Main Themes. Future Directions from Translational And Molecular Research 2/6/2013. Regulation of Notch in Breast Cancer
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1 Future Directions from Translational And Molecular Research Clodia Osipo, Ph.D. Assistant Professor of Pathology Cardinal Bernardin Cancer Center Loyola University Chicago Health Sciences Division Main Themes Notch Signaling Endocrine Resistance Role of Metabolism on Breast Cancer HER+ Breast Cancer and Response to Therapy Cancer Stem Cells and Metastasis Regulation of Notch in Breast Cancer ErbB 2 and Trastuzumab Resistance Predictive Biomarkers for Triple Negative Breast Cancer Opposing Roles of Notch 1 and Notch 4 in Breast Cancer 1
2 Notch dependent Regulation of Novel Genes Associated with Trastuzumab Resistance Clodia Osipo, Ph.D., Angela Baumgartner, Andrei Zlobin, Ph.D., and Matthew O'Toole Cell Cycle Progression of Trastuzumab Sensitive vs. Resistant Cells Differential Gene Expression Profile in Resistant vs. Sensitive Cells Assessment of Notch Signaling Pathway Components as Biomarkers for Triple Negative Breast Cancer Andrei Zlobin, Roma Olsauskas, Sarah Hodge, and Clodia Osipo mrna expression analysis in clinical specimens (N=8) TN: Triple Negative (HR /HER2 ) TP: Triple Positive (HR+/HER2+) Nm: Normal Tissue from reduction Mammaplasty 2
3 Assessment of Notch Signaling Pathway Components as Biomarkers for Triple Negative Breast Cancer Opposing Roles of Notch 1 and Notch 4 in Mammary Tumorigenesis Induced by c-myc and KRASV12 Elena M. Rodriguez and J. Michael Bishop Expression of Notch Receptors In Different mouse models of Breast Cancer by Western blotting Notch 4 is overexpressed in c Myc + KRas Driven Breast Cancer by IF Opposing Roles of Notch 1 and Notch 4 in Mammary Tumorigenesis Induced by c-myc and KRASV12 Elena M. Rodriguez and J. Michael Bishop What role do Notch 1 and Notch 4 play in growth of Breast Tumors that harbor c Myc and Kras mutations? Knockdown of Notch 4 Knockdown of Notch 1 Notch 4 is required for c MYC + Kras Driven Breast Tumor Growth Notch 1 is potentially a tumor suppressor in c MYC + Kras Driven Breast Tumor Growth 3
4 Endocrine Resistance PTEN as a novel Predictive Biomarker for sensitivity When should anti HER2 therapy be given to ER+/HER2 patients? Overcoming Endocrine Resistance Related to PTEN Loss by Combinations with mtor, AKT, and/or MEK inhibitors Xiaoyong Fu, Vijetha Kumar, Martin Shea, Nrusingh C. Biswal, Sarmistha Nanda, et al. Targets and Therapeutic Strategies Lapatinib (TKI) PTEN AKT Inhibitors MEK ERK MEK Inhibitors Rapamycin Rad001 mtor Cell Survival Resistance? Cell Proliferation Resistance? Adapted from Rexer et al. Cell Cycle January 1; 8(1):
5 Overcoming Endocrine Resistance Related to PTEN Loss by Combinations with mtor, AKT, and/or MEK inhibitors Xiaoyong Fu, Vijetha Kumar, Martin Shea, Nrusingh C. Biswal, Sarmistha Nanda, et al. Strategy: Create an inducible system to knockdown PTEN in ER+ breast tumors PTEN Expression by IHC PTEN+1 PTEN PTEN+2 PTEN+1 PTEN+3 PTEN+2 PTEN+2 PTEN+1 Overcoming Endocrine Resistance Related to PTEN Loss by Combinations with mtor, AKT, and/or MEK inhibitors Xiaoyong Fu, Vijetha Kumar, Martin Shea, Nrusingh C. Biswal, Sarmistha Nanda, et al. Estrogen Estrogen Deprivation 1. PTEN expression is low when ER+ breast tumors are estrogen Dependent. 2. PTEN expression needs to be induced to increase sensitivity to anti estrogens Tamoxifen Fulvestrant Overcoming Endocrine Resistance Related to PTEN Loss by Combinations with mtor, AKT, and/or MEK inhibitors Xiaoyong Fu, Vijetha Kumar, Martin Shea, Nrusingh C. Biswal, Sarmistha Nanda, et al. Hypothesis: PTEN Loss increases AKT, mtor, and/or MEK signaling In ER+ Breast Tumors Results: Synergy between mtor + AKT or AKT + MEK inhibitors Measure of Drug Drug Synergy 5
6 PROTEIN PATHWAY ACTIVATION MAPPING OF I SPY 1 BIOPSY SPECIMENS IDENTIFIES NEW NETWORK FOCUSED DRUG TARGETS FOR PATIENTS WITH HR+/HER2 TUMORS Julia D. Wulfkuhle, Denise Wolf, Rosa I. Gallagher, Christina Yau, Valerie Calvert, Jenny Wu, Marigold Boe, Yibing Yan, I SPY TRIAL 1 Investigators, Lance Liotta, Laura van t Veer, Laura Esserman, Emanuel Petricoin III PROTEIN PATHWAY ACTIVATION MAPPING OF I SPY 1 BIOPSY SPECIMENS IDENTIFIES NEW NETWORK FOCUSED DRUG TARGETS FOR PATIENTS WITH HR+/HER2 TUMORS Julia D. Wulfkuhle, Denise Wolf, Rosa I. Gallagher, Christina Yau, Valerie Calvert, Jenny Wu, Marigold Boe, Yibing Yan, I SPY TRIAL 1 Investigators, Lance Liotta, Laura van t Veer, Laura Esserman, Emanuel Petricoin III Metabolism and Breast Cancer The use of Metformin as a treatment option Metabolic Syndrome as a novel Predictor for Metastasis 6
7 Analysis of tumour cell signaling in response to neoadjuvant metformin in women with early stage breast cancer R.J.O. Dowling, S. Niraula, M.C. Chang, S.J. Done, M. Ennis, N. Hood, et al. Analysis of tumour cell signaling in response to neoadjuvant metformin in women with early stage breast cancer R.J.O. Dowling, S. Niraula, M.C. Chang, S.J. Done, M. Ennis, N. Hood, et al. P AKT levels by IHC Insulin R levels by IHC Analysis of tumour cell signaling in response to neoadjuvant metformin in women with early stage breast cancer R.J.O. Dowling, S. Niraula, M.C. Chang, S.J. Done, M. Ennis, N. Hood, et al. Metformin Treatment and Patient Physiology Metformin Treatment and Tumor Biology 7
8 Adipose tissue from breast cancer patients with the metabolic syndrome promotes proliferation and invasion of tumor cells and influences expression of genes involved in carcinogenesis. Sarah A McGarrigle, Paul A Carroll, Laura A Healy, Terence Boyle, Graham P Pidgeon, et al. Strategy: Isolate Adipose Tissue from MS and MS+ patients: 1. Measure proliferation of ER+ breast cancer cells and 2. Measure genes that t are upregulated ltdas biomarkers HER2 + Breast Cancer and Therapy Tumor tissue polarity and access to HER2 protein restricts anti HER2 activity 8
9 Cancer Stem Cells and Metastasis ALDH1 as a Novel Biomarker for Metastasis Cancer stem cells predict engraftment and poor prognosis of primary breast cancers CHARAFE JAUFFRET Emmanuelle, GINESTIER Christophe, BERTUCCI François, CABAUD Olivier, et al. Prediction of Disease Progression ALDH1 Low ALDH1 High Implications for Treatment Notch Signaling: 1. Context of Notch activation is critical 2. Which Notch receptors should be targeted? Endocrine Resistance: 1. PTEN as a Predictive Biomarker for sensitivity 2. When to target HER2 signaling? Metabolism and Breast Cancer: 1. Metformin for treatment/prevention 2. Metabolic Syndrome to predict recurrence HER2 + Breast Cancer and Response to Therapy: 1. Tumor cell polarity and access to HER2 Cancer stem cells and Metastasis: 1. ALDH1 as a novel Predictive Biomarker for Metastasis 9
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