Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Molecular Oncology > Day 4: Therapeutic strategies CRC, Targeted and Combination therapy > Flashcards

Day 4: Therapeutic strategies CRC, Targeted and Combination therapy Flashcards

HC 11, 12

1
Q

HC11: Stage 0 CRC therapy

A

N0, M0: partial colectomy
> cancer cells are at mucosa or inner lining
> detected with colonoscopy
> mutation APC: adenomas

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

CRC stage 1 therapy

A

Local excision of polyp
> partial colectomy
> N0, M0
> cancer cell growth through mucosa and invade muscle layer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

CRC stage 3 therapy

A

Partial colectomy, adjuvant chemotherapy (5-FU/LV, capecitabine) when high grade or spread
> N0, M0
> Cancer cells have grown to/through serosa and may spread to nearby organs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

CRC stage 3 therapy

A

Partial colectomy, removal nearby LNs, adjuvant chemotherapy
> Cancer cells have grown through serosa
> spread can be observed to nearby organs
> cancer cells have spread to 1-6 LNs
> N1, M0
> adj chemo:
- 5-FU/LV/oxaliplatin (FOLFOX)
- capecitabine/oxaliplatin (CAPOX)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

CRC stage 4 therapy

A

Partial colectomy, Neo/adjuvant chemotherapy
> N1/2, M1
> cancer cells have grown through serosa
> cancer cells may have spread to lymph node
> presence of distant metastasis (eg liver)
Chemo
- FOLFOX, FOLFIRI, CAPOX, FOLFOXIRI, FTD-TPI
Targeted
- VEGF inh
- EGFR inh
- immune checkpoint inhibitors
- Multi-kinase inh

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

5-FU chemotherapeutic

A

Will be transformed in compound that blocks Thymidylate synthase (by Tymidine phosphorylase and Thymidine kinase)
> TS blocking inhibits dTTP generation for DNA replication and repair: depletion by repressing TS > DNA damage > cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

5-FU/LV:

A

LV (leucovorin) helps 5-FU to better bind the TS enzyme (Tymidylate synthase)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Capecitabine

A

Chemotherapeutic
> Precursor of 5-FU
> Same profile, survival, disease progression
> other side effects
> 5-FU has more stomatitis or neutropenia whule capecitabine will give more hand-foot syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Platinum-based drugs

A

Chemotherapeutic
Like oxaliplatin
> hydrolysis to active drug
> Cisplatin binds N7 of guanine in C-G base pair (2x)
> forming intrastrain adducts: DNA damage
> apoptosis induced

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Irinotecan (SN-38)

A

Chemotherapeutic
Transformation into SN-38 by a carboxylase
> SN-38 inhibits TOP1 (topoisomerase 1, for unwinding DNA for replication when replication fork formed)
> Collision with replication forks > double stranded DNA breaks
> DNA replication inhibited

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Trifluridine (FTD/TFT)- Tipiracil (TPI)

A

Chemotherapeutic > third-line treatment
Analog of thymidine: but methyl group to CF3 group
> misincorporation of nucleoside analog (F3dTTP) into DNA
> DNA replication stress (DRS) and replication fork stalling
> lethal DNA damage
> kill the cancer cell
> TPI has antiangiogenic effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Combining chemotherapeutics: FOLFOX

A

5-FU/LV + Oxaliplatin
> better survival rate than single agents

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

CAPOX (and vs FOLFOX)

A

Capecitabine + oxaliplatin
> overall survival equal efficacy
> in stage 3: CAPOX better than FOLFOX
> CAPOX is slightly more toxic than FOLFOX
> FOLFOX for 6 months and CAPOX for 3 months have same efficacy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

FOLFIRI (and vs FOLFOX)

A

5-FU/LV/Irinotecan
> Similar outcome as FOLFOX
> different side effects
> FOLFOX: neurological problems
> FOLFIRI: heart rate decrease, hair loss
» primary goal is survival though, because side effects are bad

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

FOLFOX/FOLFIRI doublet vs FOLFOXIRI triplet

A

> more toxicity in triplets
more toxic products: more cancer cells and healthy cells affected

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Which cells are affected by (systemic) chemotherapeutic treatments?

A

Any fast dividing cell

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Chemotherapeutics generally cause …

A

DNA damage in replicating cells
> TS inhibition (5-FU)
> Adducts (platinum)
> TOP1 inhibition (irinotecan)
> misincorporation of nucleoside analog (FTD-TPI)
» accumulation DNA damage leads to cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Which healthy tissues are also affects by chemotherapy?

A

With quick turnover: bone marrow, digestive tract
> advanced CRC treatment: combining chemo is better but not without side effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Targeted therapy concept

A

Identify important components of CRC signalling pathways to target it in specific manner

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

4 targeted routes CRC therapy

A

-VEGFR
-Wnt
-EGFR
-Immune checkpoint (CRC – T-cell)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Mutation in Wnt in cancer that forms target, and name Wnt characteristics

A

APC mutated
> Target: inhibit Wnt signaling
> APC part of b-catenin destruction complex
» proliferation and stemness
> Wnt also for tissue homeostasis in intestinal epithelial lining
> in bone: balance osteoblast and osteoclast (bone formation and resorption)
> in skin: homeostasis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Porcupine inhibitors

A

Inhibit Wnt secretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Inhibit Frizzled of Wnt pathway

A

Antibodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Tankyrase inhibitors

A

Block ubiquitination of Axin (part b-catenin destruction complex)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Problems with Frizzled antibodies, Porcupine inhibitors and tankyrase inhibitors for cancer

A

APC mutated: downstream b-catenin already stabilized, upstream targeting has no effect and no therapeutic benefit

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Blocking Wnt with lncRNAs

A
  • Restricted expression profiles in cell types: targeting specific tissues
  • lncRNAs display high tissue specificity
  • hit lncRNA in Wnt pathway are involved
    > siRNAs, ASO, CRISPR to interfere with RNAs
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Inducable shRNA against b-catenin

A

Tested in all CRC cell types known
> most CRC cells dependent on b-catenin: lowered cell proliferation
> some are independent or find bypasses

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

CRISPRi-based dropout screen

A

Epigenetic regulator is recruited: repress transcription at promotor
> repress expression of lncRNAs involved in cancer
> assess functionality of lncRNAs in cancer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

CRL-1 as target

A

CRC specific expression
> ideal candidate
> b-catenin regulated lncRNA
> reactivated for proliferation in cancer
> cytoplasmic RNA
> use shRNA to block it
> CRL1 essential for CRC cell proliferation and tumor growth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

CRL1 function (b-Catenin Regulated LncRNA-1)

A

CRL1 controls Myc protein levels
> CRL1 supports appropriate Myc and inhibits miRNA
> Myc and CRL1 both target genes of b-catenin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

KO CRL1 in CRC

A

More differentiation, less stemness
> increase keratin
> decreased Lgr5 (marker stem cell)
> POLR1A upregulated in control: depletion marks terminal differentiation (in KO CRL1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Steps towards RNAi based therapy against CRL1

A

1 siRNA screen
2 siRNA formulation
3 in vivo testing
> siRNA packaged in LNPs (lipid nanoparticles)

33
Q

HC12: VEGFR and EGFR

A

Receptor Tyrosine Kinases
> to activate MAPK route
> mutated in patients with BRAF and KRAS mutations (oncogenic)

34
Q

VEGF/VEGFR effect

A

Angiogenic effect on tumor

35
Q

When hypoxia in tumor?

A

When oxygen demands cannot keep up with proliferation
> hypoxia and VEGF upregulate abnormal angiogenesis in cancer development

36
Q

VEGF/VEGFR routes

A

Uses Akt-mTOR route and MAPK route for cell cycle activation and survival

37
Q

Therapies against VEGF route

A

-Antibodies against VEGFR (eg bavacizumab)
-Protein kinase inhibitors (PKI) which inhibit tyrosine kinase intracellular part of VEGFR

38
Q

Doublet bevacizumab + FOLFOXFIRI vs bevacizumab + FOLFIRI

A

Triplet has better survival but more side effects
> Adding bevacizumab also increases survival

39
Q

When is blocking VEGF with bevacizumab efficient

A

In KRAS and BRAF WT patients, when mutated lowered effect
> Then, MAPK pathway independent of VEGFR signalling

40
Q

Which mutation is worse: BRAF or KRAS

A

BRAF, further downstream in pathway, all upstream cannot be targeted for therapy

41
Q

EGF/EGFR activated routes

A

The routes activated are
- PI3K to Akt
- Ras to Mek/Erk pathway (MAPK)

42
Q

EGFR overexpression is associated with

A
  • LN (lymph nodes affected)
    > Tumor stage
    > may promote more aggressive CRCs
43
Q

Targeting EGFR

A

Cetuximab: mAb against EGFR
> block PI3K/Akt pathway (survival) and MAPK pathway (proliferation)

44
Q

Which patients respond worse to cetuximab?

A

KRAS and BRAF mutant patients
> reactivation MAPK route independent of blocking EGFR
> resistance mechanism

45
Q

Resistance mechanisms against chemotherapeutic cetuximab

A
  • EGFR mutation
  • Downstream mutations (KRAS, BRAF)
  • Upregulation of other receptors
46
Q

Methods to counteract resistance

A
  • Change targeting strategy (to downstream)
  • Broader approaches
  • Combination therapy
47
Q

Regulation interaction in KRAS and common mutation

A

P-loop in KRAS (GTP binding)
> G12 residue mutation in P-loop in KRAS: lock into active state

48
Q

Inhibition KRAS mutant in mCRC G12C (common mutated KRAS)

A

Keep it into the GDP bound state specifically

49
Q

Sotorasib / adagrasib

A

Makes covalent bond with KRAS (irreversible)
> selective for KRAS G12C
> Interact with inactive GDP bound form

50
Q

MRTX1133

A

Make noncovalent bond with KRAS (reversible)
> selective for KRAS G12D
> Interacts with both active and inactive form (GDP)

51
Q

How to improve adagrasib monotherapy

A

Adagrasib + cetuximab combination
> better PFS: progression free survival
> mono for better overall survival

52
Q

Specific inhibition of BRAF mutants (V600E/D/K)

A

BRAFi
> Encorafenib: block catalytic activity (bind ATP pocket)

53
Q

What drugs to use when BRAF mutation (7-10% of CRC)

A

MEKi
> Binimetinib or Trametinib: allosteric inhibitors (bind unphosphorylated Mek and prevents its phosphorylation)

54
Q

Efficacy of BRAFi and MEKi and EGFRi compared to control of FOLFIRI and EGFRi

A

better survival

55
Q

Expression Her2 in advanced CRC

A

Overexpression
> overexpressed in 3-5% of mCRC (metastasized)

56
Q

Her2 in cancer

A

Induces genomic instability or amplification
> Her2 receptor
> Activation PI3K and MAPK pathway

57
Q

Treating Her2 OE (overexpression)

A
  • Trastuzumab: mAb against Her2 (receptor)
  • Tucatinib (KI) against kinase if Her2 intracellularly
  • Tucatinib + trastuzumab dual therapy: good response: can interfere with metastatic cancer
58
Q

Regorafenib

A

Multi-kinase inhibitor
> inhibits intracellular kinases for eg VEGFR, FGFR, and more (but also of Raf!)
> block angiogenesis, cell proliferation, metastasis and immunosuppression simultaneously.
> to prevent resistance
> retains the dephosphorylated inactive state of kinases

59
Q

TAS-102 as third line treatment

A

TAS-102 = Trifluridine-Tipiracil (FTD-TPI)
Broad anticancer treatment when refractory mCRC resistant against all therapies
> gain of 2 months
> improved when also adding bevacizumab

60
Q

Why important to diversify and combine treatments

A

Adaptive rewiring of cancer cells via selection
> for example Mek1 mutation or NRAS mutation when therapies given
> block KRAS: cell uses more PI3K pathway
> cancer cells crosstalk: compensate to activate what the cell needs

61
Q

Immune checkpoint: interactions CRC cell and T cell

A

Tumor cell – T-cell
B7 – CTLA4
MHC-I with peptide – TCR
PDL1 – PD1
> B7 and PDL1 give ‘don’t kill me’ signals to T-cell

62
Q

Immune checkpoint inhibition

A

Antibodies against CTLA4, PD-1, PD-L1, B7
> reactivate the immune system against cancer cells

63
Q

Why do a lot of mutations in the unstable genome of cancer benefit immune therapy?

A

More neo-antigens made by cancer cells: unusual proteins because mutations presented.

64
Q

Mismatch repair mutated (MSI-H, dMMR) and immunotherapy

A

No repair in making neo-antigens > better efficacy immune therapy

65
Q

Most CRC tumors and MSS/MSI

A

Most MSS or MSI-L (low), pMMR (proficient Mismatch Repair), less neo-antigens,
> less benefit from immune checkpoint inhibition
> more benefit when dMMR, MSI-H: more immunogenic

66
Q

Which mutation makes patients beneficial for ICI (immune checkpoint inhibition)

A

PolE mutation (polymerase) > proofreading mutation > ultramutated genome even when MSS > higher neo-antigen presentation via MHC1 > more tumor-infiltrating lymphocytes and better prognosis
» via Nivolumab to inhibit MMR

67
Q

Effect TGF-beta signalling on ICI response

A

Attenuates response: contributes to exclusion of T-cells

68
Q

How to turn cold tumors hot

A

Inhibit TGFb with inhibitor and ICI
> block the dendritic cells from inhibiting T-cells
> immune attack once again: hot tumor
> first: T-cell response blocked: cold tumor
> only effective when dual therapy

69
Q

Regorafenib effect on anti-tumor immunity

A

Improves it
> Normalize vasculature: facilitate access for CTLs
> Reduce amount of TAM/TEM (Tumor-associated macrophages and TIE-2 expressing monocytes): promotes T-cell activity

70
Q

Potential resistance mechanisms against ICI

A

-Agonistic interaction: make T-cells better for attack
> antagonistic interaction should be blocked, could give rise to resistance

71
Q

Oncolytic viruses therapy

A
  • Healthy cells can better prevent a virus from dividing than cancer cell
  • Cancer cells are less able to do this: cancer cells die, virus multiplies
    > cell contents released: inflammation and destruction tumor microenvironment
72
Q

Onyx-015

A

E1B deleted adenovirus
> P53 can not mitigate stress response > cell dies and virus replicates
> normally: p53 and Rb bind E1A and E1B respectively

73
Q

Armed oncolytic viruses

A

Potentiating: put ICI encoded in viruses
> ONCR-177
> Transgenes delivered: activate T-cells, chemokine attractants made, expand and activate NKcells and DCs, ICI (anti-PD1 and anti-CTLA4)

74
Q

Limitations oncolytic viruses

A
  • Antiviral response > viral clearance
  • Poor distribution throughout the tumor
    > Tumor heterogeneity/ tropism (target cells p53 mutated, low IFN etc)
  • Dosing strategies
75
Q

Adoptive Cell Transfer (ACT) therapies

A

Autologous cell therapy
> own cells cultured and given back
Allogenic cell therapy
> donor cells which are engineered and given to patient

76
Q

CAR T-cell therapy

A

Chimeric antigen receptor (CAR) T-cells
> T-cells have group of proteins to make this receptor, but now chimeric protein made (all in one protein, easy to modify)
- IL-12 inducer intracellular: chemokine which helps activation T-cells
- IL-2Rb in next gen CAR: cytokine receptor (IL-2 helps T-cell proliferation, made upon binding ligand)
-Make CAR T-cells from T-cells and give back
> reognition of cancer specific epitope

77
Q

Limitations CAR T-cells

A

-Infiltrating tumor mass (especially for poorly irrigated solid tumors)
-Immunosuppressive tumor microenvironment: hypoxia, high acidity, low concentration nutrients, TGFb
-On vs Off tumor toxicities:
> targeted antigens/ tumor specificity
> high cytokine production: aggressive immune reaction: tissue damage: organ failure
- Allogenic tranfer may be rejected by host (alloimmunization)
- autologous cell transfer: variability in starting material.

78
Q

Best treatments for KRAS G12C mutant
Choose from
> anti-VEGFA: bevacizumab
> KRAS G12C inhibitor
> Regorafenib (against RTKs)
> Cetuximab (anti-EGFR)
> BRAFi and MEKi

A

BRAFi+MEKi
KRAS G12C inhibitor

79
Q

Which patients benefit from ICI (choose one or more)
> MSS tumors
> POLE mutation: polymerase epsilon
> MSI-H
> low miRNA-200 expression
> CMS4 subtyped tumor with prominent activation of TGFb

A

> POLE mutants
MSI-H

Molecular Oncology (7 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions