L8 Drug Discovery in Oncology

Question 1

What is cancer?

Answer 1

• Cancer is typically caused by genetic lesions that affect genes that promote proliferation in tandem with lesions that interfere with the elimination of cells through apoptosis.
• Cancer is not a single disease but a wide spectrum of conditions caused by a failure of the controls that normally govern cell proliferation, differentiation and cell survival
• multi-step process and involves the acquisition of a series of mutations in oncogenes and tumor suppressor genes that cooperate to achieve the fully transformed state.
• Cancer incidence varies between tissues.
• Mutagenic agents, including viruses, promote cellular transformation.

Question 2

What is the objective of targeted therapy?

Answer 2

Slide 10
- Improve tumour response to chemo and radiotherapy (often dual therapy)
- Overcome primary/acquired chemo and radioresistance from cancer cells
- Thus protecting patients from recurrence
- Protect patients from/combate metastasis of malignant tumours

Question 3

What are the differences between targeted therapy and chemotherapy?

Answer 3

Slide 11
- Higher drug distribution (Designed to interact with target), Wider therapeutic index (cytostatic vs cytotoxic), Higher selectivity (Specific molecular target)

Question 4

How do you identify targets for targeted cancer?

Answer 4

Slide 12

Question 5

What are the characteristics of targeted therapy (small mol/mAb)?

Answer 5

Slide 13

Question 6

What causes drug resistance?

Answer 6

Slide 16

Question 7

Which specific protein causes multi-drug resistance?

Answer 7

Slide 19, 21, 22, 23, 24

Question 8

How does the role of cancer stem cells/properties of cancer cell shape treatment method?

Answer 8

Slide 25, 26
- CSC are more resistant to treatment and they are capable of regenerating a new cancer
- However, when drugs specifically target CSC, non CSC can dedifferentiate back to CSC and regenerate another tumour
- Skipper Schabel model - all cancerous cells need to be killed as even 1 cell can regenerate another tumour (but must spare the host of the toxicity)

Question 9

Using the example of BCR-Abl, explain drug resistance with respect to Gleevac.

Answer 9

Slide 27, 28, 29, 30

Question 10

How do you screen for resistant mutant forms of BCR-Abl?

Answer 10

Slide 31, 32, 33

Question 11

What are some drugs to tackle the mutant forms of BCR-Abl?

Answer 11

Slide 34, 35

Question 12

Why does the immune system not recognise cancer cells/kill cancer cells

Answer 12

Slide 36
- Immune cells does not recognise tumour antigen as foreign -> Lack of T-cell costimulatory mechanism allows cancer cell to evade immune system

Question 13

Properties of tumour antigens

Answer 13

Slide 37

Question 14

What are the different types of tumour antigens T-cells recognise?

Answer 14

Slide 38

Question 15

How does T cells kill tumour cells?

Answer 15

Slide 39
- Antigen presenting cells (dendritic cells) ingest/phagocytose tumour cells
- APC presents CD40 on its surface
- CD4+ T helper lymphocyte with CD40L recognises CD40 and is activated
- Releases cytokines and recruits CD8+ T cell
- Causes the differentiation of tumour specific CD8+ T cells (memory)
- Tumour specific CD8+ cytotoxic T lymphocyte recognises tumour cell
- Leading to killing of tumour cell

Question 16

What are the different approaches to cancer immunotherapy?

Answer 16

Slide 40

Question 17

How does cancer vaccine work?

Answer 17

Slide 41, 42

Question 18

How does immunization with whole tumour cells work?

Answer 18

Slide 43
Whole cell tumour probs better bc provide a source of all potential antigens, eliminating the need to identify the most optimal antigen to target in a particular type of cancer. Multiple tumour antigens can be targeted simultaneously, generating an immune response to various tumour antigens.
- May increase risk of introducing of possible tumour source compared to peptides

Question 19

How does therapy with subunit vaccines work?

Answer 19

Slide 44

Question 20

What is passive immunotherapy?

Answer 20

Slide 45
- Monoclonal Ab that targets specific antigens eg CD20
- CD20, CD30, CD52, erbB2
- Bifunctional Ab (CD3 and CD19)

Question 21

How is adoptive T cell performed?

Answer 21

Slide 46

Question 22

How is checkpoint blockers used for therapy?

Answer 22

Slide 47

Question 23

What is the latest immunotherapy?

Answer 23

CAR T cell therapy
Slide 48 + Cancer notes

Question 24

How do you analyse which treatment is better based on immunotherapy?

Answer 24

• Blood samples
• Cytokines are only produced by T cells
• Taking the blood samples, incubate with tumour cells and measure the cytokine response