Small-cell lung cancers

Question 1

Intro to Lung Cancer background (5)

Answer 1

-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%

Question 2

What is the need for Biopsies? (4)

Answer 2

• 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

Question 3

What is a biopsy?

Answer 3

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

Question 4

Biopsy Methods (4)

Answer 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

Question 5

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

Answer 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

Question 6

SCLC Characteristics (5)

Answer 6

• 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).

Question 7

SCLC Histology (3)

Answer 7

• 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

Question 8

SCLC Staging- limited vs extensive (4)

Answer 8

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)

Question 9

Mechanisms of SCLC development (5)

Answer 9

• 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

Question 10

TP53’s link to cancer (2)

Answer 10

• 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.

Question 11

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

Answer 11

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

Question 12

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

Answer 12

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

Question 13

How does p53 work? (3)

Answer 13

• 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

Question 14

Carcinogens and p53 (4)

Answer 14

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

Question 15

Transactivation domain of p53 (3)

Answer 15

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

Question 16

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

Answer 16

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

Question 17

Mechanisms of SCLC development- PTEN (2)

Answer 17

• 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

Question 18

Mechanisms of SCLC development - RB1 (3)

Answer 18

• 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

Question 19

Mechanisms of SCLC development - c-myc (2)

Answer 19

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

Question 20

Treatment of SCLC (3)

Answer 20

• 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)

Question 21

Chemotherapy agents (5)

Answer 21

• 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

Question 22

wide range of side effects of chemo (11)

Answer 22

• 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

Question 23

Chemo Alkylating agents (4)

Answer 23

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

Question 24

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

Answer 24

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

Question 25

Platinum-based agents (MoA)

Answer 25

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

Question 26

Topoisomerase inhibitors (MoA) (2)

Answer 26

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

Question 27

Future for therapy for SCLC (5)

Answer 27

• 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

Question 28

Summary (6)

Answer 28

• 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.