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RATs

RATs. What is the Warburg effect? What is the Knudson’s hypothesis? What is the definition of epigenetic changes in tumorigenesis or carcinogenesis? Why HPV (high risk HPV) is oncogenic?. PATH 6266: NEOPLASIA. Neoplasia

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RATs

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  1. RATs • What is the Warburg effect? • What is the Knudson’s hypothesis? • What is the definition of epigenetic changes in tumorigenesis or carcinogenesis? • Why HPV (high risk HPV) is oncogenic?

  2. PATH 6266: NEOPLASIA • Neoplasia • The new and abnormal development of cells that may be benign or malignant • Malignant Tumors • Carcinoma • Breast Cancer, colon cancer, prostate cancer • Sarcoma • Liposarcoma • Osteosarcoma • Chondrosarcoma • Leimyosarcoma, rhabdomyosarcoma • Lymphoma • Diffuse large B cell lymphoma (T cell, B-Cell) • Hodgkin lymphoma • Leukemia • Acute lymphoblastic leukemia • CML t(9; 22) (BCR-ABL) • AML-M3 t(15; 17) (PML/RARa) • Multiple myeloma

  3. Differentiation • Anaplasia • Metaplasia • Dysplasia: disordered growth • Carcinoma in-situ

  4. Dissemination of Cancers • Direct seeding of body cavities or surfaces • Lymphatic spread • Hematogenous spread

  5. Invasion and Metastasis • Changes (“loosening up”) of tumor cell-cell interaction • Degradation of ECM • Attachment to novel ECM components • Migration of tumor cells

  6. EMT • Epithelial Mesenchymal Transition • Inflammatory cytokines • E-Cadherin • Reverse of EMT • COX-2 inhibitor

  7. G1 DNA Damage Checkpoint * DNA damage ATM kinase Rb------------ E2F Rb-P

  8. Follicular lymphoma t(14;18)

  9. Head/Neck SCC: HPV

  10. Molecular Classification of Breast Cancer RT-PCR using cDNA array of more than 500 genes

  11. Targeted Molecular Therapy • Gleevec: STI 571 (Imatinib mesylate) • Chronic myeloid leulemia (CML) • BCR-ABL • Gastrointestinal stromal tumor (GIST) • C-KIT mutation (80-90% of GIST) • Exon 11: 67-83% response rate • Exon 9: 40% response rate • Platelet-derived growth factor-a receptor (2% of the GIST) • No known tyrasine kinase mutation: 11% • 32% response rate to imatinib A Kit exon 11 mutation was the single best predictor of an objective response to Imatinib.

  12. Molecular Therapy • Colon Cancer • KRAS: 30% • BRAF: 10% • MSI

  13. Molecular Therapy • Breast Cancer • 20% + Her2/neu • Worse prognosis • Improved survival • Colorectal Cancer • KRAS, BRAF • Nonsmall cell lung Cancer (Adenocarcinoma) • KRAS, EGFR, ALK-1

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