Cancer 2 Flashcards
What are the four stages of developing a cancer drug?
Drug discovery
Drug development
Clinical trials
Drug marketing
Why does a drug usually not work?
Disease isn’t well understood
Pick the wrong target
List four reasons for genetic damage
Inherited mutations
Somatic/acquired mutations
Environmental
Spontaneous
What is vogelstein’s cascade?
Molecular model of the proposed evolution of a colorectal cancer through benign adenoma-carcinoma sequence
T/F:
To get a late benign adenoma (sessile polyp) in Vogelstein’s cascade, there is a mutation in p53
False
There is a mutation in DCC and ras gene
(mutation in p53 gives a colonic carcinoma)
T/F:
Cancer is heterogenous
True
What is a glioma?
Tumour derived from a glial cell
What happens when oncogenes are activated?
Self-sufficiency in growth signals
What happens when you activate bcl-2 and inactivate p53?
Evasion of apoptosis
What happens when you over express proteases?
Have the ability to invade tissues/metastasise
What is the first hallmark of cancer?
Sustaining proliferative signaling
What is a proto-oncogene?
Normal cellular genes whose products promote cell proliferation
What is an oncogene?
Mutated/overexpressed proto-oncogene promoting autonomous cell growth
T/F:
Too much growth factors is enough to cause a neoplasmic transformation
False
But does increase the risk of mutation in proliferating cells
What happens when a cell over-expresses a growth factor?
Secretes too much of it
Feeds back onto itself= autocrine
(not a major problem)
What is the EGFR family and what type of abnormal activity is it associated with? What type of cancer is associated with it?
Growth factor receptor
Mutated/amplified
Often associated with glioblastoma, lung cancer and breast cancer
What is Ras?
Signal transducing g protein
How is ras activated?
Receptor tyrosine kinase is activated by a growth factor
This leads to the exchange of GDP for GTP
Ras is activated
How do GTPase activating proteins (GAPs) affect Ras?
Binds to Ras, augments its GTPase activity, terminates signal transduction, prevents uncontrolled Ras activity
What two things does Ras activate?
Braf and PI3K/AKT arms of the RTK pathways
activates kinases
T/F:
15-20% of cancers express a mutated Ras protein
True
Really common mutation in cancers
Mutations in Ras often introduce amino acid substitutions at positions 12, 13 and 61. What do these mutations normally target??
They make Ras resistant to GTPase activating proteins (GAPs)
Ras accumulates in the active GTP- bound conformation (constantly active)
T/F:
Mutations in BRAF often affect the catalytic domain and result in increased catalytic activity
False
This is true for mutations in PI3K
BRAF= glutamic acid is substitued for valine at amino acid 600, mimics phosphrylation of the activation loop and induces constitutive BRAF protein kinase activity
What is the role of transcription factors?
Bind specifically to DNA regulatory elements to stimulate or repress transcription within the nucleus
T/F:
MYC transcription factor when mutated in commonly involved in tumour growth
True
What happens when MYC is overexpressed?
activate the expression of many genes that are involved in cell growth
Explain what the ABLE-BCR chimera is and how it is formed
ABL gene is translocated from its normal place at chromosome 9 to chromosome 22
It forms a hybrid with BCR (Breakpoint cluster region) Gene
ABL-BCR complex encodes for a ABL-BCR kinase that is very active
Also known as philadelphia chromosome
Occurs in Chronic Myeloid Leykemia and Acute Lymphoblastic Leukemia
How do they often block chronic myeloid leukemia (CML) cells?
They require ABL-BCR tyrosine kinase to survive
Inhibit this and you can stop the CML cells
Resistance is common
What are janus kinases?
Located on the cytoplasmic surface of the cell membrane, no cell receptor element
What is JAK2?
Tyrosine kinase that engages with cytokine receptors, becomes active, results in proliferation
What type of neoplasm are JAK2 mutations often associated with?
Myelo-proliferative neoplasms (MPNs)
Mutations result in cytokine independent proliferation and survival of tumour cells
What regulates the cell cycle?
Cyclins and cyclin-dependent kinases (CDKs)
What stage of the cell cycle are most cells arrested in and what is the next stage?
Mostly arrested in the G1 phase
Progress to the S phase
Once they get to the S phase they must complete the cycle (therefore proliferate)
What is the second hallmark of cancer?
Evading tumour suppression
What genes are mutated that lead to the second hallmark of cancer?
Tumour suppressor genes
What happens if you introduce an oncogene into a cell that lacks a tumour suppressor gene?
Uncontrolled proliferation (tumour suppressor genes stop proliferation)
List three ways tumour suppressor genes/proteins work
Block uncontrolled proliferation
Active growth-inhibitory pathways leading to apoptosis
Induce cell differentiation causing cells to enter a pot-mitotic stage without replicative potential
T/F:
Usually one inactive allele is required to cause a mutation in a tumour suppressor gene
False
Usually need both alleles
First is inherited and the second is a somatic mutation in susceptible tissue
What occurs at the G2/M stage of the cell cycle?
Determine the integrity of the DNA and decide whether or not to proliferate or die
T/F:
Hyperphosphorylated Rb inhibits transcription of S genes
False
Hypophosphorylated Rb does this
What do growth inhibitors stimulate?
CDK inhibitors e.g. p16
What do CDK inhibitors do?
Inactivate cyclins
What do inactive cyclins do to Rb?
Keep it hypophosphorylated
Rb reamins in the EF2 complex and S genes can’t be transcribed
In cancer, often ___ is deleted which encodes ____. This results in CDK kinase being ______ and Rb is ________.
In cancer, often CDN2A is deleted which encodes p16. This results in CDK kinase being activated and Rb is hyperphosphorylated (inactive)
E2F is then released
Cells move into S phase
What two key tumour suppressor genes does Human Papilloma Virus inactivate?
Rb (viral E7 inactivates it)
p53 (viral E6 inactivates it)
What two things does CDKN2A encode?
p16 (cyclin inhibitor) and p14 (activates p53)
What happens when CDKN2A gene is mutated?
Silences p16 and p14
Cyclins can become active and hyperphosphorylate Rb, S phase begins
no p53= no apoptosis
What is neurofibromin-1? (NF-1)
GTPase-activating protein (GAP)
Increases the GTPas rate of G proteins
T/F:
NF-1 activates Ras
False
Inactivates ras, negative regulator
If you increase the GTPase activity of Ras, Ras ______ quicker
Inactivates
What is the role of neurofibromic-2 (NF2)?
Codes for neurofibromin-2/merlin
This is a cytoskeletal protein that links actin filaments to the membrane in nervous tissue
What happens to cells when you don’t have merlin?
Can’t make cell to cell junctions, insensitive to normal growth arrest signals
What is APC and what does it down regulate?
Tumour suppressor
Down regulates growth promoting Beta catenin
What type of cancer is associated with mutations in APC
Colon cancer
What does beta catenin do??
Normally is destructed by APC and is involved in cell-cell adhesion (with E cadherin)
When it is mutated, it cant be destructed by APC and cell-cell contact inhibition is stopped
What does Wnt signalling do in terms of APC and Beta catenin??
Wnt releases beta catenin from APC complex
Beta can then go to the nucleus and active transcription of the cell-cycle progression genes
What does APC stand for?
Adenomatous polyposis coli
What happens when E-cadherin is lost?
Cells aren’t attached to each other and can invade other tissues
What is the 3rd hallmark of cancer?
Genomic instability
What is the physiological function of BRCA1 and BRCA2?
DNA repair via homologous recombination or they destroy cells if the DNA damage can’t be repaired
T/F:
In healthy cells, p53 is detectable
False
normally inhibited by MDM2
What two mechanisms stop inhibition of p53 by MDM2?
- DNA damage/hypoxia activates ATM/ATR, ATM/ATR phosphorylate p53 and MDM2, p53 is activated
- Oncogenic stress leads to MAPK and PI3K/AKT signalling, this increases expression of p14/ARF, p14/ARF can bind to MDM2 and displace p53
Explain transient p53-induced cell cycle arrest
p53 dependent transcription of CDK1A gene= this encodes p21
p21 inhibits cyclin D-CDK4
Rb is maintained in active hypophosphorylated state
Progression from G1 phase to S phase is stopped and cell can repair the dna damage and return to normal
Explain p53-induced sensescence
Senscent cells are metabolically active but not proliferating therefore the tumor can’t grow
What is the 4th hallmark of cancer?
Evasion of apoptosis
T/F:
BAX and BAK are pro-survival
False
They are pro-apoptotic
T/F:
BCL-2, BCL-X and MCL-1 are pro survival
True
What is the role of BH3-only proteins?
These inhibit the pro-survival proteins and therefore active the pro-apoptotic proteins
What do BAX and BAK do?
They disrupt the mitochondrial membrane
Both cytochrome C and SMAC are released from the mitochondria
What is XIAP?
Caspase inhibitor
What does BCL-2 protein do?
Prevents apoptosis and programmed cell death
What is the 5th hallmark of cancer?
Replicative immortality
evasion of sensecence
What happens when telomeres reach a certain point?
Chromosomes undergo end-to-end fusion and cell death occurs by apoptosis
What is the role of telomerase?
Repairs telomeres by adding nucleotide repeats to the ends of chromosomal DNAs to compensate for these losses
Cellular immortalizing enzyme
What are the 5 ways cancer genes can be activated?
Point mutations
Chromosomal translocation
Activation by gene amplification
Epigenetic changes miRNA
T/F:
Chemotherapeutic agents are non-specific
True
What do chemotherapeutic agents target?
They damage dna
T/F:
There are more side effects when using molecularly targeted therapy in comparison to chemotherapy
False
Chemo has more side effects because it is less specific
What is target validation?
Understanding of the target’s function in disease
What is druggability?
Describes a biological target that is known to bind with high affinity to a drug
T/F:
Enzymes are non-druggable
False
Druggable
Distinguish between a kinase and a phosphotase
Kinase= catalyzes the transfer of a phosphate group Phosphotase= catalyzes the removal of a phosphate group
What does Vemurabenib inhibit?
BRAF
