Specific Cancers (Lung; Glioblastoma) Flashcards
(23 cards)
Why is lung cancer important?
Leading cause of cancer mortality world-wide
Risk factors: smoking, second hand smoke, pollution, HIV
What are the main types of lung cancer?
Small cell lung carcinoma (SCLC): 6% 5 year survival rate - paraneoplastic syndromes common (NE release of ACh, ACTH, ADH)
* Fast growing, high mutation rate and strongly associated with smoking
Non-small cell lung cancer (NSCLC):
* Adenocarcinoma (LUAD) = 40% from alveolar type 2 (AT2) cells (stem cells of the lung) and club cells
* Squamous cell carcinoma (LUSC) = 30% from tracheal basal cells
* Large cell lung carcinoma (LCLC) = 15% pulmonary neuroendocrine cells
* More genetically stable and slower growing
Origins seem very heterogeneous - should they even be categorised this way?
Should screening of lung cancer be routine?
+ve: catches early cases (prevention is more successful than treatment) - better chance of successful treatment before metastasis
-ve: screening (e.g. scanning) can induce tumours and false +ves occur
*Improving with more methods of screening
*Cancer treatments have side effects which may be detrimental
How can smoking cause lung cancer
Direct: has carcinogens which cause mutations in cells accelerating proliferation (tumour suppressor/oncogenes)
*Benzopyrenes form DNA adducts and increase ROS production
Indirect: causes chronic inflammation which then leads to physical damage and mutations (pro-cancer environment)
*E.g. chronic obstructive pulmonary disease (COPD)
*Physical damage of tar/debris in lung
What is interesting about the mutation profile of NSCLC lung cancer patients?
Seem to be mutually exclusive groups in NSCLC: KRAS (most common ~31%) or EGFR or BRAF mutations (rarely together). Almost universal Rb1 and p53 mutants
Heterogeneity is clear but only starting to be harnessed.
What are the advantages of GEMM models for lung cancer?
Advantages:
* Can closely resemble human disease (e.g. metastatic pattern of development in neuroendocrine SCLC)
* Good for investigating the role of individual genes
* Good GM capabilities
* Good for initial drugs testing & toxicity
* Ethically viable
* Fast reproductive rate
What are the problems of mouse models for GEMM models for lung cancer?
Limitations:
* Preneoplastic stages do not mimic human cancers well
* Specific KOs do not represent huge profile seen in lung cancer (particularly from smoking) e.g. fewer ‘passenger mutations’
* Mouse physiology is not identical (e.g. neural involvement and metastatic properties (e.g. KRAS and p53 in conjunction need for metastasis induction in mice, but only KRAS can be sufficient in humans)).
What are the common GEMM models for SCLC in mice? What are the associated problems?
The ‘PR model’ (RB1 and p53 KOs from NE cells) (both driver mutations).
* Good representation
Better is ‘triple’ KO with Rb1, Rb2 and p53
* Shorter latency (better for study)
Addition of myc overexpression shortens latency further and changes variant profile
* ASCL1 to NEURO1 phenotype so good for study of variants
* Very short latency (good and bad)
General Problems:
* Do not include the full mutation profile (e.g. other driver mutations)
* Do not include ‘passenger mutations’
How are SCLCs currently treated?
Despite progress in understanding; 5yr survival rate is still disappointingly low (<10%)
Treatments:
- Cisplatin
- Immunotherapy (PD-L1 inhibitor; PD-1 inhibitor)
What are the common SCLC mutant groups?
Two dominant phenotypes are ASCL1 high mutants and NEURO1 high mutants: cells can be both, one or neither.
ASCL1 is a master regulator of neuroendocrine signalling (extreme overexpression of NE markers) (producing ‘NE’ cells)
NEURO1 is a myc driver and associated with ‘variant tumour form’ – reduced NE markers (i.e. ‘non-NE’ mesenchymal cell phenotype).
*Only ASCL1 is needed for tumour formation (deletion is protective)
*Distinct populations often seen (heterogeneous tumour)
How has heterogeneity between NE and non-NE cells been investigated?
Have different expression patterns which can be seen histologically or through RNA-seq.
Non-NE cells:
*CD44 marker (not seen on NE cells)
*Hes1 is also an accurate marker. Hes1 is a robust marker of NOTCH-1 (which allows paracrine signalling)
Importance: heterogeneity in tumour promotes proliferation.
Why might chemotherapy be detrimental for treating SCLC?
Though it may reduce tumour size, it can increase heterogeneity of tumour.
- non-NE cells are more resistant to chemo (e.g. cisplatin)
- Therefore non-NE cell proportion increases
- Increased heterogeneity promotes proliferation and metastasis
- non-NE cells can induce conversion of NE cells through NOTCH1 signalling - shown as same mutation profile seen with additional mutations
Why is heterogeneity important in SCLC progression?
Intertumoral heterogeneity produced by NOTCH1 signalling progresses SCLC.
- Injection of one or other group does not result in metastasis but both drives growth and metastasis. (Heterogeneous tumours metastasise together (Cheung et al) and have a high chance of survival)
- Hypothesis that electrically active NE cells are supported by ‘astrocyte like’ non-NE cells (evidence through transcriptomic profile). E.g. by providing sufficient glucose for function.
Why is understanding heterogeneity important?
Understanding molecular heterogeneity (and patient variability) can help treatment through targeted interventions.
Blanket treatments produce lower efficacy - either because they are not affecting some of the cells or they are having a mixed result (they are encouraging cancer in some cells/via some mechanisms and treating via others, so the overall effect may be beneficial but limited).
What are the main types of glioma?
Often split by IDH mutation:
Glioblastoma (GBM) = IDHwt, often in older patients with neurological deficits
Low grade glioma = IDHmt, in younger patients presenting with seizures - better prognosis (though still ~34 months)
What have been the major barriers to glioma treatment?
Difficult to surgically remove (show up using 5-ALA stain)
*Can cause damage to other brain regions
*Gliomas can put out ‘spines’ into other brain areas which are very difficult to remove and lead to resurgence
‘Homogeneously heterogeneous tumours’
Rare cancer with limited research funding
How can glioma be characterised and investigated (techniques)?
Methods:
*Histologically
*Imaging (use AI?)
*Surgically (using 5-ALA)
*Classify using genome and epigenome sequencing, transcriptomics (how heterogeneous is the tumour?)
*Metabolic data (e.g. flux of metabolites in different regions e.g. OxPhos vs. glycolysis distribution)
*Symptoms (clinical data)
Utilise precision targets for precision medicine:
*E.g. GWAS and whole transcription seq. to identify specific mutations
*Use drugs already available to target those mutations e.g. EGFR mutation identified so patient given EGFR inhibitor or same with IDH1 inhibitor
How could clinical trials be re-designed to facilitate treatment acknowledging heterogeneity?
Idea of a ‘master protocol’:
1.Patients undergo sequencing to determine treatments likely to work (rather than using blanket treatments based on percentage efficacy) - a treatment could be 30% effective because it is 0% effective in 70% pf people. If you know which category someone is in before giving the treatment this could be improved.
2. Give treatments which are already approved (for other things)
Other considerations:
*Skip mouse models/in vitro experiments which invalidate treatments before they reach patients (where they may in fact work)
*Give these specialised treatments before patients are sick from chemo/radiotherapy already
Evidence that electrical activity drives SCLC
Peinado et al 2025: AP firing of non-NE cells drives SCLC
* NE cells are capable of firing APs and electrical activity is synchronised (Ca2+ imaging)
* non-NE cells support NE cells metabolically
* Enhancing electrical activity (ChR2) increases tumorigenic potential
* TTX administration stops electrical activity while maintaining cell viability and reduces progression
* Despite having the same mutations, non-NE cells do not form liver metastasis (where NE can)
Why do treatment strategies differ across the main types of lung cancer?
SCLC: Faster growing and genetically unstable (high mutation rate) and diagnosed late (after metastases).
* Fewer targetable mutations or easily become resistent
* Chemotherapy and radiotherapy
Non-SCLC: slower growing and more genetically stable
* Targeted treatments more successful (e.g. EGR, BRAF)
* Immunotherapy (anti-PD-1)
What are IDH mutations and why can they cause gliomas?
Isocitrate dehydrogenase (IDH) mutations:
* (uncommonly) Both L and D IDH can be formed and interchanged. mtIDH causes D-2-HG accumulation leading to epigenetic changes ↑granzyme B activation → ↑complement
How does NOTCH signalling promote lung cancer? (provide evidence)
non-NE cells can induce conversion of NE cells through NOTCH1 signalling - shown as same mutation profile seen with additional mutations
Lim et al 2017:
* Reversal of NOTCH1 does not cause reversal from non-NE to NE
* Blockade of NOTCH (antibody inhibition) and chemo halts growth.
What is different about the tumour immune infiltration in gliomas? Why is this?
IDHmt gliomas exhibit significantly lower levels of immunosuppressive cells (particularly TAM such as CD163+).
Postulated that 2-HG increases methylation (through disruption of TET action) which may silence genes associated with tumour derived immune cells.
* May improve response to immunotherapy.
