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metavectum Recklinghausen

metavectum Recklinghausen. Modern Moleculare Diagnostic in Oncology. Aims of Molecular Oncology. Early Diagnosis of Tumors Detection of disseminated Tumor-Cells and Micrometastasis Deciding of therapeutic Aims und Therapy Resistance Monitoring of Therapy Individualisised Therapy.

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metavectum Recklinghausen

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  1. metavectum Recklinghausen Modern Moleculare Diagnostic in Oncology

  2. Aims of Molecular Oncology • Early Diagnosis of Tumors • Detection of disseminated Tumor-Cells and Micrometastasis • Deciding of therapeutic Aims und Therapy Resistance • Monitoring of Therapy • Individualisised Therapy

  3. Tumorprogression by genetic Alterations

  4. Dissemination/Metastasis

  5. Cancer is caused by genetic Alteration  cancer cells obtain unnormal features Unkontrolled Growth Signal Unresponsive against growth inhibitors Loss of Apoptosis Angiogenesis Metastasis creation Unlimited Replication

  6. Genetic Changes in Tumor-Cells Genes for Growth Factors Erb-b2, EGFR, c-Kit, PDGFR, K-ras Replications facilitating Genes Telomerase, c-myc Angiogenesis facilitating Genes VEGF Apoptosis facilitating Genes Bcl-2, p53

  7. Circulating Tumor-cells (CTC) • Risk-Factor for recurrance and metastasis. • indicate risk for micro-metastasis. • Easier indentification of patients profiting from adjuvant therapy. Suggested further reading: Cristofanilli M. et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004 Aug 19;351(8):781-91. Allard WJ et al.: Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases Clin Cancer Res. 2004 Oct 15;10(20):6897-904.

  8. Molekular Charakterisation of CTCs • Isolation of mRNA from CTCs • Measuring different Gene-Expression • Quantitative real-time PCR of molekular Tumor-Marker (e.g.): • Cytokeratine • PSA (Prostata), G250 (kidney), AFP (liver) • Growth / Cell-cycle-Regulating Gene (c-myc, erbb2, • Telomerase)

  9. Effect of Soy on Gene-Expression disseminated Tumor-Cells • Five Patients per group suffering from metastastastic Prostate-, Ovary- and Breast -Ca received Chemo + fermented soy • Clinical response in all patients • Question: Can molecular factors predict clinical outcome of Ca-Therapy by fermented Soy ? • Clincial : Bestimmung der modulierende Wirkung von Soja auf die Gen-Expression vor und nach 100 Tagen Einnahme des Soja-Extraktes

  10. Funktion der Östrogenrezeptoren (ER) in der Zelle a ER-alpha a ERE DNA-Doppelstrang Zellteilungsaktivität wird gesteigert (Wucherung) ß ER-beta ß ERE DNA-Doppelstrang Zellteilungsaktivität wird verringert

  11. Expression der Östrogenrezeptoren (ER) alpha und beta Tumorzellen mit Soja-Extrakt Normale Zellen Tumorzellen Brust / Ovar Prostata unbehandelt konstantes Verhältnis Anstieg Absinken Anstieg ß Absinken a a ß ß a ER-beta ER-alpha ER-beta ER-alpha ER-beta ER-alpha

  12. Estrogen-receptor beta is induced by Haelan 951

  13. Modulation of estrogen-receptor expression by Haelan 951 Circulating Tumor Cells (CTCs) of prostate cancer patients were analysed for expression of ER-alpha and ER-beta -> Expression of ER-beta was significantly induced by Haelan 951

  14. Modulation of estrogen-receptor expression by Haelan 951 Mamma-Ca. patients n= 5 Estrogenreceptor ER-beta relative Genexpression all shown breast cancer patients are ER-beta positive +

  15. Estrogenreceptor-beta (ER-beta) Expression = Haelan951 application = No Haelan951 33,9 Mamma-Ca. Patients with Haelan951 Healthy persones without Haelan951 Relative Genexpression 6,2 Healthy persones n=7 Mamma-Ca. patients n=5

  16. Estrogen-receptor beta is induced by Haelan 951

  17. Modulation of estrogen-receptor expression by Haelan 951 Circulating Tumor Cells (CTCs) of ovarian cancer patients were analysed for expression of ER-alpha and ER-beta -> Expression of ER-beta was significantly induced by Haelan 951

  18. proliferation mitogens c - myc apoptosis blocking Bcl2 NF - kB Bax (survival signals) Stoffwechselweg der Apoptose Duales Signal von c-myc: • Der apoptotische Stoffwechselweg wird blockiert durch bcl2 / bax und c-myc fördert Proliferation • Nach Verlust des bcl2 Überlebenssignals, fördert c-myc die Apoptose

  19. Apoptotic conditioning induced by Healan 951 CTCs of prostate cancer patients showed an increased gene expression ratio of apoptosis-triggering genes bax/bcl2 after Haelan951-therapy

  20. Apoptotic conditioning induced by Healan 951 Mamma-Ca. patients n= 5 without Haelan951 Haelan951 application 100 days BAX/BCL2 no significant change relative Genexpression 1,2 1,1

  21. Apoptotic conditioning induced by Healan 951 Ovarian-Ca. patients n=6

  22. Apoptotic conditioning induced by Healan 951

  23. The p53 Signaling Pathway Bax block p53 MDM2 Caspases Bcl-2 block Cell cycle inhibitor Apoptosis p21 (Ovarian Ca.) Cyclin D1 CDK4 Cyclin E CDK2 block Cell Cycle Progression

  24. p21 Involvement in Cell Cycle p53 Proliferation p21 CIP1 Cell cycle inhibitor G1 Mitosis block DNA-Synthesis M-phase entry M Cyclin A/B CDK1 CDK2 G2 S Chromosomes Duplication

  25. Cellcycle Inhibitor P21 is induced by Haelan951 Prostata-Ca. patients n=5 Haelan951 (100) Days) without Haelan951 56,3 37,8 relative Genexpression 12,4 7,1 1,9 1,0 0,9 0,9 0,5 0,6 cases

  26. Cellcycle Inhibitor P21 is induced by Haelan951 Haelan951 (100 days)‏ without Haelan951 Mamma-Ca. patients n=5 332,5 211,9 15,8 15,0 14,3 scale unit progressive relative Genexpression 7,36 4,5 2,28 1,11 0,11 cases

  27. Cellcycle Inhibitor P21 is induced by Haelan951 Mamma-Ca. patients n= 5 without Haelan951 Haelan951 application 100 days p21 CIP increased relative Genexpression 2,0 13,1

  28. Cellcycle Inhibitor P21 is induced by Haelan951

  29. Schlussfolgerungen • Alle Patienten zeigten auf die Gabe fermentierten Soja-Extraktes klinischen Response • Fermentiertes Soja-Extrakt fördert den pro-apoptotischen Zustand der Prostata-Karzinomzellen durch Herunterregulation von Bcl2. Dies dürfte die Zellen sensitiver machen für eine Chemotherapie und somit für eine Kombinationstherapie mit konventionellen Chemotherapeutika sprechen. • Zugabe von fermentiertem Soja induziert die Expression des antiproliferativen ER-beta bei Prostata- und Ovar-Ca Patienten. • Fermentiertes Soja-Extrakt induziert die Transkription des p21, welches zu einem Stillstand des Zellzyklus führt und damit das Krebswachstum unterdrückt, sowohl bei Prostata-, Ovar- als auch bei Mamma-Ca Patienten.

  30. metavectum Interaction The classical view of biological organization is to consider the flow of information from the genome to the transcriptome, to the proteome and then the metabolome. The metabolome can be used to monitor changes in the genome or to measure the effects of downregulation or upregulation of a specific gene transcript.

  31. Invluence of Haelan951 to VEGF Expression Haelan951 (100 Days) without Haelan951 Vascular Endothelial Growth Factor 37,5 relative Genexpression No alteration 1,46 0,97 0,97 Prostata-Ca. patients n=5 Mamma-Ca. patients n=5

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