Lecture 8 - Cancer Targeted Therapies

Question 1

Fundamentally, what is cancer?

Answer 1

Uncontrolled cell proliferation caused by genetic mutations in genes controlling cell growth/division

Question 2

What is the term for cancers that are not inherited? Where do the mutations occur?

Answer 2

Sporadic

Mutations occur in somatic cells i.e. not in the germline cells

Question 3

What are ‘driver’ and ‘passenger’ mutations?

Answer 3

Driver mutations = cause changes in cellular function that contribute to the growth and spread of the cancer
Passenger mutations = acquired due to the weakening of genomic stability but don’t contribute anything

Question 4

What is targeted therapy?

Answer 4

Treatment that targets the specific physiological mechanisms that are altered by the mutation the patient has

Question 5

Name 6 types of cancer that have targeted therapies available

Answer 5

Breast cancer
CML
Non small cell lung cancer
Colorectal cancer
Gastrointestinal stromal tumours
Melanoma

Question 6

What is the cause of CML?

Answer 6

Chromosomal translocation forms BCR-ABL fusion gene

Creates constitutively activate tyrosine kinase receptor that is linked to cell proliferation

Question 7

What was the original treatment for CML?

Answer 7

Hydroxyurea and interferon

Suppress white blood cell production

Question 8

What is the targeted therapy for CML and how does it work?

Answer 8

Imatinib
Tyrosine kinase receptor inhibitor
Blocks the ATP binding site of the BCR-ABL protein, preventing phosphorylation and activation

Question 9

What is the cause of BRAF melanoma?

Answer 9

BRAF = a tyrosine kinase receptor linked to cell proliferation
Normally activated by extracellular growth factors
When mutated, it is constitutively activate

Question 10

What is the targeted therapy for BRAF melanoma and when can it be used?

Answer 10

BRAF inhibitors that are reversible, competitive inhibitors of the kinase domain of the BRAF receptor
Only works in patients with v600 mutation - patients are screened first

Question 11

What is the most common cause of colorectal cancer?

Answer 11

Overexpression of epidermal growth factor receptor (EGFR) which is a type of tyrosine kinase linked to cell proliferation
Signals through pathway involving KRAS

Question 12

What is the targeted therapy for colorectal cancer?

Answer 12

Anti-EGFR monoclonal antibodies

Blocks growth factors from binding EGFR

Question 13

When do anti-EGFR antibodies not work for colorectal cancer therapy?

Answer 13

If the patient has a mutation in a downstream component of the signalling pathway, such as KRAS

Question 14

What is the cause, and targeted therapy for breast cancer?

Answer 14

Caused by HER2 overexpression

Treated with Herceptin, a monoclonal antibody

Question 15

How are patients tested for overexpression of the HER2 receptor?

Answer 15

Immunohistochemistry shows overexpression of the receptor protein in tissue. Usually done first, then if results unclear use
Fluoresence in-situ hybridisation (FISH), which shows the RNA levels of the gene

Question 16

What is the cause, and targeted therapy for non small cell lung cancer?

Answer 16

Overexpression of epidermal growth factor receptor (EGFR) which is a type of tyrosine kinase linked to cell proliferation
Treated with tyrosine kinase receptor inhibitor

Question 17

Why do only 10% of those with non small cell lung cancer respond well to targeted therapy?

Answer 17

They have a specific mutation in the kinase domain of the EGFR that causes increased susceptibility to the inhibitor

Question 18

Name 3 limitations of targeted therapies for cancer

Answer 18

1. Resistance mutations may arise
2. There may be more than one mutation contributing to the cancer
3. The cancer may be caused by a rare variant that is not detecting with testing or not known how to treat

Question 19

What 4 things will future research into targeted therapies focus on?

Answer 19

1. Extending scope of drugs available
2. Overcoming resistance mutations
3. Targeting of KRAS or other signalling molecules that are common to the pathways of many cancers
4. Identification of rare variants with unknown significance