1. The Challenge of Prostate Cancer Genitourinary Cancer Center at M. D. Anderson PERSONALIZED MEDICINE

2. 30,000 Die of cancer ~ 350,000 patients diagnosed ~125,000 need treatment Prostate Cancer Dilemma!

3. 30,000 Die of cancer ~ 350,000 patients diagnosed ~125,000 need treatment WE MAY BE OVER DIAGNOSING 150,OOO ANNUALLY !

4. Androgen-Dependent Prostate Cancer Acquisition of Complementary Genetic Lesions Clonal Expansion Cancers Adapt to Challenge of Therapy Adaptation Hormone Ablation Therapy

5. “Ability to adapt” can be used to distinguish cancer types Finasteride Lethal genetic networks Indolent genetic networks Surgery Surveillance

6. Assessing response to Finasteride will distinguish cancers with lethal potential from those that can be observed & spared complications of therapy

7. Cancer Cell Fat Cell

8. Weight Change age 25 to Dx Mean Time to Biochemical Failure (months) Loss/No Change <0.5kg/yr... 40.9 Gain 0.5 - 1.5 kg/yr......... 25.8 Gain > 1.5 kg/yr............ 16.7 p=0.003

9. Reversal of Obesity by Targeted Ablation of Adipose Tissue Control Treated Kolonin et al, Nature Med., 2004, 10, 625-32

10. Increased number of fat cells induce prostate cancer aggressiveness & if blocked will retard cancer growth

11. The Challenge

12. PSA Relapse (>0.4 ng/ml) Radiotherapy Observation 100 80 60 40 20 0 80 6040 20 0 Years From Registration Percentage Log-Rank P<.001 No. at Risk Thompson et al JAMA 11/06

13. If Prostatectomy were a drug! Benefited 7%* Incomplete 18%** Unnecessary 40% Futile 35% Total 100% * By survival** By PSA recurrence

14. Principles of Therapy (Localized Cancers) 1) Low stage & Low Grade cancers can be monitored for delayed therapy 2) Higher Grade Cancers generally require treatment 3) Surgery Preferred in younger patients radiation in older 4) Higher grade cancers often require combinations (Hormones & Surgery or Radiation) 5) Consideration of patient preference often deciding factor given excellent choices

15. Distinguishing cancer able to invade adjacent tissue from the remainder will allow us to individualize application of therapy

17. Cancer Cell Host Cell Environment a Determinant of Cancer Invasion & is Normally a well choreographed process

19. The effect of signaling of normal development 1 3 1 1 3 2 1 1 + + + + 1 - - 2 1 2 2 -

23. DOES NOT OCCUR IN MICE!!

24. Androgen Dependent High Risk Prostate Cancer Prostatectomy Thalidomide

25. CT Perfusion Study Pretreatment Posttreatment

27. Interrupting the "organizational sequence" used by prostate cancer for its growth will result in effective therapy

28. Modeling Human Prostate Cancer 35 models

29. Model Prostate Cancer in Bone

30. Human Prostate Cancer “Produces Bone”

31. Working Hypothesis Bone Development Pathways “usurped” by human Prostate cancer and accounts for the observed phenotype

32. Blocking Cancer Growth in Bone (A Priority Therapy Target) Results 50% of treated mice had very little tumor Control Treatment

33. Current Medical Care Reactive Medicine

34. Current Medicine Symptom Diagnosis Treatment (Reactive)

35. Medical Care In the information age (Individualized Therapy) UnderstandAnticipateApply

36. Toxicology Anatomy Medical Oncology Biostats PharmacologyPathology Tumor Biology Meaningful Knowledge Radiation Surgery Cure Rate

37. Toxicology Anatomy Medical Oncology Biostats PharmacologyPathology Tumor Biology Meaningful Knowledge Radiation Surgery Cure Rate Patients

38. A Team Effort with the Patient at the Center! Individualized Therapy

39. Power of Patient Advocacy Patient advocacy has influenced national health priorities and research direction Thank You!