Small-cell lung cancers Flashcards
Intro to Lung Cancer background (5)
-one of the MOST PREVALENT cancers in the UK (alongside breast, prostate, bowel = accounts for more than 50% of cases)
-single MOST COMMON cause of cancer-related mortality with nearly 1.8M deaths worldwide in 2018 or nearly 21% of cancer
mortality as a whole. (similar variation across the world)
-Over half of the respiratory deaths are due to lung cancer or COPD, conditions that are mainly caused by tobacco smoking.
-more prevalent in MEN than women
- 5-year survival <20%
What is the need for Biopsies? (4)
- To perform a correct diagnosis of the ailment.
-To determine cancer
-To study functional characteristics of the cancer
- identify if small cell lung cancer or non- small cell lung cancer
What is a biopsy?
Sampling a piece of tissue from a node or tumour for examination
Biopsy Methods (4)
- Fine and core needle of the lung aided by CT or ultrasounds imaging (tissue or fluid)
- Bronchoscopy (trachea and large airways) - microscopy ight/lens tube
- Endobronchial ultrasound (EBUS)(lymph nodes) - microscopy w/ US (360o image) - no tissue needed
- Navigational bronchoscopy (deeper and smaller spots in the lung) - GPS like image
What is the histopathology of lung cancer? small vs non-small (5)
classified into 2 main groups
10-15% = small cell
- small cell carcinoma (oat cell cancer)
- combined small cell carcinoma or mixed small cell and Non small cell cell carcinoma
85-90% = Non-small cell
- adenocarcinoma
- squamous Cell Carcinoma
- large Cell Carcinoma
SCLC Characteristics (5)
- Small cell lung cancer (SCLC) accounts for 10-15% of all lung cancers.
- Likely due to smoking (>90%).
- Aggressive (rapid metastasis to brain, liver, bone).
- High mortality (~ 1 yr prognosis).
- More responsive to traditional cancer therapies (chemotherapy).
SCLC Histology (3)
- Typically centrally located, arising in peribronchial locations.
- Thought to develop from neuroendocrine cells.
- Composed of sheets of small, round cells with dark nuclei, scant cytoplasm, and fine, granular nuclear chromatin.
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SCLC Staging- limited vs extensive (4)
For treatment purposes:
Limited stage:
* Cancer is found in one side of the chest, involving just one part of the lung and nearby lymph nodes
* Chemo+Radio (to cure)
Extensive stage:
* Cancer has spread to other regions of the chest or other parts of the body
* Chemo to control (not cure)
Mechanisms of SCLC development (5)
- Loss of tumour suppressor function
- Mutations of TP53 gene – 80% of primary tumours.
- Point mutations and small deletions of PTEN gene – 10% of primary tumours.
- Others include alterations in Retinoblastoma (RB1)
- Gain in oncogenic mutations
- Amplification of c-Myc – 9% of primary tumours
TP53’s link to cancer (2)
- Over 50% of cancers contain mutations in the TP53 gene (80% primary SCLC tumours) - protein = P53
- Most commonly affected tumour suppressor gene in human cancer.
Why is TP53 known as “The Guardian of the Genome”? (5)
(multiple cellular functions)
- Transcription factor
- Detects cellular stress, especially DNA damage
- Induces cell cycle arrest
- If failure to repair damage, it induces apoptosis
p53 roles and why is it a protector and killer? (3)
p53 can help to promote the repair and survival of damaged cells, OR it can promote the permanent removal of damaged cells though death or senescence.
(main job = Detects cellular stress esp. DNA damage)
during oncogenic growth/high/sustained stress/irreparable damage -> activates apop to eliminate cells
Hypoxia, DNA damage, Ribosomal stress, Oncogene activation, Senescence, Genomic stability, DNA repair, Survival, Cell-cycle arrest. Apoptosis. Nutrient Deprivation, Telomere erosion
How does p53 work? (3)
- Normal unstressed cells p53 protein is low
- Levels regulated by MDM2 protein (-ve feedback) : it binds to the p53 N-terminal transactivation domain = promoting p53 ubiquitination and degradation by E3 ligase activity
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Carcinogens and p53 (4)
UV: single strand break
Ionizing radiation (IR): double strand breaks
Chemical Carcinogens- (chemo- Etoposide): double strand break
breaks = phosphorylation of central players in DNA Damage response( i.e. p53) response in each transactivation domain (through NMDA pathway)
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Transactivation domain of p53 (3)
transactivation = disruption of the interaction b/w p53 and MDM2 (bc domain is required in binding of p53 to MDM2) (PHOSPORYLATION)
= MDM2 phosphorylation in c-terminal (usually involved in …)
= accumulation of p53 in cytoplasm and nucleus
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What happens if the breaks are not repaired? (2)
p53 activates function of proteins involved in apop activation by protein-protein interaction.
missense mutations in hotspots (DNA binding domain) = inactivate p53 (by preventing binding to DNA + thus reg of transcrip) = expression of mutated protein or absence of protein
could be due to carcinogens i.e. tobacco
Mechanisms of SCLC development- PTEN (2)
- PTEN (phosphatase and tensin homolog) encodes a lipid phosphatase
which influences cell survival through signalling down the phosphoinositol-3-
kinase/Akt pathway - Loss of PTEN = activated AKT cell survival signalling + apoptosis
Mechanisms of SCLC development - RB1 (3)
- In almost all cases of SCLC, the product of RB1 is not expressed as a consequence of deletion, point mutations, chromosomal loss or other mechanisms.
- Prevents cell growth by inhibiting cell cycle until cell is ready to divide in G1 phase (binding of E2F protein) controlled
- Phosphorylation=inactivation of RB1= permanent activation of cell cycle
Mechanisms of SCLC development - c-myc (2)
Myc: family of genes which encode for TF’s that regulate cell growth and metabolic genes.
= almost all cellular pathways
usually works w/ max = activate + carry out function
Treatment of SCLC (3)
- Surgery for non-metastatic - only for early cancers
– Lobectomy (one lobe)
– Pneumonectomy (whole lung)
– Wedge resection (small area affected) - Chemotherapy (etoposide/cisplatin) w/ radio
- Radiotherapy(2nd month of chemo + after surgery)
Chemotherapy agents (5)
- identified because they kill cells
- Act on specific molecular targets associated with cancer
- Act on all rapidly dividing cells (cancerous and normal)
- Cytotoxic
- Mainly intravenous, some oral agents
wide range of side effects of chemo (11)
- Hair loss
- Mouth sores
- Loss of appetite
- Nausea and vomiting
- Diarrhoea or constipation
- Increased chance of infections (decreased white blood cells)
- Easy bruising or bleeding (decreased blood platelets)
- Fatigue (decreased red blood cells)
- Cancer- leukaemia
Chemo Alkylating agents (4)
Alkylating agents - most common drugs
- Antimetabolites
- Topoisomerase inhibitors
- Anthracyclines
- Etc.
Combined chemotherapy: etoposide/irinotecan + cisplatin/carboplatin (5)
Topoisomerase inhibitors (etoposide/irinotecan)
* Enzymes involved in DNA winding, prevent DNA replication
* Topo type 1 – cut one strand
* Topo type II – cut both strands
Platinum-based agents(cisplatin/carboplatin)
* Cross-linking of DNA, inhibits repair and DNA synthesis
Platinum-based agents (MoA)
Cross-linking of DNA intrastrand + interstrand or even cross link b/w DNA + proteins
= inhib repair and DNA synthesis in cancer cells + other sites more rapidly
- more they divide, the more they’re likely to to be affected by these chemical compounds
Topoisomerase inhibitors (MoA) (2)
chemical compounds that block the action of (both) topoisomerase = winds the DNA
Topoisomerase = create changes in DNA structure by catalysing the breaking + joining of phosphorylase DNA backbone strands during normal cell cycle
Future for therapy for SCLC (5)
- Combinations of chemotherapy – limited approach
- Loss of tumour suppressor genes not as amenable for therapeutic
targeting - Difficulty in restoring function despite years of research e.g.
restoring p53 function with viral vector delivery of wild-type p53 - c-Myc targeted therapeutics in preclinical development, issues with targeting transcription factors slowly being improved e.g. myc/max dimerization (specificity issues)
- Promise of immunotherapy? – PD-1 inhibitors- on going clinical trials
Summary (6)
- Lung cancers are histopathologically classified into two types: Small Cell Lung
Cancer (SCLC, 10-15% of the total cases) and Non-Small Cell Lung Cancer
(NSCLC, 85%). - SCLC is a more aggressive form of lung cancer whose primary risk factor is
tobacco. - For treatment purposes, SCLC is usually classified into two main stages:
limited stage disease and extensive stage disease. - SCLC usually arises from mutations in TP53, followed by alterations in PTEN, c-myc and RB1.
- Affected individuals are treated with chemotherapy and often radiation therapy.
Surgery may be recommend it in early stage cancer.
