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Principles of Cancer Biology and Therapy

Principles of Cancer Biology and Therapy. David Dingli, MD, PhD Hematology and Molecular Medicine Mayo Clinic Rochester. Cancer and Age. Breast. Colon. Testicular. CNS. ALL. NCCC 1988 - 2004. Nomenclature. Benign “ Polyp ” Malignant Epithelial ‘Carcinoma’ Mesenchyme ‘Sarcoma’

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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

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