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Principles of Cancer Biology and Therapy

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  1. Principles of Cancer Biology and Therapy David Dingli, MD, PhD Hematology and Molecular Medicine Mayo Clinic Rochester

  2. Cancer and Age Breast Colon Testicular CNS ALL NCCC 1988 - 2004

  3. Nomenclature • Benign • “Polyp” • Malignant • Epithelial • ‘Carcinoma’ • Mesenchyme • ‘Sarcoma’ • Hematopoietic • Leukemia, lymphoma, myeloma

  4. Etiology • Nature • Inherited cancer syndromes • p53, BRCA1 and 2, MMR • Immune deficiency syndromes • Inherited/Congenital or acquired • Nurture • Radiation (cosmic, fallout, radon) • Chemotherapy (MDS) • Viruses and bacteria • EBV, HTLV-I/II, H. pylori • Repeated injury (Acid reflux, hepatitis)

  5. Cancer pathogenesis • Oncogenes • myc, ras, src, abl, bcl2 • Tumor suppressor genes • p53, Rb, APC, MEN1, NF1 • MicroRNA • Transcriptome control

  6. The path to cancer • Clonal proliferation • Starts from a single cell • Expansion in steps • Pre-malignant states • Polyp, MDS, MGUS • Serial accumulation of mutations • Clonal evolution • Resistance

  7. “Hallmarks of cancer” • Self-sufficiency in growth signals • Insensitivity to anti-growth signals • Evading apoptosis • Limitless reproductive potential • Sustained angiogenesis • Tissue invasion and metastases • Genomic instability Hanahan & Weinberg, 2000

  8. “I always thought that record would stand until it was broken.” Yogi Berra

  9. Tissue and tumor architecture Dingli & Pacheco, 2008

  10. Cancer stem cells • Present in most (all) tumors • Small fraction of population • No universal marker • Often resistant to therapy • May be important target of therapy • Cancer initiating cells in mice

  11. Genomic instability • Is it necessary? • Normal vs abnormal mutation rate • 2 current views • Chromosomal instability • Gross translocations, loss and gain of chromosome parts • Mutator phenotype • Repair genes • Xeroderma pigmentosum • MMR etc

  12. Translocations Balanced Reciprocal Aneuploidy Pseudodiploid Hyperdiploid Complex Random loss or gain Cytogenetic abnormalities

  13. Limitless reproductive potential • Hayflick hypothesis • Limited number of doublings • Telomere maintenance • Telomerase • Not all tumor cells have this potential • Tumor stem cells

  14. Self-sufficiency in growth signals • Autocrine loops • Over-expression of receptor • Receptor is always ‘on’ • Downstream signals Scaltriti et al, 2006

  15. Insensitivity to antigrowth signals Hanahan & Weinberg, 2000

  16. Evading apoptosis • External triggers • Intracellular triggers • Death receptors • Caspases • Sensors (8, 9) • Executioners (3)

  17. Sustained angiogenesis • VEGF • FGF1/2 • Thrombospondin • Thalidomide • Avastin

  18. Tissue invasion and metastases

  19. Tumor burden - Staging • Tumor • Size, capsule invasion • Nodes • Involved, how many? • Metastases • Present/absent • “Unknown primary”

  20. Imaging • CT scan • PET/CT • SPECT/CT • MRI • Staging • Response

  21. Prognostic scoring systems • Host vs Disease • Disease burden • Disease biology • Co-morbid conditions • Performance status

  22. Therapy • Surgery • Radiation • Chemotherapy • Antibodies • Small molecules • Adjunctive

  23. Surgery • Diagnosis • Therapy • Curative • Palliative • Debulking • Symptoms control • Prevent complications

  24. Radiation • External beam radiation • Gamma photons • Neutron beams • Radioimmunoconjugates • Antibody targeted radiation • Radioconjugates • Isotope tagged to bone seeking material • Free isotopes • 131I, Gallium

  25. Radiation targets • DNA • Water • Free radical generation • Oxygen is required • Anti-oxidants are not helpful • Direct and indirect effects • Not all cells are created equal • Geometry important

  26. Radiation • Consolidation • “Mantle radiation” • “Axillary radiation” • Palliation • Spinal cord compression • Pain relief

  27. Radio(immuno)conjugates or -emitters

  28. Free isotopes

  29. Chemotherapy • Antimetabolites • Antifolates, Purine nucleosides, nucleoside synthesis inhibitors • Alkylators • Direct DNA damage (Many), platinum • Spindle poisons • Vinca alkaloids, taxanes • Topoisomerase inhibitors • Anthracyclines, Etoposide

  30. Chemotherapy • Often used in combinations • “CHOP”, “ABVD”, “AC”, “Taxol/Carbo” • Minimizes resistance • Reduces toxicity • Different side effects • Can be curative in specific cases • AML, ALL, HD, NHL, Testicular cancer

  31. Antibodies • Target specific antigen • Specificity is relative • Various mechanisms of action • Complement activation • ADCC • Calcium entry • May synergize with chemotherapy • R-CHOP and CHOP • Expected or unexpected toxicities

  32. Antibodies

  33. Small molecules • Target oncogene product • Bcr-Abl, PML-RARA, • Inhibit signaling at key steps • Safer than chemotherapy • Specific side effects • Specificity is often relative

  34. Small molecules

  35. Adjuncts • Glucocorticosteroids • Estrogens/anti-androgens/SERMs • Bisphosphonates

  36. The target • Tumor cells do not live in isolation • Stroma • Adhesion resistance • Blood vessels • Angiogenesis inhibitors • Antibodies (Avastin) • Small molecules (Thalidomide, other IMiDs) • Immune system • Transplantation • Vaccines