1. Cancer Therapy Dr Andrejs Liepins/Science Photo Library

2. Bishop and Varmus

4. We Are Making Quite a Progress in Cancer Detection

5. And we need to remember detection when it comes to “survival rates”.

6. Cancer Therapy Traditional Therapy chemotherapy; radiation Targeted Therapy Personalized Therapy passive immunization; biology-targeted drugs

7. The logic: kill proliferating cells All proliferating cells will react, but cancer cells will have a reduced capacity to repair the damage induced by chemotherapy agents. Traditional Therapy

8. Mustard Gas (Mustard Nitrogen) From warfare to therapy

9. -cytotoxic effects by binding covalently to DNA -sulfur mustard gas; war fare agent: topical burns, lungs, mucosa and aplasia of BM, lymphoid tissue, GI ulcerations United Kingdom against the Red Army in 1919; Spain against Rif insurgents in Morocco in 1921-1927; Italy in Libya in 1930; Soviet Union in Xinjiang, China in 1934 and 1936-1937; Italy in Abyssinia (now Ethiopia) in 1935-1940; Poland against Germany in 1939 during an isolated incident, British product; Germany against Poland and the Soviet Union in a few erroneous uses during WWII; Japan against China in 1937-1945; Egypt against North Yemen in 1963-1967; Iraq against Iran in 1981 and 1983-1988; Iraq against Kurds in 1988; Possibly Sudan against insurgents in the civil war, in 1995 and 1997 Mustard Nitrogen From warfare to therapy

10. alkylating agents: crosslink DNA (e.g. cisplatin) alkaloids: inhibit microtubules (e.g. Taxol) anti-metabolites: inhibit nucleotides synthesis (e.g. MTX) And other chemicals that affect DNA replication, transcription, anything that would arrest proliferation. chemotherapy

11. Example: Methotrexate (MTX) The first designed drug Folate Synthesis in Humans dihydrofolate reductase DHFR dihydrofolate (DHF) tetrahydrofolate (THF)

12. Reducing Folate is the first step in synthesis of nucleotides Assaraf Can Met Rev 07

13. Methotrexate (MTX) was the first designed drug. Acts as a Folate antagonist. 1948 Sydney Farber

14. Assaraf Can Met Rev 07

15. Leucovorin (folinic acid) We treat cells with MTX, in combination with leucovorin, to achieve a leucovorin rescue

16. but... cancer cells have a response Drug Resistance

17. Targeted Therapy Chemotherapy works, but is not very efficient. Knowing what we know today about cancer biology, how can we improve cancer therapy (more efficient, less harmful)? How can we kill cancer cells without affecting normal cells?

18. passive immunization drugs against specific proteins other biological-active targets (e.g. angiogenesis) Targeted Therapy EGFRs example #1: Herceptin

19. Valberga, Anals. Oncogene 07 Lodish 05 HER2 is an orphan receptor. a non-receptor orphan an adopted orphan

20. Figure 20-34a Molecular Biology of the Cell (© Garland Science 2008) Gene Amplification: the main mechanism of HER2 oncogenesis.

21. Figure 20-34b Molecular Biology of the Cell (© Garland Science 2008)

22. Kim et al, JKMS 08 HER2 amplified HER2 normal HER2 is Amplified in 30% of Breast Cancer Cases

23. Figure 15.1b The Biology of Cancer (© Garland Science 2007) Herceptin: a monoclonal antibody that targets HER2 (Trastuzumab)

24. Figure 15.37c The Biology of Cancer (© Garland Science 2007)

25. FDA Expands Use of Herceptin for Early Stage Breast Cancer After Primary Therapy New England Journal of Medicine, October 20, 2005

26. Herceptin can inhibit HER2 by several mechanisms

27. Figure 15.40 The Biology of Cancer (© Garland Science 2007) Herceptin is not the only antibody. Rituxan is used for treating lymphomas.

29. Targeted Drugs Which are the good candidates? oncogenes, especially enzymes, should be druggable Hanahan and Weinberg, Cell 100:57-70 (2000)

30. c-Abl SH3 FG SH2 kinase Actin- binding FG Bcr Bcr-Abl myristate How does Bcr-Abl cause cancer? example #1: Gleevec and Bcr-Abl

31. STI571 Gleevec blocks the ATP binding site of the kinase domain

32. example #2: Iressa, Tarceva and the EGFR low-molecular weight (easy to penetrate big tumors) can act on receptors w/o extra-cellular domains much cheaper than antibodies

33. Four second generation EGFR inhibitors are now entering clinical trials EKB-569, HKI-272, CI-1033, and ZD6474 The Oncologist, Vol. 12, No. 3, 325-330, March 2007 Covalently bind EGFR Target multiple kinases including HER2 and VEGFR

34. The key property of a drug: be effective but not harmful (aka Therapeutic Index= efficacy Vs. toxicity).

35. Testing a new drug and finding the Therapeutic Index in vivo studies Phase III Phase II Phase I in vitro studies clinical trials Testing safety and adverse effects that occur as dosage levels are increased; contains selected patients that respond badly to the standard treatment and are in an advanced state of the disease; takes several months; 70% of experimental drugs pass this initial phase of testing. Testing efficacy and safety; several hundred patients; several months to two years; 30% of experimental drugs pass Phases I and II. Testing effectiveness, benefits, and the range of possible adverse reactions; several thousands patients; 70%-90% success for drugs that entered this phase.

37. The Post-Genomic Era Personalized Therapy

38. Microarrays can be used as a personal genetic signature.

41. We are making progress!! The big questions in the future might not be the technological ones but the social ones

42. The Viral Transforming Functions Reside in a Single Viral Gene: src

43. Bishop and Varmus Let’s label the src gene and follow its dynamics inside the host cell, after infection. Nobel prize in physiology and medicine 1989 A Cellular src Exists, Even Before Infection

44. Der et al. PNAS 82 The Transforming Oncogene is Ras Channing Der, UNC mouse RAS human RAS

45. We turned to model organisms to understand the cellular and molecular machinery of cancer an excellent model an even better one

46. The RTK Pathway

47. Rb, tumor suppressor gene, regulates the cell cycle

48. Retinoblastoma is Associated with Loss of Heterozygosity (LOH) at the RB Locus R. Weinberg, Cancer Biology

49. Cancer develops through gradual changes in cell morphology and properties. benign tumor malignant tumor

50. Cells Move During Development David Shook Turner, Giacoletti and Kaufman Bob Goldstein Ray Keller Dave McClay

51. Figure 14.19c The Biology of Cancer (© Garland Science 2007) cancer cells metastasize after undergoing EMT induced by stromal cells major changes: cell adhesion, cell shape changes, and secretion of MMPs

52. January 12: one day before Biol 445 started

53. And Now…