Aiming at the Wrong Target? Discussion of Abstracts CRA3507 (Alberts) and 3508 (Goldberg) Louis M....
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Transcript of Aiming at the Wrong Target? Discussion of Abstracts CRA3507 (Alberts) and 3508 (Goldberg) Louis M....
Aiming at the Wrong Target?Discussion of Abstracts
CRA3507 (Alberts) and 3508 (Goldberg)
Louis M. Weiner, MDLombardi Comprehensive Cancer CenterGeorgetown University Medical Center
Potential ConflictsRelevant to this Presentation
• Consultant, Stock Options– Merrimack Pharmaceuticals
• Research Support– Amgen
The Facts
• Cetuximab does not improve adjuvant therapy cure rates of resected Stage III colorectal cancer – Trends towards inferior outcomes– True for KRAS-wild type (Abstract CRA 3507) and
KRAS-mutant (Abstract 3508) tumors
• No significant concerns raised by study design or execution of the clinical trial– These results are definitive– Cetuximab toxicity may interfere with delivery of
chemotherapy
• Not likely that results will improve if other clinical trial designs are tested
This Should Have Worked!
• Cetuximab (and related antibodies (i.e., panitumumab) have modest activity in refractory colorectal cancer – Single-agent– Combined with
chemotherapy– KRAS mutations identify
patients who will not benefit • Minimally active
chemotherapy (i.e., 5-FU + LV) for metastatic colon cancer has benefit in the adjuvant setting
EGFR
How did we miss the target?
Cetuximab – Two Major Mechanisms of Action
1. Antibody-dependent Cellular Cytotoxicity 2. Signaling Perturbation
Possible Explanations and Implications
Tumor Cell
Killer CellNK, Macrophage, Neutrophil
Antibody
1. Antibody-Dependent Cellular Cytotoxicity (ADCC) not relevant
– True if EGFR effectively targeted– Not relevant if EGFR+ cells are not the correct targets for colon
cancer metastasis
AntigenAntigen
Fc DomainFc Domain
Possible Explanations and Implications
1. ADCC is not relevant2. EGFR Signaling is complicated
– Robust EGFR resistance networks
EGFR: a central and heavily targeted pathway
Proliferation MetastasisAngiogenesisSurvival signaling
Shc
PI3-K
RafMEKK-1
MEKMKK-7
JNKERK
Ras
mTOR
Grb2
AKT
Sos-1
EGFR
“Downstream”Signaling proteins
Cancer-Relevantoutputs
Cell membrane
ErlotinibGefitinibLapatinib
CetuximabPanitumumab
Some Molecular Determinants of Clinical Benefit of Anti-EGFR Therapies
Determinant(s) Influence References
KRAS Mutation Negative J Clin Onc 25: 3230, 2007
J Clin Onc 26: 374, 2008
BRAF Mutation,
PTEN Loss
Negative J Clin Onc 27: 5924, 2009
J Clin Onc 27: 2622, 2009
Amphiregulin or Epiregulin Expression
Positive J Clin Onc 25: 3230, 2007
J Clin Onc 27: 5068, 2009
EGFR Gene Amplification
Positive J Clin Onc 27: 5924, 2009
The EGFR Signaling Network is Vast and Complicated
Making Sense of the ComplexityDefining the EGFR Network
638 Genes
Astsaturov et al, Science Signaling, In Press
CellNucleus
DNA
Exploring the EGFR functional network with siRNA-based genomics
Gene
siRNA
mRNA
ProteinProteinX638-element siRNA library created to target each gene in the EGFR signaling network
Astsaturov et al, Science Signaling, In Press
CellNucleus
DNA
Exploring the EGFR functional network with siRNA-based genomics
Gene
siRNA
mRNA
ProteinProtein
siRNA libraries target the expression of selected genes and permit study of the effects of targeted gene knockdown on cell function
XAstsaturov et al, Science Signaling, In Press
siRNA for 638 Genes Introduced into Cells
Lethal Phenotype?
“Hit”
Synthetic Lethal Screening of an EGFR Network-directed siRNA Library
Confirm, Validate and Map Hits
Cell Line Seeded into Multi-well Plate – Each Well is Precoated with
siRNA Against One Gene
Distinct Gene Knocked Down in Cells Growing
in Each Well
± EGFR inhibitor (IC30)
Astsaturov et al, Science Signaling, In Press
EGFR Network Determinants of Response to EGFR Inhibition
• 61 validated “hits” identify the EGFR “resistance space” in multiple cell lines
• Expected and unexpected mediators of resistance
• Knockdown of KRAS modestly sensitizes cells to EGFR inhibition
Astsaturov et al, Science Signaling, In Press
Possible Explanations and Implications
1. ADCC is not relevant2. EGFR Signaling is complicated
– Robust EGFR resistance networks
3. EGFR is not a relevant target in colon cancer metastasis
Right Target, Wrong Setting?Epithelial-Mesenchymal Transition (EMT)
Adapted from Kalluri & Weinberg, J Clin Invest 119: 1420-8, 2009
EGFR SyndecanE-cadherin MUC1Cytokeratin DesmoplakinZO-1 1 (IV) collagenLaminin-1 miR200 familyEntactin
EGFR SyndecanE-cadherin MUC1Cytokeratin DesmoplakinZO-1 1 (IV) collagenLaminin-1 miR200 familyEntactin
FTS binding protein FAP SnailFSP-1 SlugN-cadherin SIP1Vimentin -SMAFibronectin Twist-catenin GoosecoidO-cadherin LEF-1Syndecan-1 FOXC2miR10b miR21
FTS binding protein FAP SnailFSP-1 SlugN-cadherin SIP1Vimentin -SMAFibronectin Twist-catenin GoosecoidO-cadherin LEF-1Syndecan-1 FOXC2miR10b miR21
Is EGFR an Appropriate Target when Cells Undergo EMT?
Epithelial EMT
EGFR pAKT
E-Cadherin PI3K
Vimentin IGF1R
Primary Tumor
Metastasis Established Metastasis
EGFR
EGFR
E-Cadherin
Vimentin
Druggable TargetsDruggable Targets
Relative Sensitivity to Cetuximab
High Low High
“EMT status may be a broadly applicable indicator of sensitivity to EGFR inhibitors.” (Barr et al, Clin Exp Metastasis (2008) 25:685–693)
Primary Tumor
Metastasis Established Metastasis
EGFR
Summary and Implications
• Cetuximab therapy does not prevent metastasis following resection of Stage III colon cancer – Likely to be true for panitumumab and other anti-
EGFR antibodies
• EGFR-directed monoclonal antibodies should not be used in Stage III colon cancer-directed adjuvant therapy regimens
• Numerous genes contribute to resistance to EGFR antagonism– May underlie resistance to cetuximab– Combination signaling inhibitor strategies are needed
• Cancer cell populations exhibit epithelial-mesenchymal transition (EMT)
• Colon cancer metastasis may not be dependent upon signaling through EGFR
• Targeting EMT-related processes may be a better approach to inhibit colon cancer metastasis
Summary and Implications
• Cancer cell populations exhibit epithelial-mesenchymal transition (EMT)
• Colon cancer metastasis may not be dependent upon signaling through EGFR
• Targeting EMT-related processes may be a better approach to inhibit colon cancer metastasis
A better understanding of colon cancer biology will inevitably lead to better treatments that
– Target the right cells at the right time
– Effectively disrupt one or more targets that are required for the function of crucial signaling networks
Summary and Implications