Treating Cancer - Targetted Chemotherapy

Question 1

What are the common patterns of oncogenic mutations?

Answer 1

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

Question 2

What are the types of targeted cancer therapies?

Answer 2

Treatments targeting oncogene-driven signalling pathways

Immunotherapies

Using approaches to treat adult leukaemias to illustrate the mix of old and new therapies

Question 3

How are leukaemias different in adults compared to children?

Answer 3

Different cytogenetics, presentations, and treatment

Question 4

What is the treatment for acute myeloid leukaemia?

Answer 4

Traditional chemotherapies:

Anti-metabolite - Cytarabine (cytosine arabinsoide / ara-C)

Cytotoxic antibiotic - Duanorubicin or idarubicin

Question 5

What mutations are responsible for leading most cases of AML?

Answer 5

Heterogeneous disease with different subgroups:

CBF translocations, mutations in FLT3, NPM1, CEBPalpha

Question 6

How is CLL treated?

Answer 6

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)

Question 7

What is the 5 year survival rate of AML?

Answer 7

in 1980 it was 10%

In 2017 it was 25%

Question 8

What is the 5 year survival rate of CLL?

Answer 8

70%

Question 9

What is the incidence of Chronic Myeloid Leukaemia?

Answer 9

350 new cases / year

Question 10

What causes chronic myeloid leukaemia?

Answer 10

Driven by reciprocal translocation event between Chr 9q and Chr 22q

The new chromosome 22 becomes the philadelphia chromosome

Question 11

How is CML treated?

Answer 11

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.

Question 12

What does the BCR-Abl fusion protein do?

Answer 12

It is a deregulated tyrosine kinase

Uncontrolled myeloid cell proliferation

Homogenous disease which makes targeted treatment possible

Question 13

What do targeted therapies do?

Answer 13

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.

Question 14

What kinases are targeted by targeted therapies?

Answer 14

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)

Question 15

What is the result of targeting kinase domains?

Answer 15

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

Question 16

What are some targeted kinase inhibitors that block the EGFR family?

Answer 16

Gefitinib

Erlotinib

Lapatinib

Question 17

What are some humanised antibodies that target EGFR?

Answer 17

Cetuximab

Panitumumab

Question 18

What does herceptin (Trastuzumab) target?

Answer 18

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

Question 19

What example of a serine/threonine kinase is targeted in anti-cancer therapy?

Answer 19

B-raf in cutaneous melanoma

Question 20

What does B-raf mutation do?

Answer 20

Gain-of-function mutation that increases activity of the Ras/Raf/MAPK pathway and leads to hyperproliferation.

Vemurafenib specifically targets B-raf mutant protein

Question 21

How is a cancer caused by B-raf mutation treated? How effective is treatment?

Answer 21

Vemurafenib, it reduces cancer to very low levels for 7 months before cancer cells acquire resistance to the drug.

Question 22

What are the limitations of targeted therapies?

Answer 22

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

Question 23

What are the side effects of targeted therapies?

Answer 23

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

Question 24

What causes resistance to targeted therapies?

Answer 24

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.

Question 25

How is resistance in cancer prevented?

Answer 25

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.

Question 26

What is immunotherapy?

Answer 26

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.

Question 27

How does immunotherapy work?

Answer 27

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

Question 28

What kind of tumours does immunotherapy work best on?

Answer 28

Works best in tumours carrying high mutational burdens

Question 29

What are the major side effects of immunotherapy?

Answer 29

Autoimmune disorders

Question 30

What are CAR T cells?

Answer 30

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