1. The Need for Organ Site Specific Cancer Research John T Isaacs Chemical Therapeutic Program Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

2. DOD Support for Prostate Cancer Research Due to the amount of money available from the DOD, should it support “good basic cancer research” or prioritized prostate cancer specific needs? How would such prostate specific needs be prioritized? (i.e., what are the most urgent prostate cancer needs?)

3. Fertilized Human Egg (One Cell) More than 7,000,000,000,000 cells living in harmony

4. Good Neighborhoods Individual Responsibilities -- Take Out Trash -- Maintain Home -- Obey Property Lines -- Pay Taxes Societal Obligations -- Provide Utilities --Provide Protection --Utilize taxes for common good

7. Normal Prostate Good Neighborhood with Good Neighbors

8. Gas & Electric Pipelines Telephone & Computer Lines Neighborhoods

9. Bad Neighbors

10. Rationale For Organ Site Specific Cancer Research While cancers within specific organ sites can share a subset of similar malignant changes, there are also unique organ site specific changes not shared with other organ site cancers which drive their lethality These organ site specific changes are often the best targets for therapies to selectively kill the specific cancer cells without killing the patient (i.e. Therapeutic Index)

11. Organ Site Specific Molecular Changes For Prostate Cancer Due to unique genetic changes, prostate cancer cells acquire the ability for androgen (i.e., testosterone) to drive the continuous lethal growth of prostate cancer-basis for androgen ablation therapy Prostate Cancer express a series of organ site specific markers (e.g., Prostate Specific Antigen, Prostate Specific Membrane Antigen, PCA3, Ets Gene-fusions etc.)

12. Prostate Cancer Specific Biomarkers Diagnosis Prognostication Intermediate End-Points

13. Prostate Cancer Biomarkers Blood and serum markers Urine markers Tissue markers Functional Imaging

14. Prostate Specific Antigen In 1980, PSA was documented to be elevated in the serum of patients with prostate cancer In 1984, FDA approved serum PSA as a marker for monitoring prostate cancer progression In 1994, FDA approved serum PSA for screening for initial detection of prostate cancer 20 Million serum PSA tests/year in North America plus 20 Million tests outside of North America

15. Whole Blood “Liquid Biopsy” For Detection of Circulating Prostate Cancer Cells In 2008, FDA approved the quantitation of the number of Circulating Tumor Cells in the blood to monitor prostate cancer progression using epithelial cell, but not prostate cancer specific markers This assay can be made prostate cancer specific using prostate cancer specific using markers like PSA,PSMA, or unique DNA based markers

16. To Develop Effective Therapies for Prostate Cancer Requires Two Distinct Processes Drug Discovery followed by Drug Development

17. Drug Discovery Process Target Identification In Vitro Testing Animal Testing Drug Selection Molecular Biology Analysis Cell Biology Techniques Biochemical Assays Chemical Libraries High Thru-put Screen Computer Modeling Medicinal Chemistry Rodent Models  Transgenic  Spontaneous  Induced Human Cancer Xenograph

18. Time Cost (in millions) Drug Selection Preclin Tox Phase I Safety Phase II Efficacy Phase III Efficacy – Tumor Progression Quality of Life FDA Review Oncology Drug Development Process Time and Costs ~2.5 yrs. ~$4 1 yr. ~$2 1 yr. $12 2 yrs. $12 3 – 4 yrs. $200-300 1-2 yrs. $25-$40 Development Stage

19. The problem with “Blind” Survival Response Criteria In Phase III Clinical Trials Under-appreciated “partial response” (aka throwing out the baby with the bath water)

20. Bad Neighbors

21. To Accelerate Drug Development for Prostate Cancer Urgent need for functional imaging to allow assessment of the response of individual metastatic sites within an individual patient