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BI407 Tumor Biology > Targeted Therapies and Immunotherapy > Flashcards

Targeted Therapies and Immunotherapy Flashcards

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1
Q

how does chemotherapy work

A

works by targeting fast growing cells ie. cancer cells however there are normal fast growing cells too which causes the side effects such as nausea coz GI tract cells turnover quickly, hair loss coz hair follicle cells turnover quickly
chemotherapy discovered indirectly through mustard gas used in war

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2
Q

what were the first onwards cancer treatments

A

-first focused on arresting cell growth, 1960s, chemotherapy
-targeted approach began with hormone therapy
-molecular targeted therapy began in late 1990s, much more specific approach as deals with small molecules

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3
Q

what is radiotherapy

A

-exposure to ionizing radiation
-pioneered by Marie Curie in 1900s
-causes extensive cell damage and formation of free radicals
-measured in grays, 1 gray can damage over 1000 bases of DNA (a lot of damage)

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4
Q

what are the approaches for radiotherapy

A

-external beam radiotherapy (XRT)
-internal radiotherapy (brachytherapy/seeded)
-radio-isotope therapy eg iodine-131 for thyroid cancer

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5
Q

what are drawbacks of radiotherapy

A

-non-specificity, not just hitting cancer cells and can even cause new cancer such as blood cancers from prolonged exposure
-requires carefully controlled administration
-unwanted side effects

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6
Q

what are the types of chemotherapy

A

-alkylating agents
-anti-metabolites
-mitotic inhibitors
-topoisomerase inhibitors
-anti-tumour antibiotics

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7
Q

what are the three key targeted cancer therapy strategies

A

-monoclonal antibodies
-small molecule tyrosine kinase inhibitors
-antibody-drug conjugates (ADCs)

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8
Q

what are the mechanisms of targeted therapies involving receptor and signalling molecules

A

-receptor activation
-signalling transduction

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9
Q

what are the mechanisms of targeted therapies involving monoclonal antibodies

A

-monoclonal antibodies which bind to the receptor extracellular domain and inhibit pathway activation causing receptor internalisation and antibody-dependent cellular cytotoxicity

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10
Q

what are the mechanisms of targeted therapies involving small molecule TKIs

A

-the TKIs reversibly bind to the receptor intracellular domain
-this inhibits pathway activation
-majority of drugs for cancer treatments focus on this mechanism of binding to a receptor kinase to inhibit it

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11
Q

what are the mechanisms of targeted therapies involving antibody-drug conjugates (aka bystander effect)

A

-the conjugates bind to the receptor extracellular domain and inhibit pathway activation
-receptor internalisation occurs followed by payload delivery which results in antibody-dependent cellular cytotoxicity

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12
Q

comparison of anti-receptor antibodies vs small molecule TKIs as anti-cancer agents

A

-target: small mol target tyrosine kinase domain, antibody target receptor ectodomain
-specificity: small mol +++, antibody ++++
-binding: small mol most are rapidly reversed, antibody receptor internalised and only slowly regenerated
-dosing: small mol oral daily, antibody intravenous weekly
-distribution in tissues: small mol more complete, antibody less complete
-toxicity: small mol rash and diarrhoea and pulmonary, antibody rash and allergy
-antibody-dependent cellular cytotoxicity: small mol no, antibody generally

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13
Q

what is the HER family composed of

A

EGFR which is HER1, HER2, HER3, HER4

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14
Q

what is the role of HER family in cancer

A

-they are receptor tyrosine kinases that are overexpressed in many cancer types
-EGFR is most notably involved in lung, head and neck, and colorectal cancers
-HER2 is overexpressed in several cancer types but most notably in breast cancer

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15
Q

how does HER family activation occur

A

dimerization occurs which leads to activation of PI3K pathway and MAPK pathway

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16
Q

what are the strategies for targeting the HER family

A

-monoclonal antibodies
-antibody-drug conjugates
-small molecule tyrosine kinase inhibitors

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17
Q

what are the three approved HER2 targeted TKIs

A

-lapatinib
-neratinib
-tucatinib

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18
Q

what is lapatinib

A

-dual HER2/EGFR TKI
-reversible inhibitor
-first HER2 targeted TKI to be FDA approved
-approved in combination with chemotherapy (capecitabine) for HER2 + BC and with hormone therapy (letrozole) for HER2 + BC + HR

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19
Q

what is neratinib

A

-Pan-HER TKI
-irreversible inhibitor
-approved for sole treatment in early stage HER2 + BC and in combination with chemotherapy (capecitabine) for metastatic HER2 + BC

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20
Q

what is tucatinib

A

-HER2-specific inhibitor
-reversible inhibitor
-approved for use in combination with targeted therapy (trastuzumab) and chemotherapy (capecitabine) for metastatic HER2 + BC

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21
Q

following cross comparison of the approved anti-cancer TKIs which was most potent

A

neratinib was most potent across many cancer types (HER2 amplified, HER2 mutant, and EGFR mutant), tucatinib came second in sensitivity

22
Q

what can neratinib be paired with to enhance/cause improvements, what are the paired improvements, and why does neratinib need to be enhanced

A

-despite being most potent neratinib is subject to the development of innate and acquired resistance with prolonged use
-can be paired with dasatinib to enhance its action
-improvements when neratinib and dasatinib used together include greater growth inhibition, apoptosis induction, cell migration inhibition, and growth signalling suppression

23
Q

what is dasatinib

A

-orally active multi-kinase inhibitor
-targets SFK (src family kinase), c-Abl, c-KIT, PDGFR, and ephrinA
-most potently inhibits Src kinase and c-Abl
-already FDA approved for treatment of myeloid leukaemia and Philadelphia-positive acute lymphocytic leukaemia so its safety profile was known

24
Q

what is p53

A

-tumour suppressor
-most commonly mutated gene in cancers (half of all cancers)

25
Q

why is a p53 mutation different to other cancer mutations

A

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

26
Q

what is the drugging strategy for p53 mutations and and what are the most common drugs used

A

-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

27
Q

what is KRAS

A

-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

28
Q

what cancers involve KRAS mutations and why are they hard to treat

A

-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

29
Q

what are the approved drugs for KRAS treatment

A

-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

30
Q

what are new potential drugs for KRAS treatment

A

-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

31
Q

what are the different subtypes of breast cancer

A

-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

32
Q

how many HER altered cell lines are there across different cancer types

A

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

33
Q

how can the immune system contribute to the anti-tumour response

A

-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

34
Q

what is a bad tumour immune profile composed of

A

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

35
Q

what is a good tumour immune profile composed of

A

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

36
Q

what are some tumour escape mechanisms

A

-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

37
Q

what are the two classes of tumour antigens

A

tumour-specific antigens and tumour-associated antigens

38
Q

what are tumour specific antigens

A

-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

39
Q

what are tumour associated antigens

A

-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

40
Q

what is the anti-tumour response shown by NK cells (innate immune cells)

A

-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

41
Q

what is the anti-tumour response of macrophages M1 (innate immune cells)

A

-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

42
Q

what is the anti-tumour response of T cells

A

-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

43
Q

what is the anti-tumour response of B cells

A

-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

44
Q

how can cancer evade the immune system

A

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

45
Q

what are the details of 1- active immunosuppression in tumour environment

A

-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)

46
Q

what are the details of 2- chronic inflammation

A

-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

47
Q

what are the details of 3- evasion of immune recognition and activation

A

-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

48
Q

what are the details of 4- tumour cell avoidance of apoptotic signals

A

-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

49
Q

what are the details of 5- poor co-stimulatory signals provided by tumour cells

A

-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

50
Q

what are the details of 6- expression of co-inhibitory molecules

A

-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

BI407 Tumor Biology (4 decks)

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