1. Recent Developments in Oncology Robert H. Cassell, M.D., Ph.D. Medical Director, Cassidy Cancer Center Clinical Assistant Professor, Dept. of Medicine, University of Florida College of Medicine

2. Recent Developments in Oncology There have been many new and exciting developments in cancer • New diagnostic modalities • New ways to predict the outcome and prognosis of various cancers • New treatment advances • New surgical techniques • New ways of delivering radiation therapy • New chemotherapy drugs • New supportive therapies

3. Recent Developments in Oncology – My Favorite Use of new knowledge in science, including genetics and molecular biology, and the new fields of genomics and proteomics, to develop “rational” therapies to treat cancer

4. “CANCER” “CRAB”

5. Crabgrass -- Cancer -- Cut It or Tear it Out Surgery How Do You Treat…

6. Crabgrass -- Cancer -- Cut It or Tear it Out Surgery How Do You Treat…

7. Crabgrass -- Cancer -- Burn It Radiation Therapy How Do You Treat…

8. Crabgrass -- Cancer -- Burn It Radiation Therapy How Do You Treat…

9. Crabgrass -- Cancer -- Poison It Chemotherapy How Do You Treat…

10. Crabgrass -- Cancer -- Poison It Chemotherapy How Do You Treat…

11. What If… • You could understand what makes crab grass crab grass, so that you could do something specific to kill only the crab grass OR • You could change the crab grass, so it behaved and looked like normal grass *********** I don't think we can do this with crab grass but we are starting to be able to do this sort of thing with cancer

12. Terminology • The current buzzword in medicine is "personalized medicine." • This means treating each patient as a separate individual based on their characteristics and the characteristics of their disease(s). • In oncology, we generally use the term “targeted therapy” or, more precisely, “molecularly targeted therapy.”

13. What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time

14. Apoptosis(Programmed Cell Death)

15. What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time • 4) Limitless replication potential – keep dividing indefinitely • 5) Sustained angiogenesis (new blood vessels)

16. Angiogenesis(New Blood Vessel Growth)

17. What Makes Cancer Cells Cancerous? • 1) Increased response to growth signals and production of their own growth signals • 2) Insensitivity to anti-growth signals • 3) Evasion of apoptosis – failure to die at the right time • 4) Limitless replication potential – keep dividing indefinitely • 5) Sustained angiogenesis (new blood vessels) • 6) Tissue invasion and metastasis

18. What Makes Cancer Cells Cancerous? Other characteristics of cancer cells: • Stem cell or progenitor cell phenotype – they start out looking like normal (or benign) cells but at a primitive stage of development • Increased mutation rate • Evasion of, or resistance to, normal immune responses

20. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100(1):57–70.

21. “Targeted” Cancer Treatment How does it work? Attack targets which are specific for the cancer cell and are critical for its survival or for its malignant behavior Why is it better than chemotherapy? More specific for cancer cells – chemotherapy hits rapidly growing cells not all cancer cells grow that rapidly some normal cells grow rapidly Possibly more effective

22. Cancer Targets From National Cancer Institute, US National Institutes of Health.

23. Cancer Targets From National Cancer Institute, US National Institutes of Health.

24. Cancer Targets From National Cancer Institute, US National Institutes of Health.

25. Targets • The targets currently being used are those that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth and progression. • The focus is on proteins that are involved in cell signaling pathways, which form a complex communication system that governs basic cellular functions and activities, such as cell division, cell movement, how a cell responds to specific external stimuli, and even cell death. • We use the term “signal transduction” to refer to the actions of these proteins.

27. ATP ATP TK TK + Tumor Cell Stimulation Metastases Survival Gene Transcription Cell Cycle Progression Antiapoptosis Cell Proliferation Angiogenesis

28. Targeted Therapy • The first molecular target for targeted cancer therapy was the cellular receptor for the female sex hormone estrogen, which many breast cancers require for growth. When estrogen binds to the estrogen receptor (ER) inside cells, the resulting hormone-receptor complex activates the expression of specific genes, including genes involved in cell growth and proliferation.

29. Therapy Targeted at the Estrogen Receptor • Selective estrogen receptor modulators (SERMs) • tamoxifen (Nolvadex) • toremifene (Fareston) • Estrogen receptor inhibitor and destroyer • fulvestrant (Faslodex) • Estrogen synthesis inhibitors – aromatase inhibitors (AIs) • anastrozole (Arimidex) • letrozole (Femara) • Exemestane (Aromasin)

30. ATP TK TK TK - - - Strategies to Inhibit Signaling Anti-ligand mAbs “-mab” tyrosine kinase inhibitors “-ibs” Anti- mAbs “-mab”

31. Philadelphia Chromosome

32. Philadelphia Chromosome (BCR-ABL Translocation)

33. BCR-ABL Translocation

34. Oncogenes c-met RAS PI3K BRAF PTEN CRAF MEK AKT p16 Cyclin D ERK CDK2 CDK4 mTor

35. Targeted inhibitors in development c-met XL880 RAS PI3K BRAF R115777 SCH66336 PTEN SF1126 XL147 Sorafenib RAF-265 PLX4032 AKT GSK690693VQD-002 PD0325901 AZD6244 MEK p16 temsirolimus everolimus AP23573 PD332991 CYC202 mTor Cyclin D ERK CDK2 CDK4 BMS-387032

36. Signal Pathways in the Cancer Cell

37. The “Nibs” Small molecule tyrosine kinase inhibitors (or TKIs) – generic names end in “-nib” Generally oral Side effects vary, depending on which enzymes they inhibit (what their target is) Eight are FDA-approved, numerous others are in development Several are effective against cancers resistant to most previous therapies

38. FDA-Approved TKIs

39. Monoclonal Antibodies Another type of targeted therapy – they are large molecules produced through genetic engineering They usually have to be given IV Side effects can include reactions to non-human proteins They can cause cell damage in several ways, most often by attacking cell-surface receptors

40. PDGF Ang VEGF TGFβ HGF bFGF NRPs Eph Tumor RAS PI3K BRAF MEK AKT Endothelial cell & Pericyte mTor ERK

41. Trastuzumab • Monoclonal antibody against epidermal growth factor receptor 2 (EGFR2, HER-2) • Very effective against breast cancers in which HER-2 is “over-expressed” (more than usual amount per cell) (about 20% of all breast cancers) • Often used in combination with chemotherapy

42. Cetuximab • Monoclonal antibody against epidermal growth factor receptor 1 (EGFR1) • Effective in colon cancer and head and neck cancer; possibly useful in lung cancer • Used with chemotherapy and with radiation therapy

43. Bevacizumab • Monoclonal antibody against vascular endothelial growth factor (VEGF), which stimulates angiogenesis (growth of new blood vessels into tumor) • Deprives tumors of the blood supply they need for growth and invasion • Effective against cancers of colon, lung, breast, kidney, and brain

44. Monoclonal Antibodies FDA-Approved “Naked” (Non-Conjugated) MoAbs

46. Monoclonal Antibodies • Conjugated antibodies currently approved • Radio-conjugated antibodies • Tositumomab (Bexxar) • Ibritumomab (Zevalin) • Both used against refractory lymphomas • Toxin-conjugated antibody • Gemtuzumab ozogamicin (Mylotarg) • Used against AML

47. Epratuzumab Matuzumab Nimotuzumab Zalutumumab Pertuzumab Mapatumumab Lexatumumab Volociximab Pemtumomab Labetuzumab ch806 CP-751,871 IMC-A12 VEGF-Trap IMC-18F1 IMC-1121B IMC-3G3 Vitaxin CNTO 95 Monoclonal Antibodies In Development

49. Types of MoAbs

50. Nomenclature of MoAbs • Last syllable is always –mab • Next to last syllable • -u- human (100%) : Panitumumab • -zu- humanized (95%) : Trastuzumab • -xi- chimeric (65%) : Rituximab • -o- mouse, -a- rat, -e- hamster, -i- primate : Tositumomab • Previous syllable • -tu(m)- for tumor in general [-ma(r)- breast, -pr(o)- prostate, -co(l)- colon, etc.] • -ci(r)- for circulatory : Bevacizumab