Small-cell lung cancers Flashcards

1
Q

Intro to Lung Cancer background (5)

A

-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%
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the need for Biopsies? (4)

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is a biopsy?

A

Sampling a piece of tissue from a node or tumour for examination

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Biopsy Methods (4)

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the histopathology of lung cancer? small vs non-small (5)

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

SCLC Characteristics (5)

A
  • 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).
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

SCLC Histology (3)

A
  • 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.

images

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

SCLC Staging- limited vs extensive (4)

A

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)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Mechanisms of SCLC development (5)

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

TP53’s link to cancer (2)

A
  • 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.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why is TP53 known as “The Guardian of the Genome”? (5)

A

(multiple cellular functions)
- Transcription factor
- Detects cellular stress, especially DNA damage
- Induces cell cycle arrest
- If failure to repair damage, it induces apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

p53 roles and why is it a protector and killer? (3)

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How does p53 work? (3)

A
  • 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

images

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Carcinogens and p53 (4)

A

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)

images

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Transactivation domain of p53 (3)

A

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

images

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What happens if the breaks are not repaired? (2)

A

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

17
Q

Mechanisms of SCLC development- PTEN (2)

A
  • 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
18
Q

Mechanisms of SCLC development - RB1 (3)

A
  • 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
19
Q

Mechanisms of SCLC development - c-myc (2)

A

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

20
Q

Treatment of SCLC (3)

A
  • 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)
21
Q

Chemotherapy agents (5)

A
  • 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
22
Q

wide range of side effects of chemo (11)

A
  • 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
23
Q

Chemo Alkylating agents (4)

A

Alkylating agents - most common drugs
- Antimetabolites
- Topoisomerase inhibitors
- Anthracyclines
- Etc.

24
Q

Combined chemotherapy: etoposide/irinotecan + cisplatin/carboplatin (5)

A

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

25
Q

Platinum-based agents (MoA)

A

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

26
Q

Topoisomerase inhibitors (MoA) (2)

A

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

27
Q

Future for therapy for SCLC (5)

A
  • 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
28
Q

Summary (6)

A
  • 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.