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MMI 436 > Liver Cancer > Flashcards

Liver Cancer Flashcards

1
Q

How does cancer progression occur?

A

proliferation of tumor cells and immunosuppressive tumor microenvironment

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2
Q

What are 4 risk factos for HCC?

A
  1. HBV and HCV chronic infection
  2. alcohol abuse
  3. aflatoxin-contaminated food
  4. T2D
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3
Q

What are the first, second, and third line treatment options for HCC?

A

first line (early stage of disease):

  • surgical resection or liver transplant

second line (surgery not possible):

  • radiofrequency ablation (RFA; heat up tumor)
  • thermal and non thermal ablation
  • TACE (blocks hepatic artery to stop blood supply to the tumor)

advanced unresectable HCC:

  • mAb against tyr kinase
  • mAb against VEGF Rs
  • immune therapy approaches
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4
Q

How does altered signaling from chronic HBV and HCV lead to HCC?

A
  • more proliferation
  • inhibits apoptosis
  • promotes metastasis
  • more stemness
  • more drug resistance
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5
Q

What are the direct effects of HCV for HCC?

A

altered signaling in infected hepatocytes:

  • lipid metabolism (leasing to steatosis)
  • oxidative stress
  • proliferation and apoptosis (favouring conditions fo cancer development)
  • genomic instability (hallmark of cancer)
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6
Q

How does HCV infection alter:

  • B-oxidation of lipids
  • free fatty acid (FA) neosynthesis

and what is the consequences of these alterations?

A

B-oxidation of lipids

  • HCV inhibits PPARa which normally functions in B-oxidation of FA (derived from pyruvate)

FA neosynthesis:

  • activates SREBP1c to increase FA synthesis
  • inhibits MTP

accumulation of FA

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7
Q

Describe STAT3 signaling immunosuppressive effects

A
  • STAT3 is constitutively active in tumor and immune cells in the tumor microenvironment
  • active STAT3 is induced in response to cytokines such as IL-6/8
  • constitutively active STAT3 is associated with IL-10 and TGFb and low levels of type 1 IFNs
  • blockade of STAT3 –> reduced HCC progression, reduced IL-10 and TGFb and increased type 1 IFNs, enhanced NK-mediated cytolysis of HCC cells
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8
Q

What are exosomes?

A
  • can be released by all cell types
  • delivery a varitey of biological molecules (e.g. DNA, RNA, proteins, miRNAs, lipids)
  • key role in intercellular communication
  • plays important roles in most cancers
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9
Q

What are three characteristics of exosomes from metastatic HCC cells?

A
  1. carry a large number of protumeriogenic RNAs and proteins
  2. promote metastasis by activating P13K/Akt and MAPK signaling pathways
  3. have been associated with signaling that conferes resistance to sorafenib
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10
Q

What are the effects of exosome signaling from HCCs?

A
  • induce P13K/Akt and MAPK signaling in neighbouring hepatocytes (promoting cancer progression)
  • promote polarization of fibroblasts to CAFs
  • promote polarization of TAMs (to favour pro-tumorigenic environment)
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11
Q

How do nucleoside analogs (NAs) work?

A
  1. converted by viral and host cell enymes to triphosphate form
  2. triphosphate form blacks: viral DNAP, viral RNAP, viral RT
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12
Q

How do we block budding and genome replication in CHB?

A
  • budding: nucleic acid polymers (NAPs) to prevent release of subviral particles
  • genome replication: nucleoside analogs = chain termination in replication, inhibitors of HBV RNaseH
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13
Q

What type of DAA (directly acting antiviral) is sofosbuvir (sovaldi)? what is a challenge with adminstering this?

A

sovaldi = NA that impairs NS5B RNAP

challenges: cost and indentification of HCV infected patients

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14
Q

What are 4 challenges for HCV vaccine devlopment?

A
  1. genotypes
  2. animal models - cant use mice or rabbits, chimps are good model but testing is banned
  3. tools in the lab are limites
  4. funding - tend to fund DAAs cause they work and not some vaccine that hasn’t proven to work
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15
Q

What are 4 current HCV vaccine approaches going on right now?

A
  1. recombinant E1/E2
  2. recombinatnt E2
  3. viral vectors
  4. viral like particles (VLPs)
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16
Q

Several countries have developed actional plans towards the elimination of hepatitis, what 3 components are part of those plans

A
  1. vaccination for HBV
  2. indentification of HBV and HCV-infected patients (screening)
  3. treatment for HBV and HCV infected pattients
17
Q

For CHB name 3 therapies that target IFN response and innate sensors

A
  1. PEG IFNa –> stimulates ISGs in hepatocytes –> boost NK cell activation
  2. RIG-l agonist –> stimulates NF-kB cytokines and type 1 IFNs
  3. TLR 7/8 agonist –> stimulates NF-kB cytokine in TAMs or DCs
18
Q

Describe how immune checkpoint inhibitors (ICIs) treat cancer

A
  1. use blocking Abs to inhibit CTLA-4, PD-1, and PD-1L
  2. restores T cell function and tumor killing
19
Q

Describe how tumor cells evade ADCC by NK cells. How can we use therapies to counter this?

A

tumor associated Ags (TAAs) and activating lignads (e.g. MIC-A/B) for NK cells may be upregulated, but inhibitory signals (e.g. MHC-I) overrides –> NK cell tolerance

solution: give cancer patient TAA-specific Ab or vaccine Ag –> IgG mAb binds to TAAs –> more activating signals to override inhibitory signals –> NK cell activation and killing

20
Q

Describe three different strategies to replace the endogenous adaptive response in CHB

A
  1. TCR-redirected T cells: engineer TCR of T-cells to specific HBV-specific Ags
  2. CAR T cells: create a non-TCR receptor towards a specific HBV Ag
  3. soluble engineerred TCRs: soluble TCR against a specific HBV Ag that includes a domain that binds to CD3 –> cross-links CD3 –> activate T cells
21
Q

What is the primary difference between first gen CAR T-cell therapies and second/third gen?

A

1st gen –> T-cell activation only
2nd/3rd gen –> T-cell activation + cytokine release

22
Q

What are three challenges for CAR T-cell therapy?

A
  1. cost and time to generate
  2. highly trained individuals required
  3. side effects: cytokine release syndrome and neurotoxcity
23
Q

What are stategies being investigated right now to target TAMs in HCC?

A
  1. inhibit monocyte recruitement - less TAMs in the liver
  2. eliminate TAMs - reduce TAMs in tumors
  3. ‘re-education’ - shift the phenotype of TAMs to promote resolution (M2 –> M1)
  4. neutralization of products - neutralize molcules that favor tumorigenesis
24
Q

What is a problem with TGFb?

A

can supress immune therapy efforts

strategy: number of treatments in development aimed at neutralization of TGFb

MMI 436 (14 decks)

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