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L33 - Targeted Therapies
Cancer treatment usually combines multiple…
L33 - Targeted Therapies
- Cancer treatment usually combines multiple modalities -surgery, radiotherapy, chemotherapy, targeted therapies
- While traditional chemotherapies target proliferating cells, targeted therapies target specific mutant or over expressed proteins in cancer cell they spare normal proteins and cells
- Thus they spare normal proteins and cells
- Traditional and targeted therapies are used in specific combinations for improved results
- Know specific examples of cancer therapies
- Understand problems associated with these therapies
Targeted Therapies - Example of Leukaemia
- Treatments targeting oncogene driven signalling pathways
- Drugs targeting immunotherapies
2. Leukaemia in Adults
- Different cytogenics, presentation and treatment to child leukaema
AML - Acute Myeloid Leukaemia
- Aggressive; 5 y SR = 10% (1980) => 25%
- Heterogeneous disease -
subgroups: CBF translocations,
mutations in FLT3, NPM1, CEBPα
Classical chemotherapy:
- Anti-metabolite - Cytarabine/ara-C
- Cytotoxic antibiotic - Idarubicin
Targeted therapies,
E.g. FLT3 inhibitors, not yet routine
CML - Chronic Lymphocytic Leukaemia
- Indolent Disorder: 5y SR > 70%
- Treatment - combnation of; Chemo, immuno and targeted therapy
FCR =
Fludarabine+Cyclophosphamide+Rituximab
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Targeted Therapies
- Ibrutinib → Bruton’s TK
- Idelalisib → PI3K p110δ
Immune Modulation
- Lealidomide
- Derivative of Thalidomide
CML - Chronic Myeloid Leukaemia
- ~350 annual incidence
- Homogeneous Disease → Chr 9q & Chr 22q reciprocal translocation → Philadelphia Chr
Mechanism
Uncontrolled proliferation due to the philadelphia translocation resulting in fusion of BCR-ABL genes
BCR-ABL protein
- Unregulated tyrosine kinase activation (100%)
- uncontrolled proliferation of myeloid cells
- Treatment → targeted therapy
Targeted Therapies
- Inhibit oncogene-driven cancer
signalling pathways
- Inhibitors → target specific
proteins via 2 mechanisms:
- Antibodies - humanised proteins, extracellular (-abs)
- Small molecule inhibitors - membrane permeable → target the kinase domain (-ibs)
- Both pathways switch off proliferation, survival and migration signalling
Targeting Kinases
Many oncogenic mutations occur in at least one of the following pathways involving kinases
- Ras/Raf/MAPK pathway
- PI3K/Akt pathway
- JAK/STAT pathway
All of these pathways are onco-genic and signal survival, proliferation, migration
Kinase - Mechanism of Action
- Relies upon ATP to bind to the cleft between (N-ter minor lobe) and (C-ter major lobe) and activate enzyme
- Kinases uses PO4 to phosphorylate AA residues
- Small molecule inhibitors sits in the cleft between two lobes and inactivates enzyme
Small Molecul Inhibitors
Imatinib and CML
- Imatinib sts in BCR-ABL kinase cleft
- Switches off BCR-ABL activation
- Reduces proliferation and increases survival Rates
Humanised Anti-body Therapies for solid tumours (E.g. EGFR family)
Oestrogen growth factor receptor (breast cancer)
Trastuzumab (Herceptin)
- Partciularly effective at blocking ErbB2/HER2
- Expression of this gene is amplified in breast cancer
- Tratuzumab - sensitive to EC domain
- Believed to induce immune-mediated cell death
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Limitations
- Side effects are generally well tolerated
- Acquired Drug Resistance from cancers (selects for resistant cancers in evolutionary pressure)
- Effective in homogeneous tumours, limited against hetereogeneous tumours
- Extraordinary Costs due to R&D
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Patterns of Oncogenic Mutations (Slide 6)
- Tumour sequencing reveals driver and passenger mutations
Ras/Raf/MAPK & PI3K/Akt signalling pathways are often affected - signal for growth & survival
- Specific tumours have different mutations driving growth, e.g. K-Ras in pancreatic cancer
Gain of Function Mutations
These occur at sites of oncogenes within DNA
Loss of Function Mutations
These occur in tumour suppressor genes
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Recap from Cancer Pathogenesis
- Only minority of cancers are familial
- Majority of common cancers are induced by external genotoxic factors
- Whilst some cancer rates are constant (e.g. Rb), most cancer ates very greatly (ext. genotoxic. f.)
Immuno-Therapies
Immune homeostasis - T-cells are either activated/inhibited by a series of co-stimulatory and co-inhbitory pathways
Ensures that immune response is effective yet not destructive of our own tissues
Work best in tumours carrying
high mutational burdens
Inhibition of T-cells
- Interaction between PDL1 ligand on an MHC presenting cell and PD1 receptor on T-cell suppresses cytotoxic response
- Activation of CTLA-4 on T-cell inhibits their activation by CD86 ligand on dendrocytes
Impilimumab
→ ipilimumab blocks CTLA-4 checkpoint → enabling T cell priming
Inhibits the inhibitory response
Nivolumab
cancer cells express PD-1L → stops activated T cell cytotoxicity. Nivolumab blocks PD-1 → release of T cell activity
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Antibodies target the EC ligands/receptors
Small molecule Inhibitors target IC kinase domain
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