The Need for Organ Site Specific Cancer Research

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The Need for Organ Site Specific Cancer Research
John T Isaacs Chemical Therapeutic Program
Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins
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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?)
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Fertilized Human Egg (One Cell)
More than 7,000,000,000,000 cells living in
harmony
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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
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Good Neighborhood with Good Neighbors
Normal Prostate
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Telephone Computer Lines
Gas Electric Pipelines
Neighborhoods
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Bad Neighbors
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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)

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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.)

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Prostate Cancer Specific Biomarkers
Diagnosis
Prognostication
Intermediate End-Points
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Prostate Cancer Biomarkers
Blood and serum markers
Urine markers
Tissue markers
Functional Imaging
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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

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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

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To Develop Effective Therapies for Prostate
Cancer Requires Two Distinct Processes
Drug Discovery followed by Drug Development
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Drug Discovery Process
Target Identification
In Vitro Testing
Animal Testing
Drug Selection
Human Cancer Xenograph
Molecular Biology Analysis
Biochemical Assays
Rodent Models
Chemical Libraries
Computer Modeling

• Transgenic
• Spontaneous
• Induced

Cell Biology Techniques
High Thru-put Screen
Medicinal Chemistry
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Oncology Drug Development ProcessTime and Costs

Drug Selection
Preclin Tox
Phase I Safety
Phase II Efficacy
Phase III Efficacy Tumor Progression Quality
of Life
FDA Review
Development Stage
Time Cost (in millions)
1-2 yrs.
2.5 yrs.
1 yr.
1 yr.
2 yrs.
3 4 yrs.
4
2
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200-300
25-40
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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)
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Bad Neighbors
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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