This is a brief overview of the current state of personalized medicine and its scientific and clinical challenges.

1. Personalized Medicine:Scientific and Clinical Challenges Andrew Helicher and Tieming Lang INS 497C April 30, 2010

3. Scientific Challenges

4. Clinical Challenges2

6. Scientific Challenges

7. Clinical Challenges3

8. Definition 4 “Use of molecular or genetic characteristics to customize therapy for individuals” But how well does individual resemble various sub-populations? Patient Sub-Populations A Patient’s resemblance to a sub-population is probabilistic vs. deterministic. This is not a perfect science, but benefits can be achieved. Kohane, 2009, p. 1

9. Categories and Benefits Ginsburg, 2009, p. 1 Aspinall, 2007, p. 1 5

10. Challenges 6 Aspinall, 2007 Davis, 2010

12. Scientific Challenges

13. Clinical Challenges7

15. Finding the right marker

17. Finding the right marker

19. Since one gene codes for one protein, mal-function of a protein can be traced back to mutation of one gene

20. If we can know the gene that is responsible for a disease, finding a mutation can certainly predict disease

21. Problem:

22. We don’t know the root genes of many diseases10

24. Many genes have multiple functions and participate in multiple cellular pathways.

25. Many diseases are result of disruption of a particular cellular pathway or function, which often involves many genes

26. Problem:

27. Which gene(s) can be used as diagnostic marker?11 The Molecular Mechanisms of Diseases

29. Cancer cells are usually genetically heterogeneous

30. Disruption of many cellular pathways can contribute to cancer

31. Most cancer cells are result of accumulation of mutations on multiple genes

32. Cancer stem cells may be the root cause of resistance and malignancy

33. Problems:

34. Marker to which gene to use?

35. What’s the utility of marker if the associated gene is not the root cause of cancer?12 The Molecular Mechanisms of Diseases

37. Finding the right marker

39. Types of mutation:

40. Single nucleotide mutations

41. Deletions and insertions

42. Change of repetition numbers

43. Epigenetics

44. For complex genes, such as BRCA1 and BRCA2, there are thousands of known polymorphisms and mutations

45. Many mutations, although change protein activity, do not result in diseases14 Finding the Right Marker

47. Deletion and insertion

48. Single nucleotide polymorphism (SNP)

49. Microarrays

50. Associated marker

51. Expression profile

52. metabolites15 Finding the Right Marker

54. Finding the right marker

56. Participants are more likely to have disease.

57. Investigators are biased toward positive results.17

60. Gene complementation/ redundancy

61. Mutation of DNA repair genes

62. How to interpret testing results?18

65. Patient responses may be inaccurate (i.e. what is your race?)1/3 of disease risk predictions differ between genetic testing companies 23andMe and Navigenics1 Ng, 2009, p. 1-3

67. Scientific Challenges

68. Clinical Challenges20

69. Challenges to Clinical Adoption Aspinal, 2007, p. 1 Ginsburg, 2009, p. 25-26 Kalota, 2010, p. 1 Downing, 2009, p. 3 21

70. Pre-Requisites to Clinical Adoption 22 Genomics incorporated into medical education4 FDA clarifies genomic regulatory requirements1 Pharma produces robust clinical guidance on genomic drugs5 Payers create CPT codes and reimburse genomic drugs/diagnostics2 Increased Clinical Adoption Scientific advances improve accuracy and clarify of genomic tests Providers are reimbursed for genomic tests3 Genomics incorporated into EHR/CDS systems6 Ratain, 2007 Apinall, 2007 Davis, 2010, p. 8 Ginsburg, 2009 Woodcock, 2007, p. 3 Downing, 2009

71. Questions? 23

72. References 24 Aspinall, M. & Hamermesh, R. (2007) Realizing the Promise of Personalized Medicine. Harvard Business Review. October, 2007. David, J., Ma, P. & Sufaria, S. (2010) The Microeconomics of Personalized Medicine. McKinsey Quarterly. Retrieved from http://www.mckinseyquarterly.com/The_microeconomics_of_personalized_medicine_2527. February, 2010. Downing, G., Boyle, S., Brinner, K. & Osheroff, J. (2009) Information Management to Enable Personalized Medicine: Stakeholder Roles in Building Clinical Decision Support. BMC Medical Informatics and Decision Making. Retrieved from http://www.biomedcentral.com/content/pdf/1472-6947-9-44.pdf. October 8, 2009. Ginsburg, G. & McCarthy, J. (2009) Transforming the Practice of Medicine Using Genomics. Clinical Cases in Bone Metabolism. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781216/pdf/ClinicalCases-6-0025.pdf, April 28, 2010. Kohane, I. (2009) The Twin Questions of Personalized Medicine: Who Are You and Whom Do You Resemble? Genome Medicine. Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651581/pdf/gm4.pdf. January 20, 2009. Ng., P., Murray, S., Levy, S. & Venter, J. (2009) An Agenda for Personalized Medicine. Nature. Vol. 461. October 8, 2009. Ratain, M. (2007) Personalized Medicine: Building the GPS to Take Us There. Clinical and Pharmacology Therapeutics. Volume 81, Number 3. March, 2007. Woodcock, J. (2007) Molecular Medicine: How, What, and When? Nature. Volume 82, Number 4. October, 2007.