cancer and the therapeutic options available Flashcards
cancer metastasis , therapeutic options present
what is cancer
this is the unregulated growth of the cells caused by changes in the genome
cancer that affects the epithelial cells
that is the squamous ,cuboidal , columnar they are known as carcinomas
sarcoma
cancer that affects the mesoderm that is the bone, muscle
adenocarcinoma
cancer that affects the glandular cells that is the breasts , oesophagus and the lungs .
what is gene silencing
interruption or suppression of gene
expression at transcriptional or translational level
why is cancer prevalent among the ageing population ?
Accumulation of mutations over a period time explains why
cancer is more frequent in the ageing population
what does mutation of the caspaces result into
results into the evasion of apoptosis
physiological conditions where cell death occurs
menstruation and embryogenesis
what are somatic mutations
mutation of the somatic chromosomes DNA
what are germline mutations
mutations of the sex cells and they are hereditary
the spread of cancer
metastasis
process 1 of metastasis
destruction of the basal membrane
what does metastasis involve
the destruction of the cell to cell adhesion
destruction of the cell to ECM adhesion
what are the theories of the spread of the cancer
En Route Theory
Seed & Soil
Pre - metastatic niche
what is the extracellular matrix and what is it composed of
the extracellular matrix is a complex meshwork of proteins and carbohydrates and collagen fibres .
cadherin
cellular adhesion molecules of the cells and the ECM
adherin
cellular adhesion molecule between the epithelial cells.
what are the mechanisms of metastasis
monoclonal and polyclonal metastasis
monoclonal metastasis
cells from the same single primary tumor cell creates more secondary tumor
polyclonal metastasis
creation of the secondary tumor cells by collaboration of multiple diverse primary tumor cells
epithelial mesenchymal transition
EMT is the conversion of closely connected epithelial cells becoming
independent mesenchymal cells with the ability to move and invade their
local environment
physiological occurrence of emt
embryogenesis
what changes occur during epithelial mesenchymal transition
1.loss of the apico - basal polarity and the gain of the mesenchymal proteins.
2.the loss of E - cadherin proteins, cytokeratin and the gain of N -cadherin and vimentin.
journey to metastasis
invasion -intravasation -transport -extravasation -colonisation .
invasion
movement of the tumor past the basal membrane into the ECM
intravasation
the movement of the tumor into the blood vessel or lymphatic system for circulation
process of invasion
process begins by release of signals from the tumor stroma ( HGF , and TGF-beta ) which stimulate the kinase receptors and induce the MAPK pathway.
molecules involved in invasion
1.proteases that make the pathway through the metalloproteins contribute to loss of cell junctions.
2.integrins - they enable the cells to break free and become mobile.( receptors for the ECM components )
3.cell adhesion molecules - cadherins and catenins.
factors favouring the process of intravasation
there are serine proteases and MMP( matrix metalloprotein) they help to degrade the basement membrane.
process of transportation of the tumor
there is the transportation of tumor cells in the bloodstream after entry into the vessel.
could be solo travelling cell or could be clumps in one direction.
certain cancers however have favoured sites that they like to travel to.
extravasation
exit of the tumor cell form the vessel od=r lymphatic system.
process of extravasation
takes place in the endothelial side of the blood vessel.
there is also degrading of the basement membrane before the cells migrate to the stroma of the ECM.
E selectin is a receptor that enables attachment of the cancer cells to the endothelium of blood vessel and favour transendothelium migration
molecule that enables the migration if the tumor cell form the endothelial space to the ECM
E selectin
colonisation in metastasis
site of the metastasis is the same point of extravasation but it also depends on the microenvironment
factors favouring the site of metastasis after extravasation of the tumor cells
the site of extravasation
the micro-environment they must be able to use up nutrients and angiogenesis.
factors that promote angiogenesis
VEGF
Fibroblast growth factor
epidermal growth factor
hepatocyte growth factor
platelet derived growth factor(mmemonic if vegf , fehp)
factors that do not favour angiogenesis
angiostatin
endostatin
prolactin
protein 53 that is p53
thrombospondin 1 and 2
rationale of angiogenic inducers
VEGF inducers run form A - D and placental
growth factor.
The VEGF inducers that bind on the VEGF receptors 1-3.
VEGF Receptors have to be phosphorylated to become activated.
angiogenic inhibitors
plasminogen when cleaved to form angiostatin.
Inhibitors help to regulate angiogenesis
* Plasminogen is cleaved to form angiostatin
* Endostatin blocks the MAPK pathway thus inhibiting gene expression
* Concomitant resistance - enabling growth in distant metastases
* Angiogenic switch is controlled by hypoxia
* Tumours create a hypoxic environment activating HIF1 alpha & beta
subunit triggering VEGF.
* Many drugs have been developed to inhibit angiogenesis eg TKI
Afatanib.
how is chemotherapy administered
orally and intravenously
what parts of cancer does chemotherapy target ?
targets the DNA , RNA and the proteins hence forcing the cells into apoptosis.
chemotherapy is specific to cancer cells ( yes or no )
no
method of delivery for chemotherapy
IV and oral preparations
and administered in cycles which are determined by the pharmacokinetics of the cells.
there could be a combination of chemotherapy drugs to increase the efficacy of the drugs.
types of chemotherapy
1.Alkylating agents and platinum drugs - form DNA adducts blocking DNA replication (all phases of cell cycle)- that is making the hydrogen bonds so strong that they cannot be separated for the DNA to undergo replication.
2. Antimetabolites - structurally mimic essential molecules( they are fake building blocks during DNA formation ) required for cell division (S phase of cell cycle).
3.Organic drugs - vinca alkaloids / taxanes / anthracyclines.
what is meant by neoadjuvant therapy ?
therapy before surgery to shrink the tumor
what is meant by adjuvant therapy
surgical treatment
palliative therapy
near death preventive therapy
how do organic chemotherapy drugs work e
- Vinca alkaloids - bind to tubulin and prevent
microtubule assembly - Taxanes - bins to beta tubulin subunit inhibiting
depolymerisation and disrupting mitotic spindle - Anthracyclines - microbial antibiotic targets
topoisomerase II
what are the sites of action for chemotherapy drugs
alkylating agents function in all of the phases of the cell cycle.
antimetabolites function in the s phase and the G2 phase.
vinca alkaloids are mitotic inhibitors on the m phase.
taxoids are also function on the m phase they are also mitotic spindle inhibitors.
mechanisms of action for antimetabolites
there is addition of methotrexate in the formation of purine nucleotides instead there is formation of thymidylate synthetase therefore the DNA is formed with weak building blocks.
what are the side effects of chemotherapy
alopecia - loss of hair
pulmonary fibrosis - formation of clots.
vomiting and nausea
diarrhoea
sterility
neuropathy
renal failure
local reaction
cardiotoxicity
examples of personalised systemic therapies
hormonal therapy
targeted therapy
immunotherapy
example of hormonal therapy
anti- oestrogen for breast cancer
how is breast cancer caused by increased oestrogen levels.
oestrogen hormone promotes cell division in the breast tissue.
increase in the cell division increases chances of contracting cancer in the cells.
oestrogen
also known as estradiol or esterone hormone
rationale for function of anti - breast cancer hormonal drugs
anti -oestrogen example is tamoxifen which binds to the oestrogen receptor.
aromatase inhibitors like letrozole which block the conversion of androgen to oestrogen.
what is targeted therapy
targeting specific molecules or receptors that promote the process of cell division .
types of targeted therapy
EGF receptor signalling pathway
tyrosine kinase inhibitors
example of EGF receptor cancer
breast cancer - her receptor
colorectal cancer.
tyrosine kinase inhibitors
1st generation - gefitinib and erlotinib - PFS 9.4 months vs Doublet
chemo 5.2 months4
* 2nd generation - afatanib - PFS 11.1months vs Doublet chemo
6.9months5
* 3rd generation - osimertinib - T790m exon 20 - treatment in EGFR
mutation positive metastatic NSCLC who received prior TKI treatment
what are the side effects of EGF receptors
Side effects: diarrhoea / dry skin / rash / hypertension /
liver dysfunction
cyclin dependent kinase 4/6 inhibitors
they block the progression of the cells through the cell cycle.
the cyclin D function
Cyclin D along with CDK 4/6 pushes cells out of G0 to G1 phase
* Cyclin D regulates cyclin E - pushes cells from G to S phase
what is immunotherapy
therapy that aims to make the immune system stronger in order to fight cancer.
examples of immunotherapy
immune checkpoints
therapeutic agents.
rationale of immune checkpoints
immune checkpoint aim is to ensure that there is self tolerance of the tumor cells.
however this checkpoint is switched off so that there is extreme response which will help to destroy the harsh cancer.
molecules involved in immune checkpoint inhibitors
Activated by receptor ligand
binding (PD-1 to PD-L1)
(CTLA-4 to B7)- they are all destroyed by the inhibitors so that there is increased T cell activity.
examples of therapeutic agents
pembrolizumab
therapeutic agents that work to activate the t cell and immune cells that have been switched off by the tumor.
They enable the T cell to continuously bind to the PD-L1 and PD-L2 receptors.
what is pembrolizumab
pembrolizumab is a type of targeted therapy drug called an immune checkpoint inhibitor (a type of immunotherapy). It is a monoclonal antibody that binds to the protein PD-1 on the surface of immune cells called T cells. It works by keeping cancer cells from suppressing the immune system. This allows the immune system to attack and kill the cancer cells.
side effects of immunotherapy
Colitis - most common - 30% develop diarrhoea of any grade and
10% have severe grade 3-4 in dual IO.10
* Pneumonitis - more common in PD-L1 treatment reference 11
* Hypophysitis/ Thyroid dysfunction/ Diabetes - 5-10% develop
endocrine adverse events reference 12
* Dermatitis - most frequent toxicity for PD-L1 and CTLA-4 11
* Hepatitis - occurs <5% 11
* Nephritis - <1 % 11
* Neurological <0.2%
