Principles of Cancer Biology and Therapy

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

6. 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)

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

8. 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

9. “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

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

11. Tissue and tumor architecture Dingli & Pacheco, 2008

12. 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

13. 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

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

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

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

17. Insensitivity to antigrowth signals Hanahan & Weinberg, 2000

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

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

20. Tissue invasion and metastases

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

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

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

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

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

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

27. 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

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

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

30. Free isotopes

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

32. 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

33. 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

34. Antibodies

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

36. Small molecules

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

39. 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