Lecture 9 Flashcards
What are targeted therapies?
Specifically target molecular changes in cancer cells to prevent their growth, progression or metastasis
Chemo vs targeted
Target all rapidly dividing cells vs Target cancer cells specifically
Generally identified as kill cells vs designed to interact with specific cancer targets
Cytotoxic i.e. leads to cell death vs cytostatic e.g. blocks signalling pathway
Affects all cancer cells vs specific to cancer type and subtype
+++ side effects vs + side effects
Types of targeted therapies
Hormone therapies e.g. hormone receptor-positive breast cancers e.g. 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’
Angiogenesis inhibitors e.g. VEGF inhibitors
Toxin delivery molecules e.g. monoclonal antibodies delivering radioactivity
Immunotherapies
What are targeted?
Usually oncogenes (sometimes tumour suppressor)
e.g. BCR-Abl, Her2, BRAF, p53, VEGF
Knowing the target
BCR-Abl - Translocation occurs in >95% of all CML patients. Subtyping not required
Her2 - Overexpressed in over 15% of breast cancers
Other 70%: no effect (or may have slight negative effect), therefore molecular subtyping of breast cancer essential
Mechanisms for oncogene activation
Deletion or point mutation in coding sequence e.g. Ras, B-raf, Kit, Src
Regulatory mutation
Gene amplification e.g. EGFR, HER2, myc
Chromosome rearrangement:
Nearby regulatory sequence causes normal protein to be overexpressed e.g myc
Fusion to actively transcribed gene produces hyperactive fusion protein e.g. bcr-abl
Bcr-abl oncogene
- Translocation between chromosomes 9 and 22 results in ‘Philadelphia chromosome’ and bcr-abl oncogene
Encodes bcr-abl fusion protein, a constitutively active tyrosine kinase
Found in over 95% of chronic myelogenous leukaemia (CML)
What is Imatinib
Small molecule inhibitor of BCR-ABL
Outcomes significantly better with targeted therapy
Side effects significantly less severe with targeted therapy
Works well for CML, that has relatively simple genetic profile
Molecular subtypes of breast cancer
HR+/HER2- ——> Luminal A
73% of breast cancers
Best prognosis
Most common subtype for every race, age and poverty level
HR/HER2 ——> Triple negative
13% of breast cancers
Worst prognosis
Non-Hispanic blacks have the highest rate of this subtype at every age and poverty level
HR+/HER2+ ——> Luminal B
10% of breast cancers
Little geographic variation by state
HE-/HER2+ ——> HER2-enriched
5% of all breast cancers
Lowest rates for all races and ethnicities
TP53
Often mutated in cancer
Oncogenes - Pro-growth
Tumour-suppressor genes - Anti-growth
Oncogenic signalling should lead to cell-cycle arrest or apoptosis
Active mdm2 causes more ubiquitination of p53, so more p53 is degraded
Stress e.g. oncogenic signalling causes Arf to bind to mdm2 to inactive it
This causes stable, active p53 leading to cell-cycle arrest or apoptosis
