest and cell death in Herceptin resistant cell lines and xenografts. Based on our intriguing results, we hypothesize that ceramide nanoparticles could be a better option to treat both HER2 resistance and sensitive tumors. To determine the effectiveness of ceramide nanoparticle as an alternative option to treat both resistant and sensitive HER2+ breast cancer, we will determine: 1) the effects of ceramide nanoparticles on cell lines- and xenografts-resistant to anti-HER2 therapies, 2) the molecular mechanisms of anti-tumorigenic effects of ceramide nanoparticles in HER2+ breast cancer and finally, 3) the therapeutic efficacy of ceramide nanoparticles in HER2 transgenic and PDX animal models, resistant to anti-HER2 therapies. It is expected that at the conclusion of this project we would discern the therapeutic value of ceramide nanoparticles in treating HER2 resistant and sensitive breast cancer, and perhaps other sub-types. It is important to note that it is reported that ceramides damage specifically tumor but not normal cells and therefore we expect that our results will provide an innocuous therapeutic to treat HER2+ breast cancer with minimal, or no collateral damage.
Terms: <AKT><AKT Signaling Pathway><Akt protein><Animal Model><Animal Models and Related Studies><Anti-ERB-2><Anti-HER2/c-erbB2 Monoclonal Antibody><Anti-c-ERB-2><Anti-c-erbB2 Monoclonal Antibody><Anti-erbB-2><Anti-erbB2 Monoclonal Antibody><Anti-p185-HER2><Antibodies><Antibody-drug conjugates><Apoptosis><Apoptosis Pathway><Apoptotic><Binding><Breast Cancer><Breast Cancer Cell><Breast Epithelial Cells><Breast Neoplasms><Breast Tumors><Cancer Model><Cancer Prognosis><Cancer Treatment><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Death><Cell Line><Cell Signaling><Cell Survival><Cell Viability><CellLine><Cells><Ceramides><Clinical><Clinical Trials><Collaborations><Corpus Luteum Hormone><Data><Delta4-pregnene-3,20-dione><Dimerization><Disease><Disorder><Distal><Drugs><EGF Receptor><EGFR><EPH- and ELK-Related Tyrosine Kinase><EPH-and ELK-Related Kinase><ER Positive><ER+><ERBB Protein><ESI gene><ESI protein><Elastase-Specific Inhibitor><Ephrin Type-A Receptor 8><Ephrin Type-A Receptor 8 Precursor><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Essential Drugs><Estrogen receptor positive><Estrogens><External Domain><Extracellular Domain><Family><Family member><Future><HER1><HER2 Monoclonal Antibody><Herceptin><Heterograft><Heterologous Transplantation><Human><IGF1><IGF1 gene><IGF1R><IGF1R gene><IGFI><Insulin-Like Growth Factor 1 Receptor Gene><Intracellular Communication and Signaling><JN kinase kinase><JNK kinase><JNK-activating protein kinase><JNKK><Jun amino-terminal kinase kinase><Kinases><Laboratories><Lipids><MCF-10A><MCF10A><MCF10A cells><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Neoplasms><Mediating><Medication><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mind><MoAb HER2><Modern Man><Molecular><Molecular Interaction><Molecular Marker of Prognosis><Nanotechnology><Neoplasm Metastasis><Nodal><Oncogenesis><Outcome><PI3><PI3 gene><PTK Inhibitors><Pathologic><Pathway interactions><Patients><Pertuzumab><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Play><Pregn-4-ene-3,20-dione><Pregnenedione><Progesterone><Prognosis><Prognosis Marker><Prognostic Marker><Programmed Cell Death><Protein Dimerization><Protein Kinase B><Protein Phosphorylation><Protein Tyrosine Kinase><Protein Tyrosine Kinase EEK><Protein Tyrosine Kinase Inhibitors><Proteinase Inhibitor 3><Proto-Oncogene Proteins c-akt><RAC-PK protein><Ras/Raf><Receptor Protein><Relapse><Reporting><Resistance><Role><SKALP><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Source><Strains Cell Lines><TGF-alpha Receptor><TK Inhibitors><TRAPPIN 2><Testing><Therapeutic><Therapeutic Estrogen><Therapeutic Progesterone><Therapeutic Uses><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Transgenic Organisms><Transphosphorylases><Trastuzumab><Treatment Efficacy><Tyrosine Kinase><Tyrosine Kinase Inhibitor><Tyrosine-Protein Kinase Receptor EEK><Tyrosine-Specific Protein Kinase><Tyrosylprotein Kinase><Urogastrone Receptor><Work><Xenograft><Xenograft procedure><Xenotransplantation><anti-cancer therapy><anticancer therapy><assess effectiveness><base><biological signal transduction><breast cancer survival><breast tumor cell><c-akt protein><c-erb-2 Monoclonal Antibody><c-erbB-1><c-erbB-1 Protein><cancer metastasis><cancer therapy><cancer-directed therapy><cultured cell line><determine effectiveness><develop therapy><drug/agent><effectiveness assessment><effectiveness evaluation><elafin><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><evaluate effectiveness><expectation><humanized antibody><hydroxyaryl protein kinase><inhibitor><inhibitor/antagonist><intervention development><intervention efficacy><lapatinib><malignancy><malignant breast neoplasm><malignant breast tumor><mammary epithelial cells><mammary tumor><member><model of animal><model organism><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><necrocytosis><neoplasm/cancer><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathway><pre-clinical><preclinical><prevent><preventing><prognostic biomarker><prognostic indicator><proto-oncogene protein RAC><proto-oncogene protein akt><proto-oncogene protein c-erbB-1><rac protein kinase><receptor><related to A and C-protein><resistance to therapy><resistant><resistant to therapy><response><rhuMAb HER2><rhuMAb2C4><skin-derived antileukoproteinase><small molecule><social role><therapeutic efficacy><therapeutic resistance><therapy development><therapy efficacy><therapy resistant><transgenic><treatment development><treatment resistance><tumor><tumor cell metastasis><tumorigenesis><tumorigenic><tyrosyl protein kinase><xeno-transplant><xeno-transplantation>