Targeted Therapies Flashcards
What are some targeted therapies?
= specifically target molecular changes in cancer cells to prevent their growth, progression or metastasis
Hormone therapies
= e.g. hormone receptor-positive breast cancers: monoclonal antibodies
Signal transduction inhibitors
= e.g. BCR-Abl inhibitors or BRAF inhibitors
Gene or protein expression modulators
= e.g. nutlins and p53
Apoptosis inducers
= e.g. nutlins
Angiogensis inhibitors
= e.g. VEGF inhibitors
Toxin delivery molecules
= e.g. monoclonal antibodies delivering radioactivity
Immunotherapies
What is being targeted?
= often oncogenes, sometime tumour suppressors
e.g.
BCR-Abl = translocation occurs on >95% of all CML patients, subtyping not required
Her2 = overexpressed in ~15% of breast cancers
BRAF
p53
VEGF
= components of growth factor signalling pathways are good candidates for targeted therapies (cell signalling pathways)
(target the hallmarks of cancer)
How are molecular profiles used? Give example.
70% of breast cancers (not affected by Her2)
= therefore molecular subtyping used
= breast cancers fall into distinct molecular subtypes
HR+/HER2- (Luminal A)
= 73% of all breast cancers
= best prognosis
= most common subtype
HR+/HER2+ (Luminal B)
= 10% of all breast cancer cases
HR-/HER2+ (HER-2 enriched)
= 5% of all breast cancers
HR-/HER2- (triple negative)
= 13% of all breast cancer cases
= worst prognosis
What is an example of growth factor receptors (receptor tyrosine kinases) as oncogenes?
= deregulation of receptor firing in cancer
= e.g. HER2 oncogene and breast cancer
= some breast cancers = overexpression of HER2 protein on surface of breast cancer cells
(more aggressive, faster growing breast cancers)
= HER 2 protein promotes cell growth and division
= HER2 protein can be targeted by drug therapy to kill HER2-positive cancer cells
(E.g. trastuzamab - herceptin, pertuzumab, ado-trastuzumab emtansine)
How does Herecptin (transtuzumab) work?
= targets HER-2 positive breast cancer cells
= binds to HER2 protein = inhibiting its function
(slows down growth / division of cancer cells)
= also activates immune system to help target the cells
(recruits NK cells to site of tumour)
EXTRA READING
= usually given intravenously every few weeks
= in combination with chemotherapy
What is an example of G protein and intracellular serine/threonine kinases as oncogenes?
= Mutant RAS or downstream serine/threonine kinases leads to abnormal proliferation
= Mutations in downstream components of the cascade also occur
e.g. B-raf V600E and V600K mutations are frequently seen in melanoma
BRAF V600E inhibitor used for malignant melanoma
= e.g Vemurafenib
= patient’s tumours genotypes and found to contain BRAF V600E mutation
= initial success BUT resistance very common
Why is resistance a common problem in target therapies?
= cancer cells may undergo genetic changes / mutations making them drug resistant
= may activate alternative signalling pathways
= downstream targets can develop new mutations
(e.g. MEK in tyrosine kinase pathway)
= cancer cells can adapt to local environment and develop resistance to the drug through mechanisms
(e.g. increased DNA repair, altered metabolism, changes in tumour microenvironment)
= tumours are often heterogenous
(subpopulations may respond differently to targeted therapy)
Why is TP53 often mutated in cancer?
Oncogenes = pro-growth
(direct p53 gene mutation)
Tumour suppressors = anti-growth
(can also be indirect mutation in other part of pathway)
Normally Oncogenic signalling (e.g. stress) should lead to cell-cycle arrest or apoptosis
= due to stable and active p53
BUT cancers often upregulate Mdm2
= meaning p53 is degraded / inactivated
= allows cancer cells to evade normal cellular responses
= Mdm2 can also inhibit p53 activity by physically interacting with p53 and preventing it from binding to its target genes
= impairs ability of p53 to promote cell cycle arrest or apoptosis
What are Nutlins?
= inhibit binding of Mdm2 to p53
(target hydrophobic pocket on surface of Mdm2 that normally binds to p53)
(prevents binding to and degrading of p53 = p53 accumulates in cell)
= allowing cell cycle arrest / apoptosis
= cause p53 re-expression and induction of apoptosis
How is Angiogenesis used as a target?
= tumour unable to sustain growth without a vascular network
= prevents metastasis
VEGF (vascular endothelial growth factor)
= promotes blood vessel growth
= stimulates growth and migration of endothelial cells (by binding to VEGFR1 and VEGFR2)
= activation leads to proliferation and migration of endothelial cells + formation of new blood vessels
= cancer cells promote large amounts of VEGF
= promoting new blood vessel growth that supply tumour with oxygen and nutrients
= allows tumours to grow and metastasise
= can also promote tumour cell survival and resistance to chemotherapy
= can suppress immune system
What is Avastin ?
= anti VEGF monoclonal antibody
= delays progression of lung and colon cancer
(Thalidomide)
= inhibits VEGF and basic fibroblast growth factor - dependent angiogenesis
= cheaper and more effective than many newer drugs
= must ensure birth control measures prior to treatment
