Cancer Biology & Medicine Flashcards
(76 cards)
1
Q
- Name the 14 hallmarks of cancer
A
Sustaining proliferative signalling
Evading growth suppression
Inducing angiogenesis
Activating invasion and metastasis
Enabling replicative immortality
Resisting cell death
Genomic instability/mutation
Avoiding immune destruction
Deregulating cellular metabolism
Tumour promoting inflammation
Unlocking phenotypic plasticity
Non-mutational epigenetic reprogramming
Polymorphic microbiomes
Senescence
2
Q
- Describe ‘selective toxicity’ in radiotherapy (2 points)
A
- Treatment designed to cause minimal damage to normal tissue, and maximal damage to tumour tissue
- Ideally tumour cells should not regenerate as quickly as normal tissue, but the reality is there is quicker shrinking of tumour tissue but not complete restoration of normal tissue in-between cycles
3
Q
- Name the factors that effect efficacy of radiotherapy (8 points)
A
[TONED CIG]
Type of radiation
Number of treatment fractions
Endpoint (i.e., tissue treated)
Oxygen (hypoxic tissue < well oxygenated)
DNA repair
Cell division (speed of)
Genomics (risk stratification - some are more susceptible to toxicities)
Immunology (radiotherapy ‘vaccine effect’)
4
Q
- Name the treatment intents of chemotherapy (4 points)
A
- radical: curative intent
- palliative: not curative intent; improve quality of life and symptoms
- adjuvant: reduces cancer risk after surgery (i.e., once there is no macroscopic, visible tumour left)
- neoadjuvant: before surgery, aims to shrink tumour; may make inoperable tumours operable
5
Q
- Why is IV administration preferred over oral for chemotherapy?
A
IV administration avoids first-pass metabolism and hepatic enzyme polymorphisms
6
Q
- Describe the standard length of chemotherapy treatment and why it is staggered over cycles (2 points)
A
- 21-28 day regimens, treatment lasting 4-12 months
- tumour response is affected by location of cells in the cell cycle. if a cell in G0/G1 progresses to S/M by the next chemo cycle it will be killed
7
Q
7a. Describe the mechanism of alkylating agents, along with metabolism, a drug example and side effect (4 points)
A
- mechanism: directly damages DNA by adding an alkyl group, causing distorted base pairing of C/T (e.g., a bulky adduct)
- metabolism: metabolised by liver, excreted by kidney
- drug example: temozolomide (TMZ), used to treat glioma (brain cancer) as it is BBB-penetrant
- side effect: haemorrhagic cystitis (protect patients with mesna)
8
Q
7b. Describe the mechanism of platinum agents, along with drug examples and side effects (3 points)
A
- mechanism: direct damage to DNA by adding platinum group. also inhibits thymidylate synthase, RNA synthesis, binding of transcription factors, and stimulates interferon gamma
- examples: carboplatin, cisplatin, oxaliplatin
- side effects: nephrotoxic (reduces potassium and magnesium); peripheral neuropathy, ototoxicity, nausea and vomiting
9
Q
7c. Describe the mechanism of action of anthracyclines, along with drug examples and side effects (3 points)
A
- mechanism: blocks enzymes in DNA replication, causes double stranded DNA breaks
- examples: doxorubicin, bleomycin (a glycopeptide)
- side effects: cough/wheeze (avoid in smokers), pulmonary fibrosis (grade 3 and 4 toxicities)
10
Q
7d. Describe the mechanism of action of taxane drugs, along with their metabolism, drug examples, and side effects (4 points)
A
- mechanism: inhibits formation of mitotic spindle. works in M phase of cell cycle by binding microtubules, causing mitotic arrest and DNA damage
- metabolism: metabolised in the liver, excreted by gut and kidney
- examples: paclitaxel and vinca alkaloids (vincristine, vinblastine)
- side effects: alopecia, peripheral neuropathy, myalgia, joint pain
11
Q
7e. Describe the general mechanism of anti-metabolite drugs, along with drug examples and side effects (3 points)
A
- mechanism: greatest activity in S phase, blocking DNA and RNA synthesis
- examples: methotrexate, 5-fluorouracil (5-FU), thioguanine, gemcitabine, hydroxyurea, 6-mercaptopurine
- side effects: thrombophlebitis, hand-foot syndrome, vein tracking, hepatotoxicity, nausea and vomiting, myelosuppression
12
Q
7f. Describe the mechanism of topoisomerase drugs, along with drug examples and side effects (3 points)
A
- mechanism: prevents DNA strand unwinding. trapping of the topoisomerase enzyme mid-replication causing supercoiling and DNA breaks (single and double strands)
- examples: irinotecan, camptothecin, etoposide, topotecan
- side effects: alopecia, anaemia, sepsis
13
Q
- Describe how Rous sarcoma virus (RSV) causes sarcoma in chickens (3 points)
A
- via the viral v-src (“v-sark”) gene, RSV transforms the c-src proto-oncogene into the src oncogene
- v-src has tyrosine kinase activity, converting viral RNA to DNA via reverse transcriptase
- viral DNA integrates at random. almost always, this provirus integration has no effect on the infected host cell, but on rare occasions the provirus integrates, by chance, next to the c-myc gene, converting it into a potent oncogene
14
Q
- Describe the mechanism of phosphorylation (2 points)
A
- kinases hydrolyse the gamma-phosphate from an ATP and transfers it to its target
- only three amino acids (serine, threonine, and tyrosine) may be phosphorylated due to their hydroxyl group
15
Q
- Give examples of tyrosine kinase receptors (RTKs). Describe how they may contribute to cancer development based on the mutant location (3 points)
A
- examples: MET, ROS1, EGFR, ALK, HER2, RET
- activating mutations of RTKs may contribute to cancers depending on the mutation location, e.g. outer region (glioma), middle (colorectal cancer), intracellular (NSCLC)
- as there are multiple cancer, signalling may occur through other RTKs, even if one is deactivated by cancer therapies
16
Q
- Describe the mechanism of ubiquitylation (3 points)
A
- Ub is transferred from E1, 2, and 3 proteins multiple times to a protein substrate (via a lysine or methionine residue)
- this forms a Ub chain on the protein
- the 26S proteosome recognises the Ub chain and degrades proteins via chymotrypsin, caspases and trypsin
17
Q
- Name the stages of the cell cycle, including their function, checkpoints, and associated proteins (4 points)
A
- G1 phase: growth of the cell. G1 checkpoint for cell size, nutrients, DNA damage, and growth factors. proteins: cyclin D/CDK6, 4; cyclin E/CDK2
- S phase: synthesis of DNA and RNA. S checkpoint: DNA damage and replication. protein: cyclin A/CDK2
- G2 phase: growth of the cell. G2 checkpoint: cell size, DNA replication. protein: cyclin A/CDK1
- M phase: division of the cell and DNA contents via mitosis. spindle assembly checkpoint: chromosome attachment. protein: cyclin B/CDK1
18
Q
- Describe the role of CDKs in the cell cycle (2 points)
A
- cyclin subunits bind CDKs. cyclins activate CDKs by releasing their active site
- CDKs release E2Fs from RB, allowing E2F to induce gene expression, growth and proliferation
19
Q
- Describe how cancer cells may drive tumorigenesis via the G1 checkpoint (7 points)
A
- amplifying genes coding cyclin D
- amplifying genes coding cyclin E and E2F
- prevent inhibitor binding of CDK4
- cause loss of CDK4/6 inhibitors by deleting INK4a genes
- loss of RB protein, allowing E2F signalling
- inactivation by viral proteins (e.g., E7 protein of HPV)
- increase degradation of tumour suppressors (e.g., p27)
20
Q
- Define haploinsufficiency and loss of heterozygosity (LOH)
A
- haploinsufficiency: loss of one copy of a gene, sufficient to permit development of a disease
- loss of heterozygosity (LOH): the events leading to loss of one copy of a gene (haploinsufficiency), such as duplication of mutation, gene deletion, and chromosome alteration or loss
21
Q
- Describe the activation and main function of p53 and its associated cancer syndrome (3 points) [see also card 36]
A
- p53 (‘guardian of the genome’) acts mainly as a transcription factor. it is short lived but is stabilised upon stress such as DNA damage, ionising radiation, hypoxia/ROS etc.
- p53 may arrest the cell cycle temporarily or permanently via the cell cycle checkpoints
- cancer syndrome: Li-Fraumeni syndrome. lifetime cancer risks of 75% in men, 100% in women
22
Q
- Describe the relationship between p53 and MDM2 [see also card 36]
A
- p53 and MDM2 operate within a negative feedback loop
- p53 stimulates transcription of MDM2 (an E3 ubiquitin ligase) which ultimately degrades p53, meaning p53 is a short-lived protein with fast turnover kinetics
- MDM2 can be inhibited by e.g. ATM, ATR, CHK1, p38 to stabilise p53
23
Q
- Describe the relationship between hypoxia inducible factors (HIFs) and pVHL, and how this may lead to cancer development (4 points) [see also card 35]
A
- pVHL is stabilised upon binding another protein (VBP1, name irrelevant), meaning it avoids degradation
- when stabilised, pVHL binds HIFs and causes their degradation
- when not bound to pVHL, HIFs stimulate gene transcription and EMT (epithelial-mesenchymal transition) by binding VEGF
- cancer cells can stimulate HIF transcription by mutating pVHL or by causing hypoxia (increasing levels of HIFs)
24
Q
- Define aneuploidy and describe how it arises (2 points)
A
- aneuploidy: the presence of abnormal number of chromosomes in a cell (e.g., a human cell with 45 or 47 chromosomes instead of the usual 46)
- errors in mitosis mean duplicated chromosomes fail to segregate properly
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20a. Name and describe the four stages of mitosis (4 points)
- prophase: nucleus still present, chromosomes condense and become visible
- metaphase: chromosomes line up in the middle of the cell
- anaphase: the chromatids break apart and move away to the cell periphery via spindle fibres
- telophase: two new nuclei form and the cell splits via cytokinesis
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20b. Describe the process of prometaphase within mitosis (5 points)
- mitotic tubules project towards chromosomes and stabilise, if they attach to the chromosomal kinetochore
- tubule stabilisation is dependent on the cyclin B/CDK1 complex. this complex keeps seperase bound to securin, preventing isolated seperase separating chromosomes
- kinetochores inhibit APC (anaphase promotor complex) when unattached to tubules
- APC causes the degradation of securin from seperase. seperase then separates chromosomes in metaphase
- Aurora B, adjacent to the kinetochore, phosphorylates substances (adding a negative charge), ensuring only one tubule attaches to a kinetochore
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20c. Describe the four regulatory mechanisms that safeguard against chromosomal instability in prometaphase (3 points)
- mitotic checkpoint: unattached kinetochores produce a mitotic checkpoint complex (MCC), which inhibits APC, and causes mitotic exit
- error correction: aurora B kinase phosphorylates nearby kinetochores, causing removal of incorrect microtubule attachment
- cohesin complex: this complex holds sister chromatids together. it is cleaved at anaphase to allow chromosome segregation.
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20d. Describe the main consequences of incorrect mitosis (3 points)
- tetraploidy (a form of aneuploidy). occurs due to failed cytokinesis. this means cells have four copies of chromosomes instead of the normal two. double the amount of DNA can directly induce errors in mitosis
- chromothripsis. this is a mutational process by which thousands of clustered chromosomal arrangements occur in a single catastrophic event in a localised genomic region. also produces extra-chromosomal DNA circles (ecDNA, 'double minutes')
- dicentrics: chromosomes that contain 2 centromeres.
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21. Name the main types of gene-level and chromosome-level mutations (1+4 points)
- gene-level: amplification, deletion
- chromosome-level changes are numerical, structural, arm-level changes, and complex
-- numerical: monosomy, trisomy
-- structural: translocation, inversion, tandem duplication, dispersed duplication, deletion, insertion)
-- arm-level changes (gain or loss of arm)
-- complex types (chromosomal rearrangements, chromothripsis)
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22. Describe how aneuploidy leads to proteotoxic stress (3 points)
- varying chromosome levels leads to unbalanced protein expression
- unstable proteins must be constantly chaperoned and degraded
- constant degradation of proteins leads to proteotoxic stress
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23. Describe how aneuploidy links to inflammation and senescence (5 points)
- aneuploidy induces DNA replication stress and DNA damage
- this leads to DNA contained in a micronucleus (a nucleus that does not have a surrounding nuclear envelope)
- DNA in contact with the cytoplasm (i.e., in a micronucleus) activates the cGAS pathway; the cGAS pathway is typically activated for e.g. viral DNA
- aneuploidy may permanently exit the cell from the cell cycle and trigger the SASP
- the SASP also leads to chronic inflammation
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24. Describe the mechanism of KRAS oncogene (4 points)
- KRAS proto-oncogene mutation (valine to glycine) converts it into an oncogene
- inactive KRAS is bound to GDP. GEF hydrolyses the GDP to GTP and activates KRAS
- GAP hydrolyses GTP back to GDP and inactivates KRAS
- oncogenic block of hydrolysis of GTP to GDP causes KRAS to be constitutively activated (e.g., it is always 'on' and is never turned 'off')
33
25. Describes the function of 53BP1 (53 binding protein 1), gamma-H2AX, and ATM/ATR kinases (4 points)
- 53BP1 binds selectively to DNA breaks
- H2AX phosphorylates to gamma-H2AX at DNA breaks
- ATM and ATK kinases are then recruited to sites of DNA breakage, where they phosphorylate downstream regulators of the cell cycle Chk2 and Chk1 respectively.
- thus, 53BP1 and y-H2AX recruit ATM and ATK and are interdependent
34
26. Describe how stalled forks arise in cancer (5 points)
- oncogene expression shortens the length of the cell cycle (particularly G1)
- origins of DNA replication are normally located out-with transcription genes, but shortening of G1 means origins of DNA replication fire within RNA transcription windows
- thus DNA polymerase and RNA polymerase collide (co-directional or head-on), causing a stalled fork
- stalled forks cause DNA to collapse
- stalled forks may also create R loops, creating an RNA-DNA hybrid, which increases the number of collisions that occur
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27a. Name the main types of reactive oxygen species (ROS) (6 points)
- superoxide (O2*-)
- hydroxyl radical (*OH)
- ozone (O3)
- singlet oxygen (1-O2)
- hydrogen peroxide (H2O2)
- peroxide (O2^2-)
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27b. Describe how hydrogen peroxide (H2O2) regulates biological redox (2 points)
- oxidative eustress: intracellular H2O2 concentration is low and promotes proliferation, differentiation, migration, and angiogenesis [PMAD]
- oxidative distress: high intracellular H2O2 and promotes stress responses (inflammation, fibrogenesis, tumour growth, metastasis, growth arrest, cell death)
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27c. Describe how redox homeostasis links to glycolysis (3 points)
- unstressed cells: NAPDH is generated within normal metabolism and prevents entry to the pentose phosphate pathway (PPP); it does this by inhibiting the G6PD enzyme (glutathione metabolism)
- oxidative stress: there is no inhibition of the G6PD enzyme and there is shunting into the PPP
- ROSs inhibit ATM, PTEN, and mitochondrial complexes, reducing oxidative phosphorylation
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28a. Describe the NRF2 'floodgate' in relation to oxidative stress (2 points)
- in moderate oxidative stress, low concentrations of ROSs trigger NRF2, which acts alone to protect against oxidative damage
- in high oxidative stress, NRF2 defences are overwhelmed (or shut down by KLF9), allowing activation of other ROS-responsive transcription factors
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29b. Describe the functions of NRF2 in oxidative stress and how it relates to KEAP1 (3 points)
- pharmacologic activation of NRF2 protects against cancer, and its deficiency increases susceptibility to carcinogens
- excess activation may promote survival, growth, and resistance to therapy in cancer
- loss of KEAP1 stabilises NRF2 and allows NRF2 to promote tumorigenesis
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30. Describe glutamine/glutamate synthesis and metabolism (5 points)
- glutamine is converted to glutamate (by SLC1A5), and glutamate is converted to glutathione (GSH) (by the glutaminase/GLS enzyme)
- conversion of glutamate to glutathione (GSH) by glutaminase (GLS) is the rate-limiting step
- xCT is a transmembrane transporter which exchanges glutamate for cysteine (glutamate out, cysteine in) to increase cellular cysteine
- removal of glutamate by xCT means cancer cells are reliant on glutaminase (GLS) to produce glutathione for fatty acids and the Krebs cycle
- thus, cancer cells are sensitive to glutaminase (GLS) inhibitors
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31. Describe the Walberg effect (4 points)
- the Walberg effect is the observation that cancer cells produce energy through 'aerobic glycolysis', unlike normal cells, which produce energy through oxidative phosphorylation
- lactic acid fermentation (pyruvate, the end product of glycolysis, is converted to lactate instead of entering the Krebs cycle) takes place in the cytoplasm. lactate is then removed by the MCT transporter
- cancer cells thus burn through very high amounts of glucose
- glucose uptake is increased by upregulating PI3K/PTEN, AKT, and glucose transporters (e.g., GLUT1)
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32a. Describe how glycolysis uncouples from oxidative phosphorylation, and instead couples to biosynthesis (4 points)
- the pentose phosphate pathway (PPP) produces NADPH and ribose-5-P (used in DNA synthesis)
- hexosamine creates N-acetylglucosamine (used in post-translational modifications)
- the DHAP shuttle produces G3P (glycerol-3-phosphate) (used in phospholipid cell membranes)
- 3-phosphoglycerate (used as a precursor for serine and glycine amino acids)
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32b. What is the use of the high production of glutamine in cancer cells? (3 points)
- glutamine is a key nitrogen source
- nitrogen is required for nucleotide synthesis (purines and pyrimidines) an non-essential amino acids
- often the rate limiting step in cell cycle progression, as glutamine only has one usable nitrogen per molecule
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32c. Why do cancer cells upregulate the amount of asparagine they produce? (3 points)
- some cancer therapies remove glutamine from their cells
- removal of glutamine from cancer cells causes their apoptosis (the basis of the therapy)
- production of asparagine does not replace nitrogen or carbon metabolism, but prevents cancer cell apoptosis (thus is a form of acquired resistance)
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33. Define cell scavenging and the five main methods (6 points)
- scavenging: the mechanism which enables cancer cells to metabolise dead cell debris for nourishment
-- micropinocytosis: RAS/c-SRC remodel cancer cells to capture extracellular macromolecules
-- entosis of living cells (also driven by RAS)
-- phagocytosis of dead cells
-- lysophospholipid uptake (when fatty acid synthesis is repressed by hypoxia)
-- macroautophagy: an autophagosome takes in cellular organelles. this fuses with a lysosome (to form an autophagolysosome) and recycles organelles into nutrients
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34. Describe the integrated stress response (ISR) (3 points)
- short-term, the ISR causes selective expression of pro-survival genes.
- long-term, the ISR activates CHOP and apoptosis. cancer cells evade CHOP via an unknown mechanism
- four kinases are involved: GCN2 (amino acid starvation), PERK (protein misfolding stress), HRI (haem/iron starvation), and PKR (dsRNA/viral infection)
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35a. Describe the 'angiogenic switch' (4 points) [see also card 18]
- angiogenic switch: the point where the number or activity of pro-angiogenic factors exceeds that of the anti-angiogenic factors
- as angiogenesis can be discerned in premalignant lesions, it is thought to be an early-mid stage event in many human cancers
- anti-angiogenic factors include p53 and thrombospondin-1 (which binds CD36; these factors are linked), VHL, and angiostatin (a metabolite of plasmin)
- pro-angiogenic factors include RAS, proteases, VEGF, and plasmin
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35b. Describe anti-angiogenic therapies (3 points)
- anti-VEGF therapies come in two main types, including monoclonal antibodies (bevacizumab, aka Avastin) and tyrosine kinase inhibitors (e.g., sunitinib)
- benefits of anti-VEGF therapy are, at best, transitory and are followed by restoration of tumour growth and progression
- Avastin is used in glioma therapy, as it is blood-brain barrier (BBB) penetrant and there are very few other therapies for glioma
49
36a. Describe the genomic location of p53 and the basics of its splicing (4 points) [see also cards 16 & 17]
- p53 is located on chromosome 17
- there are two promotors within the p53 gene, meaning it can be read in different ways, which can produce 9 mRNAs
- the 9 mRNAs can be modified to produce 12 total p53 isoforms, which are expressed in normal human tissues in a tissue-dependent manner
- [cancer cell invasion is driven through the delta 133p53-beta variant - do not need to know this]
- intracellular and extracellular signals (such as glucose, cell signalling, infection, oxidation etc.) influence the post-translational modifications that p53 can undergo and thus the isoforms that are produced
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36b. Describe the main functions of p53 (6 points)
- inflammation, ageing
- CNS development
- tissue regeneration
- growth arrest, apoptosis, cell repair
- blocks angiogenesis
- metabolism (prevents Walberg effect)
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36c. Describe how the E6 and E7 oncoproteins of HPV influence tumour suppression (2 points)
- E6 degrades p53 causing cellular proliferation (e.g., in the form of a wart or cancer) and preventing senescence and apoptosis
- E7 inhibits RB, allowing progression of the cell cycle by freeing E2F
52
37. Define metastasis and its five major steps
- metastasis: the process by which a tumour cell leaves a primary tumour, travels to a distant site via the circulatory system, and establishes a secondary tumour. it causes 90% of cancer deaths
1. invasion and infiltration of surrounding host tissue, lymphatic or vascular channels
2. release of neoplastic cells into circulation
3. survival in the circulation
4. arrest in capillary beds of distant organs
5. penetration of the lymphatic or blood vessel walls followed by growth and colonisation of the disseminated tumour cells
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38. Describe the process of EMT (epithelial-mesenchymal transition) (4 points)
- normally epithelial cells become mesenchymal, allowing movement of cancer cells
- epithelial cells have polarity, are adherent (to each other and the extracellular matrix), have high E-cadherin and low N-cadherin
- mesenchymal cells have no polarity, no adhesion, are able to migrate and invade, have low E-cadherin and high N-cadherin
- the mesenchymal phenotype increases levels of metallomatrix proteinases (MMPs), degrading the basement membrane and allowing invasion
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39. Describe how a metastasising cancer cell leaves the bloodstream and enters a secondary organ (5 points)
- cancer cells bind to surface receptors such as CXCR4 and 7
- stromal cells release growth factors and chemokines, which contribute to cancer cell adhesion and motility
- Rho proteins regulate cell shape and motility:
-- Rho: forms stress fibres
-- Rac: forms lamellipodia
-- Cdc42: forms filopodia
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40. Describe the concept of metastatic organotropism (3 points)
- organ selectivity of metastases
- theories include mechanistic (pattern of blood flow), and seed and soil (fertile environment in which compatible tumour cells can grow)
- factors include growth factors, compatible adhesion sites, and selective chemotaxis
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41a. Describe phase I and II metabolism (4 points)
- phase I products (which are lipophilic/hydrophobic) are metabolised by enzymes to make them more lipophobic/hydrophilic, making it easier to excrete them
- phase I is controlled mainly by the cytochrome P450 superfamily, which introduce reactive or polar groups to molecules
- phase II reactions include glutathione (GSH) conjugation, sulphation, acetylation, and glucuronidation
- excretion then occurs by phase III efflux pumps
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41b. Describe how diet links to phase II metabolism and cancer chemoprevention (4 points)
- cruciferous vegetables contain a family of acetonitrile phytochemicals (glucosinolates). common sources include green cabbage, cauliflower, kale, and broccoli
- these phytochemicals induce phase II metabolism enzymes
- sulforaphane, the principle phase II inducer from broccoli, targets multiple agents, including KEAP1/NRF2 and STAT3
- biologic effects are strongly dependent on dose
58
42. Name the primary factors considered when personalising medicine in cancer (5 points)
[DR MEG]
- drugs (metabolism, pharmacokinetics and -dynamics, polypharmacy)
- ethnicity (differences in polymorphisms)
- tumour genotype (mutations, amplifications, deletions, rearrangements)
- tumour microenvironment (stromal interaction, immune system)
- regulation (signalling, transcription factors, epigenetic changes)
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43. Name the drugs used out-with the usual empirical approach in cancer
- tamoxifen (ER+ve cancers)
- herceptin (HER2+ve cancers)
- imatinib (aka Glivec, Philadelphia chromosome)
- 6-mercaptopurine (TMPT genotype)
- PARP inhibitors (BRCA1/2 mutation)
- cetuximab (EGFR mutant)
- vemurafenib (V600E mutations in melanoma)
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44. Describe how patient factors can influence treatment with tamoxifen (3 points)
- tamoxifen is a SERM, and a 'prodrug' of endoxifen, which is 10x more potent than tamoxifen
- the CYP2D6 enzyme converts tamoxifen into endoxifen
- thus, patient polymorphisms affect the processing capability of tamoxifen. in 10% of Caucasians, the enzyme is reduced, and in 2% of Scandinavians, the enzyme is elevated
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45a. Describe the Darwinian selection pressures exhibit (3 points)
- tumour cells remaining after therapy reproduce and repopulate (clonal selection)
- this population of cells is resistant to the initial therapy and thus this therapy cannot be used again
- additional acquired mutations provide additional positive selection pressures on cancer populations
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45b. Describe patient factors that can influence tumour resistance to chemotherapy (2 points)
- toxicity of normal tissues (and patient factors that influence toxicity experienced)
- pharmacokinetic effects (ADME) limit the amount of drug that reach the tumour; patient variability mean drug concentrations are variable (e.g., low distribution, high elimination)
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45c. Describe how cancer cells may confer resistance to therapy
- general methods:
-- increase efflux and reduce influx,
-- inactivate drugs,
-- alter drug targets (modify target structure to prevent binding, increase amount of target),
-- upregulate survival pathways, dysfunctional apoptosis
- intrinsic resistance: cancer cells are resistant prior to therapy
- extrinsic resistance: disease progression after an initial response to therapy; this happens when tumours that were initially sensitive stop responding to therapy
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45d. Describe the three main methods of extrinsic resistance
- target modification: amplification of target gene, second site mutation within target gene, alternative splicing of target gene
- bypass signalling: activation of compensatory loops to circumvent the inhibited target
- histologic transformation: cancer changes its phenotype (e.g., SCLC -> NSCLC, EMT)
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46a. Describe how immunotherapy works (3 points)
- PD-1 (T cell) and PD-L1 (tumour cell) [programmed death/ligand] interaction 'hides' cancer cells
- cancer cells thus upregulate the amount of PD-L1 they express
- antibodies (e.g., Nivolumab) that block these interaction can therefore enable T cell killing of cancer cells
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46b. Describe how cancer cells may be resistant to immunotherapy (2 points)
- intrinsic resistance:
-- absence of antigenic proteins, or presentation;
-- genetic T cell exclusion (MAPK, EMT etc.),
-- insensibility to T cells (interferon gamma signalling)
- extrinsic resistance:
-- absence of T cells,
-- inhibitory immune checkpoints,
-- immunosuppressive cells
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47. Describe the relationship between the MGMT gene and the alkylating agent temozolomide (TMZ) (4 points)
- the MGMT gene encodes a DNA damage repair protein that removes alkylating agents, resulting in resistance to chemotherapy
- tumours upregulating MGMT will be more resistant to therapies
- personalised medicine means identifying the patients who have lower levels of MGMT and treating them with TMZ
- inhibition of MGMT does work but exhibits bone marrow toxicity and myelosuppression, and thus is of little clinical benefit
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48a. Define synthetic lethality (1 point)
- in two overlapping genes, one is knocked out by a mutation. knocking out the remaining functioning gene results in synthetic lethality and death of the cell
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48b. Describe the synthetic lethality between BRCA and PARP (3 points)
- BRCA and PARP are DNA repair genes, which repair DNA damage by homologous recombination (HR) and base excision repair (BER) respectively
- BRCA mutations are present in many breast and ovarian cancers, meaning these cancers rely on PARP to repair their DNA damage (as BRCA has been knocked out)
- knocking out PARP in BRCA mutated cells therefore means there are no DNA repair mechanisms in these cells and results in the death of these cells
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48c. Describe the potency of PARP inhibitors (3 points)
- different PARP inhibitors have different potencies while inhibiting PARylation to the same degree
- varying potency is due to PARP trapping - different amounts of PARP stick to chromatin - the more PARP inhibitor stuck to DNA, the more efficacious the inhibitor
- this is not just inhibition of a pathway, but DNA damage itself by causing a covalent adduct of the PARP inhibitor
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48d. Describe how cancer cells may display resistance to PARP inhibitors (5 points)
general
-- increased efflux (upregulates ABC transporters)
-- decreased PARP trapping
genetics
-- restoration of homologous recombination (HR; e.g., by bypass pathways or reactivation of BRCA)
-- competing activities (e.g., MGMT and TMZ)
-- stabilisation of stalled forks
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49. Describe the biochemistry of kinase inhibitors and the 'gatekeeper residue' (3 points)
- kinase inhibitors may be ATP-competitive, covalent, allosteric, or 'mixed'
- the main type, the ATP-competitive type, competitively binds the ATP site of kinases to prevent ATP binding
- the gatekeeper residue controls binding of molecules to the ATP site. if it is a small amino acid (e.g., threonine), an inhibitor may easily bind. if larger (e.g., methionine), the drug exhibits a steric clash and therefore cannot bind
73
50. Describe the history and biochemistry of EGFR tyrosine kinase inhibitors (6 points)
- EGFR is upregulated in non-small cell lung cancer (NSCLC)
- the first developed inhibitors, including gefitinib, improve survival but relapse eventually occurs
- relapse occurs when the getekeeper residue of EGFR, T790, undergoes an amino acid mutation (threonine to methionine), bumping the inhibitor due to steric clash
- afatanib was developed, which binds cysteine in T790. however, there is little selectivity between mutant and wild type EGFR, meaning much higher toxicity
- Osimertib was developed, which kept cysteine binding but moved away from methionine preventing steric clash; resistance develops when cysteine mutates to serine
- no futher available therapy at this time
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51. Define the terms 'stem cell' and 'potency' (2 points)
- stem cells: cells which can self-renew and differentiate (e.g., change into another cell type, often meaning a change in cell function and morphology)
- potency: the repertoire of future fates (e.g., what a stem cell can become; totipotent means a cell can become anything, nullipotent means stuck in current cell type)
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52. Describe the characteristics of embryonic and adult (aka somatic) stem cells (2 points)
- embryonic stem cells come from the pluripotent compartment of the blastocyst and are immortal, meaning they do not undergo senescence
- adult/somatic stem cell populations vary within the body (for example, very low in bone marrow, very high in the gut) and most divide asymmetrically (a stem cell and a specialised cell)
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53. Describe the two main theories explaining clonal heterogeneity
