L7 - Aberrant cell signalling in cancer provides targets for therapeutic intervention Flashcards
What does aberrant mean?
Diverging from the normal type
How do we identify appropriate therapy for an individual cancer patient?
There are common mutations in lots of cancer types
There are also subtle gene differences that can give 1 patient a lot more aggressive tumour than another
We need to be able to identify these differences to give the optimum treatment
Tumour heterogeneity in diagnostics & metastatic spread
The main problem we have is the fact that tumours can be very heterogenous
There are differences between individuals, and areas of a single tumours are also different – can create problems in trying to identify which is the most important clone to treat
Do we want to target one or all of them? Which one is the driver of the cancer?
Does the primary cancer usually kill the patient?
NO
Its more likely to be due to the cancer metastasising
Step wise progression of cancers
tumours will grow and can be released into the blood stream
Alternative hypothesis for the progression of cancers
Tumour starts releasing cells at an early stage and disseminated into the blood stream, as they are released they are evolving all the time
The tumour cells will lie dormant in the body for long periods of time – this is true for lots of breast cancer patients
Issues with cancer drugs
Lots of drugs will kill the primary tumour, but in later years they will come back as they’ve been dormant – acquire mutations to form the secondary tumours & metastasize
Genomic alterations that cause cancer
- Point mutations
- Gene amplification
- Deletions
- Altered gene expression
- Translocations
- Epigenetic modifications
- Aberrant RNA splicing
- microRNAs
Genomic perturbations promote cancer cell survival affecting the hallmarks of cancer by altering:
- Cell cycle control
- Differentiation
- Tumour vascularisation
- DNA repair
- Apoptosis
- Metabolism
Breast cancer classification
Breasts are made of many ducts & lobes
Different types of cancer can occur in breasts
Can define breast cancer into carcinomas or sarcomas
Carcinoma types
Epithelial
Ductal carcinomas in situ
– Cancers that will grow to a certain size & then no further (CIS)
– Don’t tend to be metastatic
– Don’t form their own blood supply so cant become that aggressive
Lobular carcinomas in situ
– More aggressive
– Develops into the lobes of the breasts
Invasive ductal carcinomas
– Rare invasive ductal subtypes
Sarcoma
Stromal (connective tissue)
• Develop into the stromal compartment
Examples:
• Phyllodes tumour
• Angiosarcoma
Breast cancer subgroups
Based the subgroups on the expression of certain genes
The breast is an oestrogen-dependent organ
Removal of ovaries to block oestrogen production was previously used as an effective therapy
Subgroups: • Estrogen Receptor positive (70%) • ERBB2 (HER2) positive (10%) • Triple negative (lack ER, PR + ERBB2) (15%) • Normal-like (5%)
Estrogen Receptor positive (70%)
Many woman with breast cancer express the oestrogen receptor
Within this group of ER breast cancer they can be divided into luminal A & B tumours which have slight differences between them:
– Luminal A – more favourable prognosis for a woman
– Luminal B
Tamoxifen treatment (anti-oestrogen)
ERBB2 (HER2) positive (10%)
Woman who express the ERBB2 transmembrane receptor
Treatment for this would be the antibody trastuzumab which binds to the HERB2 receptor & blocks its action
Triple negative (lack ER, PR + ERBB2) (15%)
They have breast tumors that don’t express estrogen receptors, progesterone receptors or ERBB2 receptors
Standard treatment for these cancers is chemotherapy – very aggressive & heterogenous cancers
Gene expression signatures segregate breast cancer subtypes & predict metastatic spread & patient survival
Tumour is looked at to see which genes it expresses
Based on the expression of the genes you can put patients into groups
Can then define the different subtypes
Some subtypes of cancer have a better predicted survival of metastases than others
Way of taking biopsies and then predicting a prognosis
Breast cancer subgroups have distinct clinical outcomes - next generation sequencing
We can use this to predict patients are likely to have a favorable or unfavorable outcome
Tamoxifen & fulvestrant
Tamoxifen & fulvestrant are drugs that block the estrogen receptors
Estrogen receptor antagonists – block the estrogen receptor signaling pathway
Important as the pathway drives a lot of effector proteins – cyclin G1, apoptosis, protein BCL2 – inovled in driving the cell cycle
Also affects autophagy
Targeting the nuclear estrogen receptor (ER) in breast cancer
Estrogen stimulates breast development and maintains ER+ve tumour growth
Estrogen withdrawal decreases ER+ve cell proliferation (>90%)
Endocrine therapy is mainstay of treatment for ER+ve tumours
– ER antagonists – Tamoxifen
– Estrogen deprivation – Aromatase inhibitors
– Destabilise and antagonise ER – Fulvestrant
Majority of patients receive endocrine therapy for 5 years post-surgery
Endocrine therapy reduces recurrence and mortality
ESR1 (ER-alpha) mutations identified in primary and metastatic advanced ER+ve breast cancer
Problem that arises is that the tumours evolve
They acquire resistance – ER becomes mutated in breast cancer in response to therapies
3 domains of estrogen receptors
Activation domain at the N terminus
DNA binding domain
Ligand binding domain where tamoxifen or estrogen will bind to
Where do most mutations occur in ER+ve breast cancer?
They acquire mutations in the LBD & the major mutations occur in the tyrosine-537 or glutamic acid-538
This causes a conformational change in the LBD such that it can no longer binds to the tamoxifen & end up with a constitutionally active ER that drives the tumours growth
Reduced sensitivity to anti-estrogens compared to wild type ER – higher doses of Tamoxifen/ Fulvestrant required to achieve effective inhibition
Alternative signalling networks to the estrogen receptor in breast cancer epithelial cells
ER in BC cells can cross talk with other CS pathways
Also other signaling pathways such as the GFR, integrins & cytokine signaling pathways that can cross-talk with the ER – provide alternative routes to try to stop the action of the tumour in BC patients
