Treating Cancer - Targetted Chemotherapy Flashcards
What are the common patterns of oncogenic mutations?
Tumour sequencing reveals driver vs passenger mutations
Gain-of-function mutations occur in oncogenes
Loss-of-function mutations occur in tumour suppressor genes
Ras/Raf/MAPK & PI3K / Akt signalling pathways are often affected - signal to growth, survival, and migration
Specific tumours have particular mutations driving growth, eg K-Ras in pancreatic cancer, B-Raf in melanoma
What are the types of targeted cancer therapies?
Treatments targeting oncogene-driven signalling pathways
Immunotherapies
Using approaches to treat adult leukaemias to illustrate the mix of old and new therapies
How are leukaemias different in adults compared to children?
Different cytogenetics, presentations, and treatment
What is the treatment for acute myeloid leukaemia?
Traditional chemotherapies:
Anti-metabolite - Cytarabine (cytosine arabinsoide / ara-C)
Cytotoxic antibiotic - Duanorubicin or idarubicin
What mutations are responsible for leading most cases of AML?
Heterogeneous disease with different subgroups:
CBF translocations, mutations in FLT3, NPM1, CEBPalpha
How is CLL treated?
A combination of traditional chemotherapy + immunotherapy (early form) + targeted therapies
Traditional chemotherapy:
Fludarabine + Cyclophosphamide
Immuno therapy:
Rituximab (alphaCD20)
Targeted therapy (BCR):
Ibrutinib (Bruxton’s TK)
Idelalisib (PI3K p110sigma)
Immune modulation:
Lenalidomide (thalidomide derived drug which blocks angiogenesis)
What is the 5 year survival rate of AML?
in 1980 it was 10%
In 2017 it was 25%
What is the 5 year survival rate of CLL?
70%
What is the incidence of Chronic Myeloid Leukaemia?
350 new cases / year
What causes chronic myeloid leukaemia?
Driven by reciprocal translocation event between Chr 9q and Chr 22q
The new chromosome 22 becomes the philadelphia chromosome
How is CML treated?
BCR-Abl is a deregulated tyrosine kinase which attacks uncontrolled myeloid cell proliferation.
This deregulated tyrosine kinase can be targeted using rational drug design and this is how imatinib works.
Imatinib switches off BCR-Abl signalling.
What does the BCR-Abl fusion protein do?
It is a deregulated tyrosine kinase
Uncontrolled myeloid cell proliferation
Homogenous disease which makes targeted treatment possible
What do targeted therapies do?
Inhibit oncogene driven cancer signalling pathways
Inhibitors target specific proteins via 2 mechanisms:
Antibodies - humanised proteins, when extracellular they are called
“abs”. When they are intracellular they are called “ibs”
They switch off proliferation and survival signalling.
What kinases are targeted by targeted therapies?
Many oncogenic mutations occur in at least one of three pathways that signal to survival and proliferation:
Ras/Raf/MAPK
PI3K/Akt
JAK/STAT
All 3 pathways involve kinases:
Receptor Tyrosine Kinases (eg EGFR)
Non-receptor TKs (JAK)
Serine/threonine kinases (B-Raf)
Lipid kinases (PI3K)
What is the result of targeting kinase domains?
Kinases normally phosphorylate substrates
When targeted they switch mechanism in signalling on and off
Kinase domains are highly conserved
ATP sits in cleft between the N-ter minor lobe and the C-ter major lobe.
Kinase transfers γ-PO4 from ATP to Y, S, or T residues
Small molecule inhibitors sit in the clefts and block enzymes
What are some targeted kinase inhibitors that block the EGFR family?
Gefitinib
Erlotinib
Lapatinib
What are some humanised antibodies that target EGFR?
Cetuximab
Panitumumab
What does herceptin (Trastuzumab) target?
ErbB2/HER2 which is amplified in 20 - 25% of breast cancers.
Trastuzumab is a humanised antibody against HER2 extracellular domain
This causes increased immune-mediated cell death in cancer cells resulting in increased survival in a type of breast cancer previously associated with a poor prognosis even after metastasis
What example of a serine/threonine kinase is targeted in anti-cancer therapy?
B-raf in cutaneous melanoma
What does B-raf mutation do?
Gain-of-function mutation that increases activity of the Ras/Raf/MAPK pathway and leads to hyperproliferation.
Vemurafenib specifically targets B-raf mutant protein
How is a cancer caused by B-raf mutation treated? How effective is treatment?
Vemurafenib, it reduces cancer to very low levels for 7 months before cancer cells acquire resistance to the drug.
What are the limitations of targeted therapies?
Side effects are well tolerated (but are uncomfortable)
Specificity of inhibitors is very variable
Drug resistance is a major problem
Usually not tumouricidal
Tumour heterogenicity: Tumour genomes vary within tumours.
Costs are extraordinary due to costs of research & development
What are the side effects of targeted therapies?
Generally less toxic than traditional chemotherapy:
Cutaneous effects (EGFR/ErbB2 inhibitors):
Acne like rash
Other effects:
GI - diarrhoea is very common
Skin/hair depigmentation (c-Kit, PDGFR)
Cardiovascular - HT, thrombosis and ischaemia
Liver - hepatitis and elevated enzymes
Endocrine - hypothyroidism, bone density changes, altered glucose metabolism, dyslipidaemia
What causes resistance to targeted therapies?
Resistance can be:
Primary/intrinsic (seen at first dose):
Wrong target - mutant protein not present -> genotype tumour first
Resistant mutation already present
Acquired (develops during pathogenesis):
ATP binding site mutation making inhibitor no longer fit in the cleft.
Gene amplification
Oncogenic bypass activating a different kinase.
How is resistance in cancer prevented?
Using combination therapy: Targeting several targets at once.
But genomes vary from cancer to cancer and there is an increased risk of side effects in combination therapy.
Targeted therapies are also combined with traditional chemotherapy.
What is immunotherapy?
T cells are activated via co-stimulatory and coinhibitory pathways which increases or decreases T cell activation. To mount an effective not destructive immune response.
How does immunotherapy work?
CTLA-4 blocks DC activation of T cells
Ipilimumab (switches on T cells) blocks CTLA-4 checkpoint thus activating T cells.
Nivolumab: (Activates cytotoxic destruction of cancer cells) Cancer cells express PD-1L which stops activated T cell cytotoxicity. Nivolumab blocks PD-1 leading to release of T cell activity.
These drugs are often used in combination for more potent effect
What kind of tumours does immunotherapy work best on?
Works best in tumours carrying high mutational burdens
What are the major side effects of immunotherapy?
Autoimmune disorders
What are CAR T cells?
Modified T cells from patient’s own body.
T cells are collected and made to attack tumour cells.
Engineer T cells to express altered T cell receptors
CAR T cells are formed.
CAR T cells attack tumour antigen
