What do cells respond to?
Specific chemicals that signal them to divide
What do the pathways for cell signalling utilised by cells have in common?
They all display the same fundamental characteristics
What do all signalling pathways involve?
- Chemical messenger
- Cellular response
What is signal transduction?
Essentially, the transmission of a signal from the outside of a cell to the nucleus
What can the signal transduced from the outside of the cell to the inside result in?
Alterations in cell metabolism, gene transcription, and/or cell shape
What does alteration in gene transcription lead to?
Changes in protein expression
What are proto-oncogenes?
Genes coding for proteins that help regulate cell growth and differentiation
In what physiological process are proto-oncogenes fundamental?
What happens to proto-oncogenes in malignancy?
They become activated to an oncogene due to mutations, or increased expression
Where is oncogene activation an important mechanism?
In human cancers
What are the types of mutations that can cause cancer?
What can be deleted in mutations?
- Base pair(s)
What can be inserted in mutations?
- Repeats of base pair(s)
- Novel insertions
What can be substituted in mutations?
Base pairs .
What can be amplified in mutations?
What can be translocated in mutations?
What kind of proteins are encoded for by oncogenes?
- Growth factors
- Growth factor receptors
- Protein kinases/proteins that activate protein kinases
- Proteins that control the cell cycle
- Proteins that affect apoptosis
- Transcription factors
What do growth factors do?
Stimulate cells to divide
Give an example of a growth factor
What do growth factor receptors do?
Transduce signals from the outside of the cell to the inside
Give an example of a growth factor receptor
EGF receptor (erbB)
Give two examples of protein kinases
Give an example of a protein that activates protein kinases
Give an example of a protein that controls the cell cycle
Give an example of a protein that affects apoptosis
Give an example of a transcription factor
What is the significance of Myc in malignancy?
It is one of the most commonly altered oncogenes
What are the mechanisms of oncogene activation?
- Insertional mutagenesis
- Chromosomal translocation
- Chromosomal amplification
- Point mutation
- Ras signalling
What happens in insertional mutagenesis?
DNA viruses incorporate a viral oncogene, which is inserted into the host DNA
Give two examples of viruses capable of insertional mutagenesis
- Human papillomavirus 16/18
- Hepatitis B
What is human papillomavirus 16/18 associated with?
What advancement has been made with HPV and cervical cancer?
There is now an immunisation, so hopefully it will get eradicated over time
What is hepatitis B associated with?
Give two examples of cancers caused by chromosomal translocations?
- Chronic myeloid leukaemia
- Burkitt's lymphoma
What is the chromosomal translocation in chronic myeloid leukaemia?
9;22 - c-abl (9) is truncated onto bcr (22)
What is the result of the chromosomal translocation in chronic myeloid leukaemia?
Fusion protein has abnormal tyrosine kinase activity
What is chromosomal translocation in Burkitt's lymphoma?
8;14 - c-myc (8) is translocated onto igh (14)
What is the result of the chromosomal translocation in Burkitt's lymphoma?
It produces a strong promoter leading to constitutive MYC expression
What happens in chromosomal amplification?
Tumour genomic instability leads to amplification, and may lead to over-production of normal protein, as multiple copies of the same gene are being expressed
What can activate Ras?
Different activating mutations at codons 12, 13, and 61
What is the most commonly activated Ras oncogene?
How is Ras activated?
By receptor tyrosine kinases that sit on the inside of the membrane
What kind of protein is Ras?
A GTP-binding monomeric switch protein
When is Ras active?
When it is bound to GTP, and therefore inactive after GTP hydrolysis
What is the action of Ras?
Activates the MAP kinase pathway
What does the type of Ras mutation determine in colorectal cancer?
What is the 2 year survival in colorectal cancer patients with mutant Ras compared to wild type Ras?
It is 49% in mutant ras, compared to 69% in wt ras
What mutations were significantly associated with a high risk of recurrence of colorectal cancer?
12 TGT and 13 GAC
What did the RASCAL study find that the presence of KRAS mutation was associated with?
An increased risk of recurrence and death
How did the RASCAL II study results compare with RASCAL?
It confimed the findings, but only in Dukes C (stage 3) tumours
What are the activating mutations in the RAS-MAPK, PI(3)K signalling network?
What do activating mutations in the RAS-MAPK, PI(3)K signalling network correlate with?
Poor survival in colon cancers
What must the role of KRAS be interpreted in the context of?
Other molecular and signalling abnormalities
What is any mutation in KRAS, BRAF, or PI3KCA associated with?
A shorter 3 year survival
Where can a KRAS mutation status identify an increased risk of recurrence?
In lymph nodes of stage 2 patients
Why is it difficult for pharmaceutical companies to block Ras?
Ras is involved in widespread functions in the human body, but only 1 amino acid is changed in the mutant form, and so its hard to target.
Give an example of a physiological role of Ras
It is an important pathway for synaptic remodelling in the human brain
What % of metastatic melanomas have a mutation in BRAF?
What are the BRAF mutations found in metastatic melanoma?
Around 80% are V600E, 16% are V600K, and 3% are V600R
Are BRAF mutations found in benign nevi?
What is vemurafenib?
A BRAF inhibitor developed by Plexicon and Genentech
What were the results of clinical trials involving vemurafenib?
- In Phase I, 16 patients with stage 4 cancers were enrolled into the programme, and it increased median survival from 9 to 15 months
- In Phase II, 132 patients with stage 4 cancers were enrolled into the programme, and 53% of patients responded.
- In phase III, 375 patients with stage III or IV cancers were enrolled in the programme, which compared vemurafenib to decarbazine. The trial was stopped early, and decarbazine patients were moved to vemurafenib
What is the problem with vemurafenib?
It improves the patient for a window, but then the patient relapses with resistant disease
What gene is associated with human breast cancers?
Her-2 (human epidermal growth factor receptor 2)
In what % of human breast cancers is her-2 amplified and over-expressed?
What is HER-2 amplification in breast cancer linked to?
Poor prognosis - marker of aggressive cancer
How is HER-2 amplification in human breast cancers detected?
By FISH and immunohistochemistry
How is HER-2 positive breast cancer treated?
With drugs that bind to the receptor and prevent growth
What drugs are used in the targeted therapy of HER-2 positive breast cancer?
- Trastuzumab (Herceptin)
- Pertuzumab (Perjeta)
- Ado-trastuzumab emtansine (Kadcyla)
- Lapatinib (Tykerb)
What kind of drug is herceptin?
What is herceptin often used with?
Chemotherapy, but it can be used by itself
What is herceptin used to treat?
Early- and late-stage breast cancer
How long would a patient typically take herceptin for after surgery?
What kind of drug is perjeta?
What can perjeta be given with?
Trastuzumab and chemo
When is perjeta given?
Either before surgery to treat early-stage breast cancer, or to treat advanced trastuzumab in chemo
What kind of drug is Kadcycla?
A monoclonal antibody attached to a chemotherapy drug
What is kadcycla used to treat?
Advanced breast cancer in women who have already been treated with trastuzumab and chemo
What kind of drug is Tykerb?
A kinase inhibitor
What is tykerb used to treat?
Advanced breast cancer, most often when trastuzumab is no longer working
What is tykerb typically used with?
Certain chemotherapy or hormone therapy drugs