Lung cancer Flashcards
What percentage of lung cancers are caused by smoking?
71%
Why are survival rates of lung cancer so low?
Very few symptoms early on, only present in later stages
Rapid progression
Less funding so fewer advances in treatment options
Social stigma
Tumour resistance
What are the two main reasons for tumour resistance in lung cancer?
Intratumour heterogeneity
Lack of biomarkers
Which are 3 features we can use to categorize lung cancer?
Histology
Molecular mutations
Staging
Which histological features are used to categorize lung cancers?
Small cell/neuroendocrine
Non small cell
Which molecular mutations are commonly found to cause lung cancer?
EGFR
ROS
ALK
PD-L1
Which 3 features do we look at to stage non small cell cancer?
T - primary cancer
N - regional lymph node
M - distal metastasis
What is ECOG?
Scale used to assess a patients fitness to undergo treatment
0-5 scale
0 = fully active 5 = dead
What is the importance of mutations in cancer cells?
Trigger signalling pathways which confer survival advantage to cells compared to somatic cells
Which signalling pathways confer survival advantages to cancer cells?
Block oncogene pathways
Decrease apoptosis of cancer cells
Increase mutations of cells leading to relapse
What are the three main treatments of lung cancer?
Chemotherapy
Radiotherapy
Molecular therapy
Which chemotherapy is used in lung cancer?
Dual agent chemotherapy (platinum + another)
Docetaxel monotherapy
When do we use Docetaxel instead of dual agent chemotherapy?
Used for patients who do not respond to dual agent chemotherapy and are fit enough
What are the 3 types of radiotherapy?
Curative
Adjuvant
Palliative
What does molecular therapy target?
Protein mutations
Tyrosine kinase
Immune checkpoints
How does molecular therapy target tyrosine kinase?
Via tyrosine kinase inhibitors
Blocks signalling pathways preventing the tyrosine kinase from signalling to the nucleus
What is an example of a checkpoint inhibitor?
PD-1 and PD-L1 blockade
How does the checkpoint inhibitor Pembrolizumab act?
Blocks either the PD-1 on T-cells or PD-L1 on the tumour cells
Prevents the tumour cell from binding to the T cell and inhibiting it
Therefore the active T cell kills the tumour cells by cytotoxic killing
Why are MSCs immune priviledged?
Do not elicit an immune reaction
What is the role of MSCs in stromal tissue cells?
Precursors of stromal tissue cells
Where are MSCs found in the body?
Bone marrow
Umbilical cords
How often do MSCs divide?
They show 5 population doublings per week
What important fact was discovered about MSCs?
They home to tumors
Why do MSCs home to tumors?
Microenvironment created by tumour cells releasing cytokine and matrix protein
Recognised by the conjugate receptors on MSCs
Which cytokines released from tumours are MSCs especially attracted to?
MIF
Activates ERK and JNK through CXCR4
How was the importance of MIF in homing MSCs to cancer cells discovered?
Study that knocked down the MIF signalling from cancer cells
Knockout of MIF lead to no MSCs homing to cancer cells
What is the TRAIL pathway?
TNF-related apoptosis inducing ligand
Induces the extrinsic pathway of apoptosis by binding to its receptor (TRAI)
How are tumour cells related to the TRAIL pathway?
Tumour cells express TRAI
So if we can activate its apoptosis by expressing TRAIL we can specifically target cancer cells
Which apoptotic pathways do chemotherapy and radiation elicit?
Intrinsic apoptotic pathway
More of a destructive mechanism for killing mutated cells
Why can’t we use TRAIL injections to kill cancer cells?
Very short half-life
Leads to cytotoxicity due to continuous dosages needed to provide effective treatment
What is used to inject TRAIL into the host organism?
Modify MSCs to express TRAIL ligand and trigger the extrinsic apoptotic pathway
What were the steps taken to ensure MSCs modified to express TRAIL were an effective therapy against lung cancer?
Construction of the TRAIL lentivirus
Prove that MSCTRAIL was effective at killing cancer cells
Prove that MSCTRAIL homed toward the tumour
Prove that MSCTRAIL effectively reduced tumour growth
How was the TRAIL lentivirus constructed?
Lentivirus conjugated with doxycycline
Doxycycline could turn on or off the expression of TRAIL in the MSCs
Marked TRAIL with luminescent biomarker to be able to spot MSCs
How was it shown that dox effectively turned the production of TRAIL on?
Measured the concentration of TRAIL produced by the lentiviruses
Lentiviruses without dox did not produce TRAIL
Lentiviruses with dox produced TRAIL
What was used to show that MSCs homed towards tumour cells?
DiL labelled MSCs
What is TRAIL synergy?
When MSCTRAIL therapy works together with other therapies to heighten their therapeutic effects
What are mechanisms of TRAIL synergy?
Radiotherapy increases TRAIL receptors
Radiotherapy increases MSC homing
Chemotherapy increases TRAIL induced caspase cleavage
Chemotherapy downregulates inhibitors of apoptosis
What was observed in the homing of MSCTRAIL in the lungs?
DiL-labelled MSCs showed that clusters wedge into the capillaries at first pass (90%)
Ideal for treating lung cancer
Describe the extrinsic pathway of apoptosis
TRAIL L binds to the trimerised receptor
Activates FADD protein that connect the Casp8 to the receptor
Activation of FADD leads to activation of Casp8
How was it proven that the extrinsic pathway was activated upon binding of MSCs to tumour cells?
Dominant negative construct of FAD was inserted into the tumor cells
Cancer cells were no longer apoptosed
What is a dominant negative FAD construct?
Protein that no longer connect the Casp8 to the TRAIL receptor
Which ECOG patients are eligible for chemo?
0-2 stage
How many lung cancer patients survive after 10 years
5%
How common is lung cancer death?
most common cancer DEATH - 1/5 cancer deaths
Lung cancer prognosis has improved a lot since the 70s
TRUE or FALSE
False
What are the types of curative radiotherapy?
SABR (stereotactic body radiation therapy)
EBRT (external beam radiation therapy)
- with Surgery (may take wedge, lobe or lung)
