small cell lung cancer

Question 1

what are more than half of new cases of cancer?

Answer 1

breast
prostate
lung
bowel

Question 2

go over the epidemiology of lung cancer

Answer 2

Lung cancer: 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.
5-year survival <20%

Highest incidence rate in eastern Europe countries e.g. hungary and some Asian countries e.g. turkey and china

lung cancer is the second most common cancer for both men and women–> 23 to 48%

the age adjusted death rate for lung cancer is higher for men than for women or african americans. Black men have a far higher age-adjusted lung cancer death rate than white men, while black and white women have similar rate.

Question 3

Lung cancer is the most common cancer worldwide, and is responsible for the most cancer deaths, at around 1.76 million.

About 80% of lung cancer deaths are thought to result from smoking and/or secondhand smoke. Smoking is by far the leading risk factor for lung cancer.

Answer 3

Over half of the respiratory deaths are due to lung cancer or COPD, conditions that are mainly caused by tobacco smoking.

• Smoking is also the main risk factor for other respiratory disorders e.g. pneumonia and pulmonary vascular disease

Question 4

Name and describe some biopsy methods to detect lung cancer

Answer 4

• Fine and core needle of the lung aided by CT or ultrasounds imaging (tissue or fluid)
• Bronchoscopy (mainly used to extract biopsy from trachea and large airways)
• Endobronchial ultrasound (EBUS)–> lymph nodes
• Navigational bronchoscopy (Deeper and smaller spots in the lung)

Question 5

what are the two main types of lung cancer?

Answer 5

Small cell lung cancer: small cell carcinoma, combined small cell carcinoma or mixed small cell non-small cell carcinoma

Non-small cell lung cancer: adenocarcinoma, squamous cell carcinoma and large cell carcinoma

Question 6

what some characteristics of SCLC?

Answer 6

• Small cell lung cancer (SCLC) accounts for 15-20% of all lung cancers.
• Likely due to smoking (>90% of cases).
• Aggressive (rapid metastasis to brain, liver, bone).
• High mortality (~ 1 yr prognosis).
• More responsive to traditional cancer therapies (chemotherapy)–>
  As they’re very aggressive and cell divide rapidly…
  + genes affected in SCLC are not targetable= chemo is the most effective option

Question 7

describe the histology of SCLC

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.

Question 8

what are the 2 stages of SCLC?

Answer 8

Limited stage: Cancer is found in one side of the chest, involving just one part of the lung and nearby lymph nodes. To cure: chemo + radio

Extensive stage: cancer has spread to other regions of the chest or other parts of the body. Chemo to control (not cure)

Question 9

give an overview on the mechanisms of SCLC development

Answer 9

Loss of tumour suppressor function:
• Mutations of TP53 gene – 80% of the primary tumours.
• Point mutations and small deletions of PTEN gene (phosphatase and tensin homolog) – 10% of primary tumours.
• Others include alterations in Retinoblastoma (RB1)

Gain in oncogenic mutations:
• Amplification of c-Myc – 9% of primary tumours

Problem: no targeted therapies to tackle the abnormal function of these mutated genes THEREFORE need chemo!

Tumour suppressor function needs to be lost + oncogenic mutation are activating mutations that cause more protein product or increase the function levels of protein= give rise to tumorigenic process

Question 10

correlate TP53 to SCLC

Answer 10

TP53 is known as the guardian of the genome. therefore, it is not suprising that over 50% of cancers contain mutations in the TP53 gene (80% primary SCLC tumours).

It is the most commonly affected tumour suppressor gene in human cancer

Question 11

Describe TP53

Answer 11

TP53 is a transcription factor that interacts with DNA (it regulates the expression of many genes that are involved in so many pathways e.g. DNA repair genes involved in homeostasis).

It is also a tumour suppressor gene that detects cellular stress, especially DNA damage. This subsequently induces cell cycle arrest. If there is a failure to repair the damage, it induces apoptosis,

Question 12

what activates p53?

Answer 12

Nutrient deprivation, telomere erosion, hypoxia, DNA damage, ribosomal stress, oncogene activation.

p53 subsequently induces either: DNA repair, survival, genomic stability, senescence. cell cycle arrest and apoptosis.

i.e. p53 can help to promote the repair and survival of damaged cells, or it can promote the permanent removal of damage cells through death or senescence.

Question 13

describe the 2 “types” of p53

Answer 13

Normal growth…low/transient stress/repairable damage: p53 induces cell cycle arrest/growth of inhibition. This in turn regulates metabolism, DNA repair and acts an antioxidant. Tumour prevention.

oncogenic growth…high/sustained stress/ irreparable damage: p53 acts as a killer and induces apoptosis, senescence, stem cell erosion and acts as a pro-oxidant. This causes the elimination of cell–> tumour suppression

Question 14

what is the relationship between MDM2 and p53?

Answer 14

Levels regulated by MDM2 protein (negative feedback): it binds to the p53 N-terminal transactivation domain and promoting p53 ubiquitination and degradation by E3 ligase activity.

P53 due to each transcription factor function will also activate the transcription of mDM2= negative feedback/p53 self-regulates.

Question 15

what happens when there is DNA damage?

Answer 15

1. DNA damage e.g. due to:
   - UV: single strand break
   - OR Ionizing radiation (IR): double strand breaks
   - OR Etoposide: double strand breaks –>
   A chemotherapeutic agent, so toxic that they can damage DNA and cause secondary cancers e.g. leukaemia
2. ATM/ATR pathways are then activated= promotes the phosphorylation of different central players involved in DNA damage response e.g. p53 and MDM2 –> Phosphorylation in MDM2’s c-terminal domain(which normally recruits ubiquitin machinery)
3. Phosphorylation breaks the interaction between p53 and MDM2 proteins
4. Brake in the interaction between p53 and MDM2 will lead to the accumulation of p53 protein in the cytoplasm
5. p53 dimerises and trimerizes i.e. forms complexes that will activate the transcription of some proteins involved in cell cycle arrest (G1/S and G2/M)
6. p53 can also interact with other proteins= promote apoptosis in case DNA damage is not repaired

Question 16

describe PTEN

Answer 16

PTEN encodes a lipid phosphatase which influences cell survival through signalling down the phosphoinositol-3-kinase/Akt pathway. It is also involved in the inhibition of apoptosis

PTEN is an antagonist of the PI3Kinase and dephosphorylates Phosphatidylinositol 3 phosphate [PI(3,4,5)P]/PI3P into Phosphatidyl Biphosphate [PI(4,5)P]/PI2P = PI3P now can’t activate the AKT pathway involved in the promotion of cell survival proliferation + inhibition of apoptosis + other effects

• PTEN inhibits the AKT pathway
• There is also a balance of PI3P and PI2P to keep the normal function
• THEREFORE, the gene that codes for PI3K must be an oncogene (PI3K is not usually mutated in small cell lung cancer so dw lol!)

Question 17

what happens when there is a loss of PTEN function?

Answer 17

loss of PTEN leads to activated AKT cell survival signalling= pathway is continuously activated–> therefore increase in cell survival and cell proliferation etc.

Question 18

Describe RB1

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.
• Normally it prevents cell growth by inhibiting cell cycle until cell is ready to divide.
• Phosphorylation=inactivation
  o During the cell cycle, normally RB is phosphorylated
  o But in the G1 phase where it checks if everything is ready for S phase= it is unphosphorylated= allows it to do its job

Question 19

what do growth factors do (Regarding RB1)

Answer 19

Growth factors activate the RAS pathway–> they activate cyclin dependent kinases–> these kinases will phosphorylate RB protein–> inactivate its function in cell cycle RB won’t be able to dimerise with E2F–> E2F can promote the S phase gene transcription.

G1 phase: RB is not phosphorylated–> binds to E2F E2F won’t be able to activate the transcription of S phase genes.

If there is genome stability + no problem= RB is phosphorylated= allows cell cycle to progress

Question 20

describe C-myc

Answer 20

Myc: family of genes which encode for transcription factors that regulate cell growth and metabolic genes. It also promotes angiogenesis.

Amplification of c-Myc is associated with poor prognosis

There is no targeted therapy that can target c-Myc at the moment.

Question 21

what are the treatment strategies for SCLC?

Answer 21

•	Surgery for non-metastatic
o	Lobectomy (one lobe)
o	Pneumonectomy (whole lung)
o	Wedge resection (small area affected)

• Chemotherapy (etoposide/cisplatin–> usually a combination of these 2 agents)
• Radiotherapy

The normal treatment for SCLC (if patient has a limited state): combination of chemotherapy with radiation

Radiotherapy is usually applied on chest of patient after second week of chemotherapy treatment.

Question 22

outline the differences between targeted therapies and chemotherapy

Answer 22

Targeted therapies:

• design to interact with their targets
• act on specific molecular targets associated with cancer
• cytostatic
• many are oral agents

Chemotherapy:

• identified because they kill cells
• act on all rapidly dividing cells (cancerous and normal)
• cytotoxic
• mainly intravenous, some are oral agents

Question 23

what is the aim of targeted therapy?

Answer 23

Increase specificity and reducing toxicity–> kill tumour cells + maintain integrity of surrounding tissue

Question 24

what are the side effects of chemotherapy?

Answer 24

• 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 25

SCLC uses a combination of both types of chemotherapy agents.

what are they?

Answer 25

COMBINED THERAPY:

topoisomerase inhibitors (etoposide or irinotecan) + Platinum-based agents (cisplatin or carboplatin).

Topoisomerase inhibitors:

• enzymes involved in DNA winding, prevent DNA replication.
• Topo type II- cut one strand
• Topo type II- cut both strands
  i. e. inhibit the winding of DNA

molecules that inhibit topoisomerase (Enzyme) involved in breaking + re-joining of DNA during cell cycle

Platinum-based agents: cross-linking of DNA, inhibits repair and DNA synthesis

Question 26

what is the future in terms of therapy for SCLC?

Answer 26

• 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