The Need for Organ Site Specific Cancer Research

John T Isaacs

Chemical Therapeutic Program

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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?)

Fertilized Human Egg(One Cell)

More than 7,000,000,000,000 cellsliving in harmony

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

Normal Prostate

Good Neighborhood with Good Neighbors

Gas & ElectricPipelines

Telephone &Computer Lines

Neighborhoods

Bad Neighbors

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)

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.)

Prostate Cancer Specific Biomarkers

Diagnosis

Prognostication

Intermediate End-Points

Prostate Cancer Biomarkers

Blood and serum markers

Urine markers

Tissue markers

Functional Imaging

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

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

To Develop Effective Therapies for Prostate Cancer Requires Two

Distinct Processes

Drug Discovery followed by Drug Development

Drug Discovery Process

TargetIdentification

In VitroTesting

AnimalTesting

DrugSelection

MolecularBiologyAnalysis

CellBiologyTechniques

BiochemicalAssays

ChemicalLibraries

HighThru-putScreen

ComputerModeling

MedicinalChemistry

Rodent Models

Transgenic

Spontaneous

Induced

HumanCancerXenograph

Time

Cost (in millions)

Drug Selection

PreclinTox

Phase I

Safety

Phase II

Efficacy

Phase III

Efficacy – TumorProgression

Quality of Life

FDAReview

Oncology Drug Development ProcessTime 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

Dev

elop

men

t Sta

ge

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)

Bad Neighbors

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