Targeted Therapies and Immunotherapy Flashcards

Question

why is a p53 mutation different to other cancer mutations

Answer 1

in most cancer mutations only a certain area of the gene is mutated (the area that is active) but in p53 mutation the mutations are spread out all across the gene

Answer 2

-drugging strategy is to change the mutant conformation back to WT conformation to reactivate the WT p53 tumour suppressor function -APR246 is the most advanced p53 reactivator -WT p53 can also be used as a therapeutic strategy by inhibiting MDM2 binding as MDM2 increases the degradation of p53 thus there will be an increase in p53 protein levels which is good as they will have tumour suppressor action

Answer 3

-an oncogene that is mutated in about 25% of all cancers -KRAS encodes a protein called K-Ras which when mutated contributes to the development of cancer through pathways that promote growth, proliferation, and differentiation -mechanism of action of KRAS involve cycling of active and inactive state, active when bound to GTP and inactive when bound to GDP -treating KRAS mutations is difficult as mutations often keep it in its active stage but we want it locked in its inactive state to be targeted by drugs

Answer 4

-KRAS mutations common in pancreatic, colorectal, and non-small cell lung cancers -KRAS mutants are hard to treat because they cycle between active and inactive states and also because of the small size of K-Ras and its lack of binding sites

Answer 5

-sotorasib, first KRAS mutant inhibitor approved, used in targeting KRAS in non-small cell lung cancer (trialled for use in other KRAS cancers), covalent inhibitor so binds irreversibly to KRAS -adagrasib, later approved KRAS mutant inhibitor, used in targeting KRAS in non-small cell lung cancer (trialled for use in other KRAS cancers), covalent inhibitor so binds irreversibly to KRAS

Answer 6

-new pan-KRAS mutant inhibitors and KRAS-SOS1/SHP2 disrupters -both are non-covalent inhibitors so give a more generalised response probably with more side effects

Answer 7

-luminal A -normal like -luminal B -HER2 enriched -triple negative (within triple negative there are 11 more different subtypes which are currently trying to be characterised

Answer 8

22 HER altered cell lines across cancer types such as colorectal and ovarian as well as breast

Answer 9

-by destroying viruses that are known to transform cells -by eliminating pathogens to reduce pro-tumour inflammation as 20% of cancers are now thought to be associated with microbial infection -by identifying and destroying cancerous cells which is mediated by immune 'killer' cells

Answer 10

-M2 macrophages -myeloid derived suppressor cells (MDSCs) -Th2 cells -Treg cells (which calm down the would-be helpful immune response to cancer)

Answer 11

-cross-presenting APCs -NK cells -Th1 (which is more beneficial than Th2) -CD8+ CTL response

Answer 12

-loss of Tumour Ag -loss of MHC I or NKG2D -loss of IFNg responsiveness (pathway defects) -inhibition of DC maturation/function -loss of costimulatory molecules such as increasing CTLA4 -increase Treg activity which dampens down other T cells -MDSC -immunomodulatory molecules such as IL10 which dampens immune response -cancer cells use checkpoints to dampen the immune response

Answer 13

tumour-specific antigens and tumour-associated antigens

Answer 14

-they occur only in neoplastic cells, they are not expressed by normal cells at any site or stage of development -they are recognised as non-self by CD8+ CTLs -they include mutated cellular proteins such as mutant p53 and antigen processing leads to expression of novel peptides presented by MHC class I, and they include virally derived antigens such as HPV E6 and E7 proteins which are found in 80% of invasive cervical cancers

Answer 15

-normal cellular proteins with unique expression patterns, they are only expressed at specific sites or stages of development (eg. foetal) or at low levels in normal cells -reexpression of foetal or embryonic genes are called oncofoetal tumour antigens eg. CEA (carcinoembryonic antigen) - 90% of all patients with advanced CRC have increased CEA in their serum -may also be oncogenes that are expressed at abnormally high levels such as EGFR and HER2

Answer 16

-NK deficient mice showed increased sarcomas/lymphomas -NK cells kill tumour cells by showing reduced MHC I expression which is detected by KIRs (killer cell immunoglobulin-like receptors), by killing tumours that overexpress ligands for activating NK receptors, by IFNg secretion which stimulates CTL response, and by being the key mediators of ADCC

Answer 17

-IFNg drives M1 phenotype-ADCC and secrete cytokines (TNFalpha, IL-12, IL23) which exert cytotoxic activity on tumour cells -high MHC class II/costimulatory molecules (APCs) secrete chemokines that lead to Th1, CTL recruitment, and NK cells

Answer 18

-strong anti-tumour CTL (CD8+) activity correlates significantly with tumour remission and maintains state of immune mediated neoplastic cell dormancy -Th1 cells secrete IFNg which promotes M1 macrophage response and increases MHC I expression which facilitates CTL recognition of tumour antigens -Th17 cells secret IL17 which leads to secretion of pro-angiogenic factors -TILs are a prognostic indicator

Answer 19

-B cells can secrete anti-tumour antibodies -ADCC by NK cells and macrophages -bad effect is that B cells can block CTL response by masking tumour antigens -also tumour cells can evade B cells by chopping them up and excreting them

Answer 20

1- active immunosuppression in tumour environment 2- chronic inflammation 3- evasion of immune recognition and activation 4- tumour cell avoidance of apoptotic signals 5- poor co-stimulatory signals provided by tumour cells 6- expression of co-inhibitory molecules

Answer 21

-dampening of immune response by M2 macrophages, MDSCs, Tregs, and Th2 cells -IL4 drives M2 phenotype which release immune dampening cytokine secretion IL10 chemokines which lead to Treg and Th2 recruitment, pro angiogenic factors (VEGF) and growth factors (EGF, FGF) released by M2 macrophages -NK cells defective at tumour site (will likely still be active in periphery ie. blood tests) -neutrophils secrete VEGF and proteinases elastase and MMP8/9 -MDSCs are immature cells comprised of precursors of macrophages, granulocytes, DCs, and myeloid cells at earlier stages of differentiation -tumours secrete factors to promote MDSC expansion as they induce CD8+ T cell tolerance, block NK cytotoxicity, and polarise immunity (push towards pro-tumour rather than anti-tumour immune response, treatment giving to push this balance back)

Answer 22

-increases cellular stress and can lead to genotoxic stress thereby increasing mutation rate -growth factors and cytokines released by leukocytes can also lead to tumour growth -inflammation is proangiogenic -link between increased cancer risk and people with obesity as these people experience higher levels of chronic inflammation

Answer 23

-reduced MHC I/tumour antigen expression on tumour cells -secretion of TSAs -defective TAP or b2macroglobulin -IFNg insensitivity -NK cells should step in to kill these cells but tumour cells show decreased expression of ligands that bind activating receptors on NK cells

Answer 24

-upregulation of anti-apoptotic mediators (eg. Bcl2) -down regulation or expression of non functioning FAS receptor on tumour cells -secretion of soluble form FAS receptor which acts as a decoy for FAS ligand

Answer 25

-T cell activation requires 2 signals, tumour cells are self cells so tend to lack costimulatory molecules -need APCs in the tumour vicinity to activate T cells, recent therapy aims to enhance the costimulation provided to T cells

Answer 26

-immune checkpoints are cell surface molecules that regulate immune response (ie. stop immune response from killing the cancer cells) -ligands on tumour cells can dampen immune response, results in T cell exhaustion

Targeted Therapies and Immunotherapy Flashcards

(50 cards)