L8 Drug Discovery in Oncology Flashcards
What is cancer?
- 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.
What is the objective of targeted therapy?
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
What are the differences between targeted therapy and chemotherapy?
Slide 11
- Higher drug distribution (Designed to interact with target), Wider therapeutic index (cytostatic vs cytotoxic), Higher selectivity (Specific molecular target)
How do you identify targets for targeted cancer?
Slide 12
What are the characteristics of targeted therapy (small mol/mAb)?
Slide 13
What causes drug resistance?
Slide 16
Which specific protein causes multi-drug resistance?
Slide 19, 21, 22, 23, 24
How does the role of cancer stem cells/properties of cancer cell shape treatment method?
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)
Using the example of BCR-Abl, explain drug resistance with respect to Gleevac.
Slide 27, 28, 29, 30
How do you screen for resistant mutant forms of BCR-Abl?
Slide 31, 32, 33
What are some drugs to tackle the mutant forms of BCR-Abl?
Slide 34, 35
Why does the immune system not recognise cancer cells/kill cancer cells
Slide 36
- Immune cells does not recognise tumour antigen as foreign -> Lack of T-cell costimulatory mechanism allows cancer cell to evade immune system
Properties of tumour antigens
Slide 37
What are the different types of tumour antigens T-cells recognise?
Slide 38
How does T cells kill tumour cells?
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