Cancer Therapeutics

Question 1

What is the most treatable type of cancer?

Answer 1

Non-malignant melanoma

Question 2

Why do survival rates differ between Local, Regional and Distant tumours?

Answer 2

Local tumours show no sign of spreading and thus if excised will result in halting of tumour progression, high survival chance.

Regional tumours that start spreading to neighbouring tissues can have good survival rates if treated after diagnosis.

Distant tumours that have spread to different sites are difficult to treat as they are spread throughout the body.

Question 3

What current treatments are there for breast cancer?

Answer 3

Masectomy - removal of breast tissue

Chemotherapy

Question 4

What is the estimated level of over-diagnosis for breast cancer?

Answer 4

For every 56 cases, 5 diagnosed breast cancer and saved lives, 2 overdiagnosed.

It is thought that 5-10 women undergo unnecessary surgery for each women whose life was saved by surgery.

Question 5

What are the chances of a women dying from breast cancer she never undergoes screening?

Answer 5

1/200 chance that is a fatal decision

Question 6

What are the chances a women who is diagnosed with breast cancer will undergo unnecessary surgery?

Answer 6

1/65 chance of unnecessary surgery

Question 7

What factors affect the effectiveness of screening and successful treatment?

Answer 7

Efficacy of the screening method

Potential of effective treatment

Efficacy and accuracy of the screening method must outweigh the associated costs of the screening and the associated risks of the treatment = Balance

Question 8

What is the purpose of a Pap smear?

Answer 8

Pap smears attempt to detect cervical cancer (introduced in the 1930s)

Question 9

Why have survival rates of cervical cancer improved significantly over the last 40 years?

Answer 9

Screening improvements

Question 10

What is the current screening technique used to diagnose bowel cancer?

Answer 10

FOBT Foecal Occult Blood Test

Blood in the foeces can be triggered by the formation of polyps on the colon lining.

Question 11

What techniques are avaiable to diagnose bowel cancer?

Answer 11

FOBT Foecal Occult Blood Test

Colonoscopy

Question 12

Is FOBT or Colonoscopy more specific for the detection of polyps and colon cancer?

Answer 12

Colonoscopy detects 4-5x more polyps and cancers than FOBT

Question 13

What is the difference in cost between FOBT and Colonoscopy?

Answer 13

Colonoscopy is 10x more expensive than FOBT but Colonoscopy is 10x better at polyp detection.

Question 14

What is a future technique for the detection of polpys and colon cancer?

Answer 14

Virtual colonoscopy

Computerised tomography (CAT scan). A series of X-rays. Almost as sensitive as colonoscopy but 1/3 cost and lower risk.

Question 15

What are the advantages of chemotherapy?

Answer 15

Very toxic to target cells

Knowledge of the tumour is not required

Radiation can be targeted

Question 16

What are the disadvantages of conventional cancer therapies?

Answer 16

Surgery can be difficult and damaging

Toxicity from chemotherapy is not specific to cancer cells

Mechanism of chemotherapy involves DNA damage, cells that survive therapy can have sustained more damage than the starting cells.

Question 17

What types of targeted therapies for cancer are there?

Answer 17

Antibodies (most end in mab)

Small molecule inhibitors (end in nib) (kinase inhibitors, block phosphorylatory activity and prevent oncogene activity)

Synthetic Lethality (targets weakness of cancer cell, for example if one DNA pathway is already damaged, the second will be targeted, killing the cells)

Angiogenesis Inhibitors (starves cancer, can block VEGF)

Question 18

What makes a good target for a cancer therapy?

Answer 18

Tumour suppressors are poor targets as gene function must be restored

Oncogenes are much better targets as have activating mutations. These are actively promoting growth.

Question 19

What is a Phase 1 stage for in drug development?

Answer 19

To check safety and appropriate dosage.

Question 20

What are the possible recommendations from NICE regarding a drug being introduced into the NHS?

Answer 20

Recommended

Optimised - recommended but with restrictions (perhaps only a subset of patients)

Only in research (promising approach, but requires further evidence) (used only as part of a well-designed clinical trial)

Not recommended (lacks evidence to support clinical effectiveness) (substantially less cost effective than is normally considered to be an acceptable use of NHS resources)

Question 21

What are quality-adjusted life years (QALY)?

Answer 21

QALY is a measure of disease burden, including both the quality and duration of life lived.

Question 22

What is an ICER?

Answer 22

ICER = Incremental cost-effectiveness ratio

NICE accepts as cost-effective, interventions with an ICER of <£30,000 per QALY

Question 23

What is vemurafenib?

Answer 23

Vemurafenib is a BRAF inhibitor

• £1750/week
• Used to treat locally advanced metastatic BRAF V600 mutation positive malignant melanoma
• 3x cost of existing chemo treatment

Question 24

What is NICE?

Answer 24

NICE = National Institute for Clinical Excellence

Decide which drugs the NHS will use

Question 25

What increase in life expectancy do most new drugs provide?

Answer 25

**3 months**

Question 26

What is **ONYX-015**?

Answer 26

ONYX is a therapeutic, a virus that lacks the EIB gene. EIB normally binds to p53 and causes its degradation. The virus cannot replicate in cells with the wildtype p53. If the virus infects a cell with **inactive p53**, it replicates causing cell destruction that releases the virus.

Question 27

What drugs can turn p53 back on?

Answer 27

**Gendicine (China)** and **Advexin (USA)** Essentially carries p53 into cells.

Question 28

What types of cancers are Advexin/Gendicine used to treat?

Answer 28

**Head and Neck cancers** p53 mutations are common in 45-70% of tumours Usually treated with surgery and/or radiotherapy. But the tumours often recur. High level of morbidity and chemotherapy is not effective. Tumours with p53 mutations can be targeted with **ONYX-015** or **Advexin/Gendicine**. The virus is injected directly into the tumour and has some response.

Question 29

How can mouse antibodies be **humanised**?

Answer 29

The functional parts that will recognise the animal antigen are fused genetically to the coding sequence from the human antibody.

Question 30

How do antibody drugs kill tumours?

Answer 30

* Can bind to receptor and block the function * Can be linked to a drug (toxin) * Can affect protein function directly * Recruit other immune cells (T cells, killer cells) * Hyping up Immune system to recognise the cancer cell

Question 31

What is CTLA4?

Answer 31

Protein found on the surface of T cells which subdues the activity of the cells. It is associated with adverse inflammatroy responses in skin and GI tract.

Question 32

What is PD1?

Answer 32

PD1 is a receptor on the surface of a T cell that binds to a ligand **PDL1** on the surface of the tumour. The cancer cell is switching the T cell off. A common mechanism employed by cancer cells.

Question 33

What is **Nivolumab**?

Answer 33

**Nivolumab** is a PD-1/PD-L1 checkpoint inhibitor It offers a 3 month life extension for late stage metastaic NSCLC.

Question 34

What is the role of **Preimplantation Genetic Diagnosis (PGD)** in cancer therapy?

Answer 34

**PGD** is a preventative measure. A cell embryo is taken cells removed from the zona pellucida for analysis. It is then screened for cancer causing mutations.

Question 35

How can targeting **VEGF** be a cancer therapy?

Answer 35

**VEGF** can be blocked which prevents blood vessel growth to starve cancer cells. It is often used in addition to other treatments as it not currently effectient enough to be used alone.

Question 36

How can **dendritic cell therapy** be used to treat cancer?

Answer 36

The first therapeutic vaccine (**Provenge**) uses leukapheresis to isolate dendritic cells and macrophages (APCs) that can present antigens to other immune cells. APCs cultured with prostatic acid phosphatase (PAP). This vaccine is infused into the patient with the aim of starting up poweful immune cells. This tries to neutralise the tumour cells that express PAP.