The Challenge of Prostate Cancer

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

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

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

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

5. “Ability to adapt” can be used to distinguish cancer types Lethal genetic networks Surgery Finasteride Indolent genetic networks 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. WeightChange 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) 100 Radiotherapy Observation 80 60 Percentage 40 20 Log-Rank P<.001 0 0 80 20 40 60 Years From Registration 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 + + 1 1 1 - - 2 2 + + 1 1 1 2 3 3 2

23. DOES NOT OCCUR IN MICE!!

24. Androgen DependentHigh Risk Prostate Cancer Prostatectomy Thalidomide

25. CT Perfusion Study Posttreatment Pretreatment

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 Treatment Control

33. Current Medical Care Reactive Medicine

34. Current Medicine (Reactive) Treatment Symptom Diagnosis

35. Medical Care In the information age(Individualized Therapy) Understand Anticipate Apply

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

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

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

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