L7 - Aberrant cell signalling in cancer provides targets for therapeutic intervention Flashcards

1
Q

What does aberrant mean?

A

Diverging from the normal type

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2
Q

How do we identify appropriate therapy for an individual cancer patient?

A

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

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3
Q

Tumour heterogeneity in diagnostics & metastatic spread

A

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?

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4
Q

Does the primary cancer usually kill the patient?

A

NO

Its more likely to be due to the cancer metastasising

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5
Q

Step wise progression of cancers

A

tumours will grow and can be released into the blood stream

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6
Q

Alternative hypothesis for the progression of cancers

A

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

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7
Q

Issues with cancer drugs

A

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

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8
Q

Genomic alterations that cause cancer

A
  • Point mutations
  • Gene amplification
  • Deletions
  • Altered gene expression
  • Translocations
  • Epigenetic modifications
  • Aberrant RNA splicing
  • microRNAs
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9
Q

Genomic perturbations promote cancer cell survival affecting the hallmarks of cancer by altering:

A
  • Cell cycle control
  • Differentiation
  • Tumour vascularisation
  • DNA repair
  • Apoptosis
  • Metabolism
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10
Q

Breast cancer classification

A

Breasts are made of many ducts & lobes
Different types of cancer can occur in breasts
Can define breast cancer into carcinomas or sarcomas

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11
Q

Carcinoma types

A

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

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12
Q

Sarcoma

A

Stromal (connective tissue)
• Develop into the stromal compartment

Examples:
• Phyllodes tumour
• Angiosarcoma

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13
Q

Breast cancer subgroups

A

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%)
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14
Q

Estrogen Receptor positive (70%)

A

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)

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15
Q

ERBB2 (HER2) positive (10%)

A

Woman who express the ERBB2 transmembrane receptor

Treatment for this would be the antibody trastuzumab which binds to the HERB2 receptor & blocks its action

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16
Q

Triple negative (lack ER, PR + ERBB2) (15%)

A

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

17
Q

Gene expression signatures segregate breast cancer subtypes & predict metastatic spread & patient survival

A

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

18
Q

Breast cancer subgroups have distinct clinical outcomes - next generation sequencing

A

We can use this to predict patients are likely to have a favorable or unfavorable outcome

19
Q

Tamoxifen & fulvestrant

A

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

20
Q

Targeting the nuclear estrogen receptor (ER) in breast cancer

A

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

21
Q

ESR1 (ER-alpha) mutations identified in primary and metastatic advanced ER+ve breast cancer

A

Problem that arises is that the tumours evolve

They acquire resistance – ER becomes mutated in breast cancer in response to therapies

22
Q

3 domains of estrogen receptors

A

Activation domain at the N terminus
DNA binding domain
Ligand binding domain where tamoxifen or estrogen will bind to

23
Q

Where do most mutations occur in ER+ve breast cancer?

A

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

24
Q

Alternative signalling networks to the estrogen receptor in breast cancer epithelial cells

A

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

25
Q

Most significantly mutated genes in breast cancer as determined by whole-exome sequencing

A

27% of BC patients have mutations in the p53 gene – also mutated in lots of other cancers

Common mutations in the PIK3CA gene – member of the PIP3 signaling pathway (27% of BC patients)

In 6% of BC cancers AKT1 is mutated – a component of the AKT signaling pathway

These mutations act as drivers of the cell signaling pathway

26
Q

The PI3K pathway in cancer

A

PI3K pathway control cancer hallmarks
– Cell cycle, survival, metabolism, motility, genomic instability

Contributes to promoting tumour microenvironment
– Angiogenesis
– Inflammatory cell recruitment

Lipid second messenger (PIP3) constitutively altered in most cancers
Most frequently altered pathway in tumours

In BC patients we see alterations in the Pi3 kinase – drives production of PIP3 to enhance AKT
We also see deletions in the phosphatase-PTEN – also drives the production of the PIP3

A way of the tumours becoming resistant to treatment

27
Q

Driver mutations in tumour growth

A

PTEN deletion/mutations

PI3K activating mutations

AKT activating mutations
– Dual phosphorylation of AKT which drives the phosphorylation of various proteins such as BAD, FOXO & p21 – this essentially results in the activation & the stimulation of cells to proliferate, grow & survive

Upstream RTK activating mutations

28
Q

Structure & function of PI3K family members

A

3 structural Classes (I, II, III)

Common domains – C2, helical, catalytic

Activated by RTKs and GPCRs
– Class IA: 3 members – 5 regulatory subunits
– Class IB: 1 member – 2 regulatory subunits

29
Q

Structure & function of ATK family members

A
  • 3 isoforms
  • Pleckstrin Homology (PH), Catalytic, Regulatory domains
  • PH domain binds PIP2/PIP3
  • Phosphorylation of Thr308 (activation loop within catalytic domain) and Ser473 (regulatory domain) by PDK-1 and mTORC2, respectively required for full activation
  • Activation mutations in cancer