Genomic Strategies to Cancer Biology and Cancer Therapy

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Genomic Strategies to Cancer Biology and Cancer
Therapy

• Joseph Nevins
• Duke Institute for Genome Science and Policy

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Transitions in Biology
Observational science
Molecular science
Genomic (data) science
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Concept of a Signature
State A State B
Gene expression analysis
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Gene Expression Profiles As Surrogates for
Biological Phenotypes
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Gene Expression Profiles As Surrogates for
Biological Phenotypes
Gene expression profiles as a common currency
for in vitro and in vivo phenotypes
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Addressing the Complexity of Cancer
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The Challenge of Personalized Cancer Treatment

• How to improve prognosis to identify the patients
  in need of further treatment?
• How to identify more effective therapeutic
  opportunities tailored to the individual patient?

Who to treat?
How to treat?
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Improved Prognosis Using Genomic Signatures
Use to refine clinical prognosis
But - how to find an opportunity to actually use
the refinement
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Early Stage NSCLC Treatment Protocol
Stage 1a Observation
Stage 1b-3 Adjuvant Therapy
Diagnosis
Tumor is resected and measured
Yet, 25 of Stage 1A patients will recur and die
- how to identify these individuals?
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A Genomic Predictor of Recurrence
Low Risk High Risk
Predicted High Risk
Probability of Recurrence
Predicted Low Risk
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Validation of the Genomic Recurrence Predictor
CALGB samples
Accuracy 79
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An Opportunity to Improve Prognosis in Lung Cancer
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An Opportunity to Improve Prognosis in Lung Cancer
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Standard-of-Care

• Cisplatin/vinorelbine
• Cisplatin/gemcitabine
• Cisplatin/docetaxel
• Carboplatin/paclitaxel

Only a fraction of patients will respond The
rest are treated ineffectively
How to choose the right therapy for the
individual patient?
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Herceptin - The Importance of Patient Selection
All Breast Cancer Patients
Her2 Breast Cancer Patients
Herceptin
Herceptin
lt 10 Response
35-50 Response
Can we do the same for commonly used
chemotherapies?
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A Strategy to Predict Response to Cytotoxic
Chemotherapies
NCI-60 Cell Panel
Drug response data Affymetrix expression data

• Identify resistant and sensitive cells
• Build expression predictor of response

Resistant Sensitive
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A Panel of Predictors for Cytotoxic Chemotherapies
Docetaxel Topotecan
Adriamycin 5-FU
Taxol Cytoxan
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Predicting Patient Response to Cytotoxic
Chemotherapies
Paclitaxel
Topotecan
Adriamycin
Probability
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Patterns of Predicted Sensitivity to Cytotoxic
Chemotherapies
Predict drug sensitivity in tumors
Etoposide Paclitaxel 5-FU Adriamycin Topotecan Cyt
oxan Docetaxel
Distinct patients sensitive to etoposide and
paclitaxel
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An Opportunity to Guide Therapy
Random Selection A or B
Outcome
Standard of Care (A or B)
Genomics-Guided A or B
Outcome
Cisplatin/gemcitabine Cisplatin/docetaxel
A B
Beyond standard of care - how to direct targeted
agents?
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Signaling Pathways Underlying the Oncogenic
Phenotype
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Predicting Pathway Status in Tumors
Ras Myc E2F
Src b-Cat
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Predicting Pathway Status in Tumors
Ras Myc E2F
Src b-Cat
Emphasizes the heterogeneity of the disease and
therapeutic challenge
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A Profile for an Individual Patient
Can we use the profile for an individual patient?
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SU6656
FTS
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Mapping Pathway Status to Cancer Cell Lines
Ras Myc E2F
Src b-Cat
Compare with drug sensitivity
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Pathway Signatures Predict Therapeutic Response
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(No Transcript)
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SU6656
FTS
Roscovitine
LY294002
Hypothemycin
Rapamycin
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Tumor Progression
Vogelstein and Fearon
Metastatic Carcinoma
Normal Colon
Adenoma
Late Adenoma
Carcinoma
K-Ras 18q loss
APC 5q loss ?-catenin
8p loss
p53 17p loss
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
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Another View of Tumor Progression
Premalignant Nevi
Primary Melanoma
Metastatic Melanoma
Normal Skin
Benign Nevi
Further emphasis of the heterogeneity of the
disease and therapeutic challenge
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The Present
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The Future
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The Future
Etoposide Paclitaxel 5-FU Adriamycin Topotecan Cyt
oxan Docetaxel
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Anil Potti Andrea Bild Jennifer Freedman Seiichi
Mori Jeffrey Chang Mike West Holly
Dressman David Harpole Phillip Febbo Geoffrey
Ginsburg Mike Kelley Sayan Mukherjee Kelly
Marcom John Olson Jeffrey Marks