Title of Slideshow To go Here

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The Rational Approach to Cancer Drug Development
Edward A. Sausville National Cancer Institute, USA
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Cancer DrugsHow Do We Know We Have a Winner?
- PHASE III CLINICAL TRIAL WINNER
- PHASE II POTENTIAL WINNER
Time?
- PRECLINICAL MODEL (e.g., mouse or rat)
Cytotoxic
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Six Essential Alterationsin Cell Physiology in
Malignancy
Hanahan Weinberg, Cell 10057 (2000)
Targets for classical drugs?
Targets for novel drugs?
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Molecular Targets
Diagnostic Path
Interventional Path
Correlational Studies
Credentialing (Interventional)

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Rational Drug Discovery
PHARMACOLOGY (to affect target)
MOLECULAR TARGET SCREEN
Biochemical Engineered cell Animal
(yeast/worm/fish)
CHEMISTRY
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STI571An Oral In Vivo Bcr-abl Kinase Inhibitor
(days)
(hrs)
(days)
Tyr phosphorylation in vivo
Antitumor activity in vivo
le Coutre et al, JNCI 91163, 1999
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Efficacy and Safety of a Specific Inhibitor of
the Bcr-abl Tyrosine Kinase in Chronic Myeloid
Leukemia
Brian J.Druker,M.D.,Moshe Talpaz,M.D.,Debra
J.Resta,R.N.,Bin Peng,Ph.D., Elisabeth
Buchdunger,Ph.D.,John M.Ford,M.D.,Nicholas
B.Lydon,Ph.D.,Hagop Kantarjian,M.D., Renaud
Capdeville,M.D.,Sayuri Ohno-Jones,B.S.,and
Charles L.Sawyers,M.D.
Ph Chromosome Cells
White Cell Count
in Metaphase
(cells x 10-3 / mm3)
Duration of Treatment with STI571 (Days)
NEJM 344 1031, 2001
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Activity of a Specific Inhibitor of the Bcr-abl
Tyrosine Kinase in the Blast Crisis of Chronic
Myeloid Leukemia and Acute Lymphoblastic Leukemia
with the Philadelphia Chromosome
Brian J.Druker,M.D.,Charles L.Sawyers,M.D.,Hagop
Kantarjian,M.D.,Debra J.Resta,R.N., Sofia
Fernandes Reese,M.D.,John M.Ford,M.D.,Renaud
Capdeville,M.D., and Moshe Talpaz,M.D.
Time to Relapse in Patients with Myeloid or
Lymphoid Blast Crisis Who Had a Response to STI571
Probability of Relapse

• Orange arrows indicate patients still enrolled
  in the study and in remission at the
• time of the last follow-up
• White arrows indicate the day on which patients
  were removed from the study

NEJM 344 1038, 2001
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Linear vs. Concentric Target Action
Drug 1
Drug 2
Stimulus
Drug A
Target A
Target B
Receptor


Drug B
Super State
A
Drug C
-

B
Drug D
Target E
Target C

C
Drug 4
Target D
Drug E
Output
Drug 3
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Complications in Definition/ Pursuit of Cancer
Targets

• One histology actually many diseases
• Plasticity of targets in natural history
• of a particular patients tumor
• Resistance mechanisms

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Distinct Types of Diffuse Large B-cell Lymphoma
Identified by Gene Expression Profiling
All patients
Probability
Overall survival (yrs)
All patients
Low clinical risk pts
Probability
Overall survival (yrs)
Alizadeh et al, Nature 403 503, 2000
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Modulation of Tumor Angiogenesis by Conditional
Expression of Fibroblast Growth Factor-2 Affects
Early but not Established Tumors
Raffaella Giavazzi, Roberta Giuliani, Daniela
Coltrini, Maria Rosa Bani, Cristina Ferri,
Barbara Sennino, Maria Pia Molinari Tosatti,
Antonella Stoppacciaro, and Marco Presta
LATE FGF OFF
EARLY FGF OFF
FGF2-B9
Tet-FGF2 15H
blood vessels/400x field
Tumor Weight (mg)
Days after transplantation
Cancer Res 61 309, 2001
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Acquired Resistance to the Antitumor Effect of
Epidermal Growth Factor Receptor-blocking
Antibodies in Vivo A Role for Altered Tumor
Angiogenesis
Alicia Viloria-Petit, Tania Crombet, Serge Jothy,
Daniel Hicklin, Peter Bohlen, Jean Marc
Schlaeppi, Janusz Rak, and Robert S. Kerbel
Cancer Res 61 5090, 2001
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Molecular Target Definition - How To?

• BIOLOGY
• RETROFIT ACTIVE MOLECULES
• CLASSICAL
• CHEMICAL GENETICS

Cytogenetics Breakpoints
Molecules (bcr-abl) Positive
selection from tumor DNA Active
oncogenes (signal transduction) Tumor
gene expression profiling (CGAP) Binding
partners (geldanamycin, rapamycin, fumagillin)
Computational algorithm (molecule
target) Cell metabolism / Cell cycle
effects Suggest single targets
Inefficient Libraries of molecules and
precisely defined organisms
- COMPARE - Cluster analysis
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Cancer Genome Anatomy Project
www.ncbi.nlm.nih.gov/CGAP/
Genes over/under expressed in cancer

The Signature of a Cancer Type is its unique
pattern of gene expression
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Cancer Biology to Define TargetsCancer Genome
Anatomy ProjectPROCESS

• Tumor material (archival)
• Laser capture microdissection of tumor cells
• from defined sections
• Creation of tumor-derived cDNA libraries
• Sequence to establish uniqueness
• Deposit in public domain

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Gene Expression The Cells Fingerprint
Normal Cell
Cancer Cell
Establishing for a cell the repertoire of genes
expressed, together with the amount of gene
products produced for each, yields a powerful
"fingerprint." Comparing the fingerprints of a
normal cell versus a cancer cell will highlight
genes that by their suspicious absence
or presence (such as Gene H ) deserve further
scientific scrutiny to determine whether such
suspects play a role in cancer, or can
be exploited in a test for early detection.
Source www.ncbi.nlm.nih.gov/CGAP/
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Geldanamycin Structure
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Three-Dimensional View of Geldanamycin Binding
Pocket in Amino Terminus of Hsp90
Stebbins et al, Cell 89239, 1997
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Hsp 90
C.
A.
B.
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Ansamycins Potently Inhibit HGF/MET Action
Webb et al, Cancer Res 60 342, 2000
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Classes of Potential Drug/Imaging Targets

• Pathogenic
• Ontogenic
• Pharmacologic
• Microenvironmental

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What Validates/Credentials a Target?

• Differential expression (tumor vs. normal)?
• Mutation (tumor vs. normal)?
• Model systems
• Epidemiology incidence/prevalence/survival
• Achilles Heel death dealing in tumor vs. normal

-Nature of target turn off an on vs. adding an
off
Cells?
Animals? (tumor/normal/stroma)
-Inducibility of phenotype
-Knock in/knock out/dominant negative
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Drug Discovery/Early Clinical TrialsPlans for
Change
GUIDING PRINCIPLES

• Cancer biology has defined molecules
  responsible
• Successful drugs of the future will be directed
  at
• The optimal drug development process allows
  test of
• Imaging tools greater insight into Rx level
  and use

for cancer occurrence and progression these
molecular targets a molecular hypothesis as
well as assessment of pharmacology, toxicity,
and anti-proliferative effect
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Questions and Discussion Thank you!