Lecture 9 Flashcards
What are the difference between chemotherapy and targeted therapies
Chemotherapy:
- Affects all rapidly diving cells
- Kill cells
- Cytotoxic
- Affect all cancer cells
- Many side effects
Targeted therapies:
- Targets cancer cells specifically
- Designed to interact with specific cancer targets
- Cytostatic - blocks signalling pathways
- Specific to cancer type and subtype
- Less side effects
Name examples of targeted therapies
Hormone therapies e.g. hormone receptor-positive breast cancers: MAb used
Signal transduction inhibitors e.g. BCR-Abl inhibitors or BRAF inhibitors
Gene or protein expression modulators e.g. nutlins and p53
Apoptosis inducers - nutlins
Angiogenesis inhibitors - VEGF inhibitors
Toxin delivery molecules - Radioactivity delivering MAbs
Immunotherapy
What do targeted therapies target
Usually oncogenes and occasionally tumour suppressors
What kind of pathways can targeted therapies target
Cell signalling
Aim to inhibit elements of a signalling pathway e.g. Ras or Raf inhibitors
Knowing the targets
BCR-Abl - Translocation occurs in >95% of all CML patients
HER2 - Overexpressed in 15% breast cancers
Other 70% - no effect, so molecular subtyping essential
Bcr-Abl
Translocation between chromosomes 9 and 22 forms the Philadelphia chromosome and the bcr-abl oncogene
Encodes for the constantly active Bcr-Abl fusion protein (tyrosine kinase)
Found in over 95% of chronic myelogenous leukaemia
Inhibitor for BCR-ABL
Imatinib
Outcomes better with Imatinib than with non-targeted treatments
Side effects less severe
Works well with CML
Molecular subtypes of breast cancer
HR+/HER2- (Luminal A) - 73% - best prognosis, most common
HR-/HER2- (Triple -ve) - 13% - worst prognosis - non-Hispanic black people have the highest rate
HR+/HER2+ (Luminal B) - 10% - little geographic variation
HR-/HER2+ (HER2 enriched) - 5%, lowest rates for all races
HER2 signalling
receptor specific ligands bind HER1-4
HER1-4 form a dimer with HER2
HER1-4 activates SOS -> RAS -> RAF -> MEK -> MAPK -> (enters the nucleus) -> cell proliferation, survival, and mobility
HER2 activates P13-K -> Akt which is phosphorylated -> Enters the nucleus -> cell proliferation, survival, and mobility
Trastuzumab on the HER2 pathway
Binds HER2 and blocks cleavage and dimerization to inhibit pathway
Activates antibody-dependent cell-mediated cytotoxicity -> tumour cell lysis
Endocytoses HER2 -> HER2 degradation
Targeted treatment for malignant melanoma
BRAF V600E inhibitor
Patients with BRAF V600E mutation were treated with Vemurafenib
Resistance to targeted therapies
Active oncogene ->
Inhibition of active oncogene via targeted kinase inhibitor ->
Disease response of oncogene reactivated via a secondary mutation, amplification etc OR BYPASS of oncogenic pathway which leads to reactivation and activation of a new pathway
Disease progresses
Resistance using MAP kinase
PDGFRbeta/IGR-1R/RTK dimerises and activates mutated Ras
Ras activates C-RAF-C-RAF
Vemurafenib typically inhibits B-RAF
MEK and ERK are activated by COT kinase overexpression
Proliferation occurs
Nutlins
Inhibit binding of Mdm2 to p53
Re-express p53 and induce apoptosis
Bevacizumab
Avastin/Bevacizumab binds VEGF and prevents VEGF from binds VEGFR, inhibiting angiogenesis
