Turning cancer targets into treatments

Best therapy for cancer is prevention
1. Quit smoking
2. Healthy diet
3. Excercise
4. Screening
  1. Applied to asymptomatic individuals who fall within a risk group
    1. Sex, age, family history
    2. NHS currently screens for...
      1. Cervical cancer (24-50yrs)
      2. Colorectal carcinoma
      3. Breast cancer (45-69yrs)
  2. Typical patient management
    1. Clinical findings
      1. Biopsy and imaging
        Diagnosis
        Staging/grading
        Therapeutic/surgical intervention
        Surgery
        Radiotherapy
        External beam
        Internal-brachytherapy
        Chemotherapy
        Cytotoxic
        Biological (e.g. Herceptin)
        Hormonal
Tumour growth kinetics
1. 10^5 cells (microtumour) - upper limit for immunotherapy alone
  1. 10^5 - 10^12 cells - bulk tumour reduction necessary (surgery, radiotherapy, multicourse intensive chemo)
    1. Diagosis poosible (symptomatic) around 10^9 cells
    2. Death at 10^12 cells (1kg of tumour)
Breast cancer
1. Prognostic factors
  1. Tumour size (graded in TNM)
  2. Number of +ve axillary nodes
  3. Lymphatic/vascular invasion
  4. Histologic tumour type and grade
  5. Oestrogen/progesterone receptor status
  6. HER2 overexpression?
2. Early treatment
  1. Local control
    1. Surgery
    2. Radiotherapy
  2. Systemic treatment for micrometastases
    1. Tamixifen if ER+ve (25% reduction in risk of death)
  3. Rehabillitation and surveillance
  4. For localised tumours 90% live >5yrs and >85% live >10yrs
3. Metastatic breast cancer
  1. ~5% of cases the cancer has already spread on first diagnosis
  2. Not curable - but controlled with treatment for some years
  3. Median duration of first endocrine response (taoxifen and arimidex - oestrogen inhibitors) = 20 months
  4. Median duration of chemo response (cyclophosphamide, epirubicin, 5-FU) = 10 months
  5. Median overall survival = 2yrs
  6. Stage 4 tumours have a 5yr survival rate of 13% and about 10% of women will survive >10yrs
  7. Palliative treatment for metastatic disease
  8. Targeting metastases
    1. We lack any detailed knowledge on the metastatic process (for any cancer)
      1. Limits ability to design therapies - to date angiogenesis inhibitors have proven diasappointing
Major classes of cytotoxics
1. DNA binding drugs
  1. Alkylating agents, platinums
  2. Cause direct damage and block replication
2. Antimetabolites
  1. Purine and pyrimidine analogues, antifolates
  2. Interfere with nucleotide synthesis, incorporated into DNA and block its replication
3. Topoisomerase inhibitors
  1. Anthracyclines, TOPOTECAN
  2. Block action of enzymes involved in DNA winding/unwinding - cause DNA strand breaks
4. Tubulin acting drugs
  1. Vinca alkyloids, taxanes
  2. Inhibit microtubule formation (vincas)
    1. Enter text here
  3. Promote microtubule formation (taxanes)
    1. Block chromatid separation
Topotecan (topoisomerase I inhibitor)
1. Topoisomerase I is an enzyme that relieves the torsional (twisting) strain in the DNA that occurs during replication and transcription
  1. To do this the topoisomerase creates a single strand break - allowing the DNA ahead of the replication fork to rotate freely
    1. Topotecan binds to topoisomerase and the DNA forming a stabile ternary (three different molecules joined together) complex
      1. This prevents re-ligation of the DNA strand -damage
        Mammalian cells cannot efficiently repair double strand breaks -> apoptosis
New approaches to treating cancer
1. Why?
  1. Cancer kills over 150,000 in the UK each year
  2. Existing treatment is effective but toxic
    1. Effectively crude poisons
  3. Current treatments dont target changes taking place in cancer cells
  4. Killing cancer cells is easy - only killing them is hard
2. New compounds/novel molecular mechanisms
  1. Typically target specific proteins altered in cancer
  2. Designed from our better understanding of what goes wrong in cancer cells
  3. Philadelphia chromosome
    1. = shortened chromosome 22
      1. Translocation to chromosome 9
        Results in a fused protein: Bcr (chr22) and Abl (chr9)
        Abl is a tyrosine kinase - activates other proteins (by phosphorylation)
        e.g. PI3K
        Bcr-fusion causes a constituitive activation of Abl
        Drives cell proliferation and blocks apoptosis
        These leukaemias are resistant to most anti-cancer drugs
        Imatinib (glivec) - the holy grail of cancer
        Glivec blocks the ATP site preventing phosphorylation of the substrate (e.g. PI3K)
        Lack of kinase signalling inhibits proliferation and survival
        Potent inhibitor of Bcr-Abl fusion protein and c-Kit
        Growth inhibition in CML and GI stromal tumous (GIST)
        Approved for clinical use after phase I/II data
        98% haematological response with 13% remission
        Substantial single agent activity in other tumours (GIST) which are dependent on kinase signalling
    2. Clasic finding in CML
  4. Current UK approved targeted treatments
    1. Rituximab (anti CD20 on B cells)
      1. Non-hodgkins lymphoma
    2. Imatinib (glivec)
    3. Trastuzumab (herceptin)
    4. Bortezomib
      1. Myeloma
    5. Cetuximab (anti-EGFR)
      1. Colorectal cancer
    6. IFN and IL-2 for melanoma
New therapeutic strategies
1. Monoclonal Ab's
  1. Current MAbs: trastuzumab (HER2 breast cancer), cetuximab and bevacizumab (colorectal cancer), rituximab (Non-hodgkin's lymphoma)
  2. Target: receptor ectodomain
  3. Specificity: ++++
  4. Binding: Recptor internalised - slow regeneration
  5. Dosing: IV, weekly
  6. Tissue distribution: less complete
  7. Toxicity: rash, allergy
2. Small molecule inhibtors
  1. Target: TK domain
  2. Specificity: +++
  3. Binding: most are rapidly reversible
  4. Dosing: oral, daily
  5. Tissue distribution: more complete
  6. Toxicity: rash, diarrhoea, pulmonary
3. RNA interference
4. Gene therapy
5. Some new therapies don't always work - e.g.gefitinib (non-small cell lung cancer)
  1. Gefitinib had a less median survival rate than the placebo group during phase III trial
6. Wnt singnalling inhibitors (anti-frizzled MAb's, NSAIDs, Wnt MAb's, small ihibitory molecules)
  1. To target cancer stem cells (rely on normal stem cell signalling - Wnt, SHH, Notch)
    1. e.g. Wnt signalling seen in prostate cancer cells with stem cell characteristics
  2. NSAIDs (such as aspirin) shown to be of benefit against Wnt-beta catenin reliant cancers (e.g. colon cancer) due to the inhibition of COX enzymes
    1. COX converts arachidonic acid into prostaglandin E2 (PGE2) which inhibits beta-catenin degradation - allowing Wnt/beta-catenin signalling
      1. The only NSAID licensed for treatment of familial adenomatous polyposis is celecoxib (inhibitor of COX2)
  3. New therapy: beta-catenin/CBP (TF complex that promotes proliferation) inhibitors eliminates imatinib (glivec) resistance in leukaemia stem cells
7. HH signalling
  1. Cyclopamine (natural compound from corn lily)
    1. Antagonist of activated smoothened
      1. Inhibits GLI activation and therefore inhibits HH signalling
    2. Potential control over basal cell carcinoma, medulloblastoma, rhabdomyosarcoma (skeletal muscle tumour)
  2. Erivedge - approved in use for advanced/metastatic basal cell carcinoma
Tumour targets
1. Ras (K-ras, H-ras and N-ras
  1. point mutations in: pancreas (90%, k), thyroid (60%, h, k , n), colon (45%, h, k, n), lung [nsc] (35%, k), melanoma (15%, k)
  2. Ras farnesyltransferase inhibitors
2. GF eceptors
  1. Ecto domain
    1. MAb's
      1. Trastuzumab (Herceptin)
        HER2+ve breast cancer
      2. Cetuximab
        EGFR - colorectal cancer
      3. Bevacizumab (avastin)
        Anti-VEGFR
  2. TK domain
    1. anti-HER1/2/4 TK inhibitors
      1. ZD1839, OSI-774)
3. BRAF (B-raf, MAPKKK)
  1. Raf inhibitors (BAY43-9006, PLX4032))
    1. Clinical trials vemurafenib (PLX4032) for use in melanoma
      1. 81% response rate
      2. Only works in B-raf with a V600 mutation (i.e. valine at position 600 mutation)
        The most aggressive form of metastatic melanoma
      3. Approved for clinical use in V600 melanoma
4. mTOR
  1. mTOR inhibitors
5. MEK1/2 (MAPKK)
  1. MEK inhibitors
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Turning cancer targets into treatments

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