Cellular Signalling Pathways

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Introduction
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Cellular Signalling Pathways

• Vital for cell cycle progression, growth,
  differentiation death.
• Growth Factors The key stone
• A delicate balance between activating and
  inhibitory signals needs to be maintained
  normally
• Alteration in this balance - Dysregulated
  cellular proliferation survival of abnormal
  cells.

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Growth Factors Cell Cycle
Receptors
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Epidermal Growth Factor Receptor (EGFR)
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EGFR Expression Rate
Tumour
Breast 14 - 91
Colon 25 - 77
Lung Cancer 40 - 80 (Non
small cell)
Head Neck 80 - 95
Ovarian 35 - 70
Pancreatic 30 - 50
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Some Landmarks in EGFR Signalling
Stanley Cohen

• EGF in mice (1960s)

• Human EGF (1970s)

• Isolation and cloning of EGFR (1980s). Link
  
  between EGFR and malignant
  transformation of cells demonstrated

Mendelsohn et al.,

• Blocking EGFR signalling to treat cancer

• Murine monoclonal antibodies targeting
  
  EGFR-TK? Humanmurine chimeric version

More than 20 anti-EGFR agents in development
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Human Epidermal Growth Factor Receptor Family
No specific ligands - often acts as dimer
partner
NRG2 NRG3 Heregulins ß-cellulin
EGF, TGFa , b Cellulin Amphiregulin, HB-EGF
Heregulins
erbB1HER1 EGFR
erbB2 HER2 neu
erbB3 HER3
erbB4 HER4
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EGFR Structure
Extracellular Domain
Transmembrane Domain
Intracellular Domain
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EGFR Stimulation dimerisation
EGFR Homo Dimerisation
erbB1HER1 EGFR
erbB2 HER2 neu
erbB3 HER3
erbB4 HER4
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EGFR stimulation cont
Hetero Dimerisation
erbB4 HER4
erbB1HER1 EGFR
erbB2 HER2 neu
erbB3 HER3
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EGFR Function in Normal Cell
Gene Transcription Cell Cycle Progression
Antiapoptosis
Cell Proliferation
Angiogenesis
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EGFR signal transduction in tumour cells
PI3-K
GRB2
pY
pY
SOS
pY
RAS
RAF
STAT3
AKT
MEK
Gene transcription
MAPK
G1
M
S
Survival(anti-apoptosis)
Proliferation/maturation
G2
Chemotherapy /radiotherapyresistance
Metastasis
Angiogenesis
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Other mechanisms of EGFR stimulation
Steroid hormone
HB-EGF
G protein
Ca
Steroid hormone receptor
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How EGFR variant differs from the wild type
EGFR - Variant III
EGFR Wild Type
No extracellular domain
Present
Ligand cannot bind
Can bind
TK constitutively active
TK activated by ligand binding
Cannot dimerise
Can dimerise
Not found in normal cells
Found normally
More propensity for cancer
Up regulation leads to cancer
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EGFR variant
Cell Proliferation
Metastasis
Anti Apoptosis
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Consequence of proliferation of EGFR receptors
Normal Cell
Cancerous Cell
Up Regulation
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EGFR A good target for lung cancer ( non small
cell )

• High level of receptor expression compared with
  healthy tissue.
• EGFR - Key role in tumour cell growth function.
• EGFR inhibition can inhibit downstream activity.
• EGFR inhibitors have no severe toxicity.

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Rationale for EGFR Inhibitors in Head Neck
cancer

• EGFR expressed in gt 90 of head neck cancers.
• EGFR over expression associated with decreased
  survival.
• Increased EGFR expression is an early event in
  carcinogenesis even present in premalignant
  lesions.
• Inhibition of EGFR TK slows the growth of
  xenograft tumour models of head neck.

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Strategies to inhibit EGFR signaling
Anti-ligand mAbs
Immune effector cell
EGFR tyrosine kinase inhibitors
BispecificAbs
Anti-EGFR mAbs
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Drugs Available

• Cetuximab Monoclonal Anti EGFR antibody

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Indications
Gefitinib Erlotinib
Monotherapy in advanced stage of NSCLC

Cetuximab
Metastatic colorectal cancer with/without
Irinotecan
Dose
Gefitinib 250 mg O.D. oral Erlotinib
150 mg O.D. oral Cetuximab 400 mg/ m2 i.v.?
200 mg / m2 i.v. wkly
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Side Effects

• Skin rash
• Diarrhoea ( EGFR TKI s )
• Fever ( EGFR mAb )
• Interstitial lung disease 1 (only for
  Gefitinib)

Discontinuation rates due to adverse
effects are very low unlike chemotherapy.
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Drug Interactions

• EGFR TK Inhibitors metabolised by CYP3A4.
• Inhibitors / inducers of CYP3A4 can alter drug
  levels.
• Warfarin interactions have occurred in clinical
  trials of Gefitinib.
• Concomitant administration with warfarin requires
  monitoring of PT, INR.

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Advantages of EGFR Inhibitors

• Orally effective
• Better quality of life.
• Can be used as monotherapy.
• No need for premedication or dose monitoring.
• No hematological toxicity.
• Potential for long term treatment.
• Reduced resistance to radiation or hormone therapy

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Current Status
Gefitinib

• FDA Approved on May ,2003 for Lung cancer-NSC
  (Accelerated Approval Programme)

Erlotinib

• FDA Approved on Nov, 2004 for Lung cancer Non
  Small Cell (AAP)

Cetuximab

• FDA Approved on Feb, 2004 for advanced colorectal
  cancer

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Clinical Trials
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Gefitinib Phase II Trials
Parameter
IDEAL I
IDEAL II
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Gefitinib Phase III Trials
Parameter
INTACT I
INTACT II
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Erlotinib Phase II Trials
Parameter
I
II
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Outcomes with Targeted Therapy

• Progression-free survival
• Quality of life
• Response to treatment
• Safety
• Overall Survival

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Unanswered Questions

• Patient selection

• How long patients should be treated

• Timing and sequencing of combination therapy

• Use in various stages of disease

• Appropriate markers for response

• Managing unique adverse events
• ?
  ILD
• 
  ? Liver toxicity

• Best use in other solid tumours

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Ongoing Trials

• Different treatment schedules for use in
  combination chemotherapy
• In other malignancies Breast, Prostate, Head
  Neck, Colon as single / combination therapy

Strategies

• Combining EGFRI with Radiotherapy / Surgery or
  other novel targeted agents like trastuzumab
• Identify subset of people who will benefit from
  TKI
• Skin rashes, Mutation in TK, KRAS

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Conclusion
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Conclusion

• EGFR inhibitors- a definite role in treatment of
  cancer
• Combination chemotherapy Further studies needed
• Improves QOL with minimal adverse effects
• Can be administered at optimal biological
  dose
  
• Potential for use in multiple tumors

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Conclusion
? Role in early stage of cancer needs to be
assertained ? Survival not significantly
prolonged ? Costly
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Reference
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Review Articles
1.Soler R.P. HER1/ EGFR Targeting Refining the
strategy. Oncologist 2004 9 58 67. 2.
Herbst R.S, Fukuoka M, Baselga J. Gefitinib a
novel targeted approach to treating canver.
Nature rev cancer 2004 4 956 65. 3.
Strausberg R.L, Simpson A.J.G, Old L.J, Riggins
G.J. Oncogenomics and the development of new
cancer therapies. Nature 2004 429 469
74. 4. Noble M.E.M, Endicott J.A, Johnson L.N.
Protein kinase inhibitors Insights into drug
design from structure. Science 2004 303 1800
05. 5.Glover K.Y, Soler R.P, Papadimitradopoulou
V.A. A review of small molecule Epidermal Growth
Factor Receptor specific tyrosine kinase
inhibitors in development for non small cell lung
cancer. Sem. Oncol. 2004 31 suppl 83 92.
6. Janmaat M.L, Giaccone G. Small molecule
Epidermal Growth Factor Receptor tyrosine kinase
inhibitors. Oncologist 2003 8 576 86.
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Review Articles cont
7. Yano S, Nishioka Y, Goto H, Sone S. Molecular
mechanism of angiogenesis in non small cell lung
cancer and therapeutics trageting related
molecules. Cancer sci. 2003 94 479 85. 8.
Vlahovic G, Crawford J. Activation of tyrosine
kinases in cancer. Oncologist 2003 8 531
8. 9. Spiro S.G, Porter J.C. Lung cancer where
are we today ? Current advances in staging and
non surgical treatment. Am J Respir Crit Care Med
2002 166 1166 96. 10. Arteaga C.L,
Epidermal Growth Factor Receptor dependence in
human tumors more than just expression ?
Oncologist 2002 7 suppl 4 31 9. 11. Raymond
E, Faivre S, Armand J.P. Epidermal growth factor
receptor tyrosine kinaase as a target for
anticancer therapy. Drugs 2000 60 suppl 1 15
23.
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Mini Review
1. Levin E.R. Bidirectional signalling between
the estrogen receptor and the epidermal growth
factor receptor. Mol. Endocrinol. 2003 17 309
17.
Original Articles

1. Kelly K, Averbuch S. Gefitinib Phase II and III
   results in advanced non small cell lung cancer.
   Sem. Oncol. 2004 31 suppl1 93 9.
2. Pao W, Wang T, Riley G.J, Miller V.A, Pan Q,
   Varmus H.E et al . KRAS mutations and primary
   resistance of lung adenocarcinoma to Gefitinib or
   Erlotinib. PLOS Medicine 2005 2 e17.

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