Targeted therapies

Question 1

Targeted therapy

Answer 1

A form of molecular medicine
Involves blocking the growth of cancer cells by interfering with specific molecules needed for carcinogenesis and tumour growth, rather than just simply interfering with all rapidly dividing cells (as with traditional chemotherapy)

Question 2

Aims of targeted therapies

Answer 2

Identify the ‘critical’ mutation (requires genetic profiling of the cancer)
Limit the growth and invasion/spread of cancer cells
Increase the specificity of the effects and limit side effects
Prolong the quality of life

Question 3

Challenge to the targeted therapy approach

Answer 3

Cancerous pathways often involve mutations in endogenous molecules on ubiquitous pathways

Question 4

Leukaemias

Answer 4

A group of cancers of white blood cells
Generally begin in the bone marrow, resulting in the production of high numbers of abnormal white blood cells (immature, blast-like)
These leukaemic cells proliferate relentlessly and end up ‘squeezing’ normal blood cells out of the bone marrow
Patients with leukaemia have blood with a ‘milky’ appearance

Question 5

Classification of leukaemias

Answer 5

Leukaemias are classified by 2 factors:

1. Acute or chronic
2. Myeloid or lymphoid (i.e. their cell of origin)

Question 6

Myeloid cells

Answer 6

Granulocytes
Neutrophils
Macrophages
Mast cells

Question 7

Lymphoid cells

Answer 7

T lymphocytes

B lymphocytes

Question 8

CML

Answer 8

Chronic Myeloid Leukaemia
Accounts for 20 % of adult leukaemias
Has 3 clinical phases:
1. Initial chronic phase (fairly mild)
2. Accelerate phase (develops after 4 years)
3. Acute leukaemia phase (blast crisis)

Question 9

Mutation in CML

Answer 9

Mutations thought to arise in stem/progenitor cells
95 % of CMLs have a chromosomal translocation between chromosomes 9 and 22 - t(9;22)
This generates a fusion between the breakpoint cluster region (BCR) gene and the Abl tyrosine kinase gene, generating the fusion protein BCR-Abl
The chimeric oncoprotein forms a tetramer that exhibits constitutive Abl kinase activity due to loss of Abl regulatory domain
This chromosomal translocation generates the diagnostic Philadelphia chromosome = a specific genetic abnormality in CML cells

Question 10

c-Abl

Answer 10

Non-receptor protein tyrosine kinase
Localised to the cytoplasm and nucleus
Cytoplasmic c-Abl plays a role in cell growth
Nuclear c-Abl interacts with pRb and p53 to regulate gene transcription
Activated by DNA damage/during S phase/downstream of integral signalling

Question 11

Glivec

Answer 11

(draw)
= imatinib
Small molecule inhibitor, phenoaminopyrimidine derivative
Blocks Abl kinase activity
Also blocks PDGFbR and c-kit Tyr kinases
Inhibits CML growth in mouse models
Inhibits proliferation of cell lines derived from human CML
Highly lethal to CML cells but spares normal cells

Question 12

Glivec phase I data

Answer 12

29/54 patients administered >300 mg/day
Showed a ‘cytogenetic response’ - the number of Philadelphia chromosomes in the blood and bone marrow decreased (decrease in the number of Philadelphia-chromosome-positive (Ph+) cells)

Question 13

Disadvantages of Glivec

Answer 13

Resistance (i.e. loss of sensitivity to Glivec) through amplification of BCR-Abl / point mutations in BCR-Abl to prevent Glivec binding

Question 14

2nd generation therapies

Answer 14

Dasatinib, nilotinib
Bind to the active conformation of BCR-Abl, so can therefore be effective in patients where a point mutation has caused resistance to Glivec
However, neither of these are resistant against the T315I mutation

Question 15

T315I mutation

Answer 15

Creates steric hindrance in BCR-Abl tyrosine kinase, preventing the binding of inhibitors

Question 16

3rd generation therapies

Answer 16

VX-680
JAK2 inhibitor
Active against T315I mutation but withdrawn from clinical trials due to cardiotoxicity

Ponatinib
Effective against CMLs with T315I mutation

Question 17

TEL-PDGFbR

Answer 17

Associated with chronic myelomonocytic leukaemia (CMML)
TEL-PDGFbR expressed as a result of the t(5;12) chromosomal translocation
TEL = transcription factor
TEL amino terminal fuses with C-terminal kinase region of PDGFR - mutant protein can then undergo oligomerisation via helix-loop-helix region, leading to constitutive activation of the kinase
TEL-PDGFbR kinase activity can be inhibited by Glivec

Question 18

Small molecule inhibitors

Answer 18

e.g. Gefitinib (Iressa), Erlotinib (Tarceva), Sorafenib (Nexavar)
Often inhibit tyrosine kinases
Block initiation of growth pathways
Orally active
Issues with specificity

Question 19

Monoclonal antibodies

Answer 19

e.g. Herceptin (Trastuzumab), Avastin (Bevacizumab)
Highly specific to cancer cells
Prone to mutation-induced resistance
Can only target extracellularly
Expensive
Require IV administration

Question 20

Iressa

Answer 20

Most effective in patients with the mutation leads to hyperactive EGFR

Question 21

Reconstitution

Answer 21

= restoration of LOF

Involves the IV administration of viral particles/nanoparticles e.g. Advexin

Question 22

Successful treatment of cancer…

Answer 22

…often requires a combination of several different approaches, because cancer is a multifactorial process

Question 23

Tailored treatment

Answer 23

Tailoring treatment according to the molecular phenotype of the tumour and the patient will result in increased tumour response rates
Patients will be spared the toxic side effects of treatment from which they are unlikely to benefit
Higher response rates and reduced toxicity would reduce the costs of patient care
Expensive treatments such as oxaliplatin could be used in a more targeted manner