Transcript Shooting at the Wrong Target?

Aiming at the Wrong Target?
Discussion of Abstracts
CRA3507 (Alberts) and 3508 (Goldberg)
Louis M. Weiner, MD
Lombardi Comprehensive Cancer Center
Georgetown University Medical Center
Potential Conflicts
Relevant 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
EGFR
– 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
How did we miss the target?
Cetuximab – Two Major Mechanisms of
Action
1. Antibody-dependent Cellular Cytotoxicity
2. Signaling Perturbation
Possible Explanations and Implications
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
Tumor Cell
Antigen
Antibody
Fc Domain
Killer Cell
NK, Macrophage, Neutrophil
Possible Explanations and Implications
1. ADCC is not relevant
2. EGFR Signaling is complicated
–
Robust EGFR resistance networks
EGFR: a central and heavily targeted pathway
Cetuximab
Panitumumab
EGFR
Cell membrane
Erlotinib
Gefitinib
Lapatinib
Shc
“Downstream”
Signaling
proteins
Grb2
PI3-K
Sos-1
Ras
AKT
MEKK-1
Raf
MEK
mTOR
MKK-7
ERK
JNK
CancerRelevant
outputs
Survival
signaling
Proliferation
Angiogenesis
Metastasis
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 Complexity
Defining the EGFR Network
638 Genes
Astsaturov et al, Science Signaling, In Press
Exploring the EGFR functional network
with siRNA-based genomics
Gene
Nucleus
Cell
DNA
mRNA
siRNA
X
638-element siRNA library created to target
each gene in the EGFR signaling network
Astsaturov et al, Science Signaling, In Press
Protein
Exploring the EGFR functional network
with siRNA-based genomics
Gene
Nucleus
Cell
DNA
mRNA
siRNA
X
siRNA libraries target the expression of
selected genes and permit study of the effects
of targeted gene knockdown on cell function
Astsaturov et al, Science Signaling, In Press
Protein
Synthetic Lethal Screening of an
EGFR Network-directed siRNA Library
Cell Line Seeded into
Multi-well Plate – Each
Well is Precoated with
siRNA Against One Gene
siRNA for 638 Genes
Introduced into Cells
Distinct Gene Knocked
Down in Cells Growing
in Each Well
± EGFR inhibitor (IC30)
Lethal
Phenotype?
“Hit”
Astsaturov et al, Science Signaling, In Press
Confirm, Validate
and Map Hits
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 relevant
2. 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)
EGFR
E-cadherin
Cytokeratin
ZO-1
Laminin-1
Entactin
Syndecan
MUC1
Desmoplakin
a1 (IV) collagen
miR200 family
Adapted from Kalluri & Weinberg, J Clin Invest 119: 1420-8, 2009
FTS binding protein FAP
FSP-1
N-cadherin
Vimentin
Fibronectin
b-catenin
Ob-cadherin
Syndecan-1
miR10b
Snail
Slug
SIP1
a-SMA
Twist
Goosecoid
LEF-1
FOXC2
miR21
Is EGFR an Appropriate Target
when Cells Undergo EMT?
EGFR
Primary
Tumor
Established
Metastasis
Metastasis
Druggable Targets
Epithelial
 EGFR
 EGFR
 pAKT
 E-Cadherin
 E-Cadherin
 PI3K
 Vimentin
 Vimentin
 IGF1R
EMT
Relative Sensitivity to Cetuximab
EGFR
Primary
Tumor
Metastasis
Established
Metastasis
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)
Summary and Implications
• Cetuximab therapy does not prevent metastasis
following resection of Stage III colon cancer
– Likely to be true for panitumumab and other antiEGFR 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
Summary and Implications
• Cancer cell populations exhibit epithelialmesenchymal 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 epithelialmesenchymal 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