New Technologies and Challenges Targeted Therapies in Cancer

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New Technologies and Challenges Targeted
Therapies in Cancer

• Ian Olver MD PhD
• CEO The Cancer Council Australia

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Changing of the Guard

• There is a paradigm shift in the treatment of
  cancer
• Conventional cytotoxic drugs interact with DNA to
  prevent cell replication but are not specific to
  cancer cells
• We are moving to targeted therapies which
  specifically target cancer cells as evidenced by
  the many presentations at this meeting

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Side Effects of Chemotherapy

• Immediate Early Delayed Late
• (hours - days) (days - weeks) (weeks- months)
  (months - yrs)
• Extravasation Myelosuppression
  Cardiotoxicity Second Cancer
• Emesis Mucositis Lung
  fibrosis Encephalopathy
• Hypersensitivity Alopecia P.
  Neuropathy Sterility
• Tumour lysis Cystitis Hepatotoxicity
  Teratogenicity
• 
  Nephrotoxicity

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Targeted therapies

• With targeted therapy the specific mechanism of
  action of the drug results in an increase in its
  therapeutic index
• However, the advantages of the specificity and
  safety of the are offset by the smaller number of
  susceptible tumour types
• Increasing numbers of these innovative and
  expensive anti-cancer drugs may exceed the
  capacity of the public purse to pay for them

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The Need to Identify the Target

• Appropriate use of newly approved and expensive
  targeted therapies for cancer first depends on
  the pathologist identifying the target for
  treatment in the tumour sample
• Currently the two major classes of targeted
  therapy are the small molecule tyrosine kinase
  inhibitors (TKIs) and monoclonal antibodies (mAbs)

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Potential mechanisms of Glivec

• Glivec may inhibit tyrosine kinases in many
  tumours, but this will be effective therapy only
  where tumour stem cells depend on these enzymes
  for survival, growth or metastasis
• Tyrosine kinases are part of the signalling
  pathways of cells which tell them to grow

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PET Before and after Glivec for GIST
7/12/00
9/1/01
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STI 571 (Glivec)

• Specific inhibitor for BCR-ABL, PDGF receptor and
  c-kit tyrosine kinases produced by these genes
  which are responsible for growth in CML and GIST
• Effective in chronic myeloid leukaemia
• Effective in GIST Gastrointestinal stroma tumours
  which over express c-kit
• Side effects
• Nausea, myalgia oedema, diarrhoea,
  myelosuppression, LFTs early storm

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Monoclonal Antibodies

• Action of the mAbs, rituximab (Mabthera) for NHL
  and trastuzumab (Herceptin) for breast cancer
  depend on the targets CD20 expression and erbB2
  gene being amplified and responsible for growth

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Rituximab
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Mabthera

• Mabthera is an Anti-CD20 monoclonal antibody for
  lymphoma
• CD20 is a protein on the surface of malignant
  lymphoma cells
• CD20 expressed on 90 of B-cells in lymphoma

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Mabthera

• Side effects include
• Infusion related fever, chills rigors
• N V, urticaria, pruritis, headache, fatigue,
  bronchospasm, hypersensitivity
• Rare heart rhythm disturbance
• Low blood counts for up to 30 days

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HER2

• HER2 gene (neu, c-erb-2) ecodes a transmembrane
  gycoprotein receptor
• HER 2 is over expressed by 1/4 human breast
  cancer and correlates with poorer outcome
• MoAb against the receptor inhibits the growth of
  overexpressing cells

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HER 2

• As a single agent 15 chance of shrinking
  metastatic breast cancer, 4 chance of a
  complete shrinkage in heavily pretreated patients
• Duration of response can be 9 months which is at
  least as good as single chemotherapy agents
• Can combine with chemotherapy

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Disease-Free SurvivalRomond H et al. Trastuzumab
plus Adjuvant Chemotherapy for Operable
HER2-Positive Breast Cancer NEJM 2005
3531673-1684
AC?TH
87
85
AC?T
75

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N Events AC?T 1679 261 AC?TH 1672 134
HR0.48, 2P3x10-12
B31/N9831
Years From Randomization
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The Paradigm Shift

• The use of these drugs is giving clinicians a
  glimmer of the paradigm shift that will occur in
  the treatment of cancer
• One or several new targeted therapies offer the
  prospect of cancer being treated as a chronic
  disease.

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Brain Tumours

• The optimal use of temozolomide chemotherapy for
  the treatment of primary brain tumours may depend
  on knowing the DNA repair enzyme status of the
  tumour
• Hegi ME et al. MGMT gene silencing and benefit
  from temozolomide in glioblastoma. New Engl J Med
  2005 352997-1003

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Dramatic response in female, non-smoking patient
with Broncho-Alveolar Carcinoma
Courtesy Dr T. Lynch, MGH
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Patient demographic factors associated with
outcome in Gefitinib Phase II studies

• Gender
• Females ORR 25 (CI 19-33)
• Males ORR 8 (CI 5-12)
• Ethnicity
• Japanese ORR 27 (CI 19-37)
• Caucasian ORR 11 (CI 6-19)
• Smoking history
• Non-smokers ORR 31 (CI 23-40)
• Smokers ORR 8 (CI 5-12)

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Patient demographic factors associated with
outcome in Gefitinib Phase II studies

• Histology
• Adenocarcinoma n275 ORR 19
• Squamous n75 ORR 7
• Undifferentiated n35 ORR 3
• Mixed n26 ORR 4
• Large cell n11 ORR 9
• Unrecorded n3 ORR 0

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EGFR Mutations and Response

• Lynch TJ et al New Engl J Med 350, May 20 2004
• Hypothesis was that a mutation of EGFR accounts
  for the response of some patients with NSCLC to
  gefitinib
• They sequenced the entire coding region of EGFR
  in tumors from patients with a response to
  gefitinib and in tumors from those without a
  response

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Use of Molecular Methods

• Increase diagnostic accuracy and thereby improve
  prognostication
• Identify clinically distinct patient subsets to
  facilitate rational clinical trial design
• Help to optimize current treatments by increasing
  their specificity and improving their safety
• Identify signaling pathways that define cancer
  vulnerabilities and thus create drug targets
• Brown M, Buckley M, Rudzki B, Olver I. How can
  we turn cancer into a chronic disease that we can
  afford to treat? J Intern Med 2006 in press

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Practical Uses of Molecular Pathology and
Targeting

• The decision to treat metastatic breast cancer
  depends on the state of the disease
• The need for additional treatment after surgery
  relies on predicting its behavior, which still
  relies on anatomic staging
• Tumor size
• Nodal status
• These are prognostic but not predictive of
  treatment outcome
• However hormone status and HER2 status have been
  shown to be both prognostic and predictive and we
  have had targeted hormonal therapy for decades

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Molecular Classification

• With technology that can rapidly measure multiple
  gene expression profiles it has been found that
• They correlate with microscopic observed
  difference e.g. one pattern of genes correlates
  with grade (Perou CM et al Nature, 2000, 406
  letter 749-52, 2000)
• They differ across tumors defined by hormone and
  HER2 status
• Breast Cancer can be subtyped

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Sorlie T et al Proc Natl Acad Sci U S A. 2001,
981086910874. 85 samples gene expression
patterns analyzed by hierarchical clustering.
Green is normal breast, red is the basal poor
prognosis group Can use to predict prognosis and
outcome of therapy and can target the therapy
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Conclusions

• Targeted therapies which improve
• the therapeutic index are the future
• of anti-cancer therapy
• Advances in molecular pathology will provide the
  means to identify the targets and will be used to
  subtype tumours and will provide predict response
  to therapy and provide prognostic information