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Carcinogensis + Anticancer drugs > Multiple genetic alterations & targeted therapies > Flashcards

Multiple genetic alterations & targeted therapies Flashcards

1
Q

What occurs when cellular stress occurs

A

ATM-ATR activates CHK2/1
this activates p53 which when HAT bind, binds to the p53 response element on DNA and cause the transcription of p53 target
either causing cell cycle arrest of apoptosis

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2
Q

what proteins cause cell cycle arrests

A

CDKN1A, SFN, TP5313, CDC25C

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3
Q

What proteins cause apoptosis

A

TNFSF10, BAX, BBC3, PMA1P1

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4
Q

Explain how p53 causes apoptosis in detail

A

Causes the expression of
- BAX interact with and opens mitochonidral pores leading to cytochrome -C release
- BBC3 = BCLA2 binding component 3 causing BAX to be free
- NOXA = candidate mediator of p53-induced apoptosis
- DR5/TRAILR2 = transmembrane protein that mediates apoptosis - cause caspases activity
- Fas - an antibody which induces antibody triggered apoptosis by activating caspases

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5
Q

describe the role of BAX in normal cell

A

BAX (BCL2 assocated x protein) forms a heterodimer with the anti-apoptotic protein BCL2
The ration of BAX:BCL2 determines survival/death following a apoptosis stimulus

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6
Q

Cytochrome C causes _

A

Caspase release there for release

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7
Q

what happens to the cell when undergoing apoptosis

A

Chromatin condensation - membrane blebbing - nuclear collapse and finally apoptotic body formation

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8
Q

Apoptosis is characterised by a variety of _

A

morphological features such as loss of membrane asymmetry and attachment, condensation of the cytoplasma and nucleus and internucleosomal cleavage of DNA

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9
Q

One of the ealriest indication of apoptosis is the

A

translocation of the membrane phospholipid phosphatidylserine form the inner to the outer leaflet of the plasma membrane
- Once exposed to the extracellualr enviroment, binding sites on PS become available for Annexin

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10
Q

what is Annexin

A

Ca2+ dependent phospholipid binding protein with a high affinity for phosphoplipid phosphayidylserine

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11
Q

What are manifestation/markers of apoptosis

A

Nuclear fragmentation/condensation
Sub-G1 peak on FACS analysis
DNA ladder
Cell surface markers = AnnexinV
Caspase catalytic activity
Cleavage of target proteins = PARP, Caspase-3

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12
Q

What are some in vitro example of p53 and drug resistance

A

○ Cell lines with mutant p53 reported to be generally more resistant to DNA-damaging agents
○ Cells selected for resistance to cisplatin show defects in p53 function

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13
Q

what are some in vivo example of p53 and drug resistance

A

○ In p53 knockout mice, thymocytes are more resistant to the cytotoxic effects of ionising radiation
○ Adenovirus-mediated transfer of a wild-type p53 gene into tumour cells in vivo shown to confer sensitivity to cisplatin

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14
Q

What are the clinical consequences of p53 inactivation in tumours

A

Loss of cell cycle arrest in response to DNA damage
- Less growth inhibition
-DNA synthesis allowed to take place on a damaged template = Promotes accumulation of further mutations, genomic instability and tumour progression
Prevention of p53-dependent apoptosis
- Less cell killing – resistance to treatment
p53 is a determinant of response to therapy

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15
Q

What is the trend in chronic lymphocytic leukaemia and its link to Tp53 & del17p status

A

Lowest survival - TP53mut + del17p positive
highest in patients either positive for either TP53 mutation or a dep17q

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16
Q

How does p53 tumour supress

A

Senescence (a process by which a cell ages and permanently stops dividing but does not die)
Angiogenesis
Autophagy
cell cyle arrest
migration
apoptosis
DNA repair
metabolism

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17
Q

T/F p53 is the only tumour supressor gene

A

no there are loads, all in different chromosomes and there disequilibrium are all linked to different cancers

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18
Q

Explain the vogelstein model for the progression of colorectal cancer

A
  • Normal epithelium is converted into hyperproliferation epithelium (by a Mut/loss of the 5q affect the FAP gene)
  • DNA hypomethylation then converts these to early adenoma
  • a Mut in 12q affects the K-ras causing teh development of an intermediated adenoma.
  • a loss of the 18q leads to an issue with the DCC causing a Lat adenoma
  • Finally a deletion in 17p = loss of p53 causes a carcinoma
  • Metastasis can occur form this point
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19
Q

Describe how the RAS-MAPK pathway is activated

A

a signal bind to a protien tyrosine kinase receptro (EGFR)
This incudes oligomerisation of the receptor, a process that results in juxtaposition of the cytoplasmic, catalytic domains in a manner that allows activation of the kinase activity and transphosphorylation
- Adaptor proteins such as Grb2 are now able to recognise sequecne homology- 2 domains (such as Shc) which recruit guanine nucleotide excahnge factors like SOS-1/CDC25
These factors are able to interact with the Ras portesn to promote the conformational change (GDP->GTP)

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20
Q

what does the Raf do in the RAS/MAPK pathway

A

Raf (serine/threonine kinase)
stimulates a signaling cascade by phosphorylation of MAPK which successively phosphorylate and activate downstream proteins such as ERK1 and ERK2

21
Q

what does activation of ERK do in the RAS/MAPK pathway

A

Activation of ERK is critical for a large number of Ras-induced cellular responses. ERK1 and ERK2 phosphorylate and activate a variety of nuclear transcription factors and kinases, including Elk-1, c-Ets1, c-Ets2, p90RSK1, MNK1, MNK2, as well as other proteins such as the anti-proliferative protein Tob

22
Q

What does MAPK (MEK) do in teh RAS/MAPK pathway

A
  • Serine/threonine kinase activated in response to multiple signals including growth factors and cytokines
  • Promote cell survival and apoptosis through a number of mediators such as JNK, SAPK, 14-3-3 and NF-KB
  • Also regulates both Raf/ERK by providing corss talk between mutiple sig pathways
  • MAPK appears to induce apoptosis by dysregulation of a number of pathways including ERK, JNK and p38.20
  • MAPK has been shown to directly interact with K-ras in a GTP-dependent manner.19, 20
23
Q

EGRF inhibitors like catuximab don’t work against

A

RAS mutant tumours

24
Q

How does K-ras mutation and the lack of benefit from cetuximab affect advanced colorectal cancer

A

Cetuximab - EGFR targeted antibody used in advanced colorectal cancer
Improved overall survival for patients with wild-type K-RAS tumours but not those with mutated K-RAS tumours

25
Q

what other tumour type is affect by K-ras mutation and its effect on cetuximab

A

non-small cell lung cancer

25
Q

what is needed before treatment of advanced colorectal cancer

A

First genetic test to be mandatory for guiding the treatment of cancer - FDA approved PCR companion diagnostic test for K-RAS
(One of the consequences of K-ras mutation is insensitivity to EGFR inhibitors)

26
Q

Prognostic & predictive biomarkers allow for

A

stratified treatment
better tailoring of therapies to individual
better disease monitoring during treatment

27
Q

what is novel therapeutic targets

A

antibody targeting, gene therapy, small molecule inhibitor of oncogenes and associated growth signal transduction pathway components

28
Q

How does the small molecules approach to targeting of specific genetic alteration in cancer work

A
  • Shift from general anti-proliferative and cytotoxic agents to mechanistically based approaches to identify cancer-specific molecular lesions as therapeutic targets
  • Exploiting the difference between cancer cells and normal cells should lead to better drugs that are toxic to cancer cells and minimise damage to normal tissues
  • Naturally leads to the concept of personalised medicine
    (Genetic profiling of tumours for targetable mutations and pathways)
29
Q

what are the properties which makes a particular target work pursuing as a drug development project

A
  • Causal link with the transformed and/or malignant phenotype
  • Mechanistic basis established
  • Tumour specificity – manipulation of the target should result in minimal normal tissue damage
  • Functional assays can be designed to screen compounds for activity against the target
  • Biomarkers available for patient selection and PD monitoring
  • The target should not be being pursued elsewhere, unless a novel and improved approach being proposed
30
Q

What is Imatinib

A

targets the philadelphia translocation
rationally tyrosine kinase inhibitor

31
Q

what is the philadelphia translocation

A
  • Philadelphia (Ph) translocation is found in 95% of chronic myelogenous leukaemia (CML) cells and in 30-50% of adult acute lymphocytic leukaemia (ALL)
  • Translocation results in juxaposition of BCR and ABL gene sequences, leading to a chimeric fusion protein, Bcr-Abl
  • Bcr-Abl is a constitutively activated tyrosine kinase with oncogenic activity
32
Q

How does imatinib work

A

□ Suppresses the growth of Bcr-Abl positive leukaemic cells and leaves normal cells unaffected
□ Dephosphorylation of the Bcr-Abl protein is seen followed by apoptosis
□ 60-90% response rates in Phase I/II trials, no dose limiting toxicities
□ Resistance can develop due to amplification or mutation of the BCR-ABL fusion gene
□ Second generation inhibitors for imatinib resistant disease: nilotinib, dasatinib, bosutinib, ponatinib
□ Active against gastrointestinal stromal tumours (GIST’s), because also inhibits the c-kit oncogene product

33
Q

What are other additional licensed small molecule tyrosine kinase inhibitor

A
  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors: IressaTM (ZD1839) from AZ, OSI-774 (TarcevaTM) Active against EGFR
  • Other small molecule EGFR family tyrosine kinase inhibitors: Lapatinib from GSK (Active against EGFR & HER2 receptor tyrosine kinases & penetrates the blood-brain barrier)
  • Pan-FGFR inhibitor - Erdafitinib (J&J). (Breakthrough therapy designation for the treatment of relapsed/refractory urothelial cancer with specific FGFR genetic alterations)
  • Vascular endothelial growth factor receptor (VEGFr) e.g pazopanib, sunitinib, sorafenib
34
Q

what is ALK tyrosine kinase

A

Anaplastic large-cell lymphoma tyrosine kinase

35
Q

how is ALK tyrosine kinase targeted

A
  • Crizotinib (Pfizer) - oral small molecule inhibitor of ALK for treatment of non-small cell lung cancer in which EML4-ALK fusions are found (4%)
  • The most common ALK mutation in neuroblastoma (Arg1275Gln) is not responsive to crizotinib. Next-generation alternatives being tested (e.g. lorlatinib)
36
Q

How is the ALK tyrosine kinase and neuroblastoma targeted

A

The ALK tyrosine kinase gene is found as a germline mutation in rare familial neuroblastoma predisposition cases and also mutated or amplified in a subset (10-12%) of sporadic neuroblastoma

37
Q

What is the link between the BRAF and melanomas

A

BRAF serine/threonine kinase V600E mutation found in 50% of melanomas, keeping the protein in an active state

38
Q

how is BRAF mutation in melanomas targeted

A
  • Vemurafenib (Roche): Oral multi-kinase inhibitor, found active against mutant BRAF
  • BRIM3 melanoma trial: Vemurafenib improved progression-free and overall survival for patients with V600E BRAF mutant tumours
  • Relapsed with squamous cell carcinomas = improved by combining with MEK inhibitors
39
Q

How are cyclins/CDKs targeting

A

Palbociclib & Ribociclib CDK4/6 Inhibitors (Licensed for ER+ HER- advanced breast cancer (+ aromatase inhibitor))
Approx doubling of progression-free survival

40
Q

how can non-genotoxic activation of p53 be targeted

A
  • Kinase inhibitors have been popular to purse because they involve ATP substrates and lend themselves to the testing and development of ATP analogues.
  • In contrast, protein-protein interactions have been considered far more difficult.
  • However, the solving of the X-ray structure of the MDM2-p53 protein complex indicated that targeting MDM2 with small molecules might be possible.
41
Q

what are nutlins

A

cis-imidazoline analogs which inhibit the interaction between mdm2 and tumor suppressor p53

42
Q

how was nutlins identified

A

highthoughput chemical libary screen, imidazoline scaffold optimised through structure based design

43
Q

what was the in vitro activity of nutlins

A
  • Selectivity for WT p53 vs mutant p53, and MDM2 amplified cell lines
  • Induction of p53-dependent genes e.g. p21, MDM2
  • Proapoptotic in tumour cells
  • Synergistic with doxorubicin, AraC, 5FU, and irinoteca
44
Q

what was the in vivo activity of nutlins

A

Nutlin-3a - single agent activity in a SJSA-1 osteosarcoma xenograft model

45
Q

how, celluray, does nutlins work

A

The sulphone group aids solubility and provides hydrogen bond linkages to tyrosine (Y) 67 and Glutamine (Q) 72 in the p53 binding pocket of MDM2, which increases binding affinity, specificity and potency

46
Q

what did the RG7112 phase 1 clinical study show

A

A neoadjuvant trial in primary/relapsed liposarcoma in patients which are chemotherapy naïve and eligible for tumour resection
20 patients (11 well differentiated, 9 de-diff)
1440mg/m2 per day x10, in a 28 day cycle
Grade 3/4 vomiting (2), neutropenia (3) and thromobocytopenia (5)
○ Biomarker evaluation indicated p53 activation, cell proliferation arrest and apoptosis
○ 1 partial response, 14 stable disease
○ 8 patients no evidence of disease at subsequent follow-up
○ Second generation compounds now developed with improved PK – e.g. RG7388 (Idasanutlin) & HDM201

47
Q

What is the challegnge of heterogeneity in cancer

A
  • Genetic instability and heterogeneity are hallmarks of cancer
  • Combination treatments are generally necessary
  • Relapse and the development of drug resistance is common
  • Nevertheless, targeted treatments are emerging which show beneft

Carcinogensis + Anticancer drugs (16 decks)

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