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MCC > Wk 5 Targeted Anti-cancer therapy > Flashcards

Wk 5 Targeted Anti-cancer therapy Flashcards

1
Q

Where do tyrosine kinases get the phosphates from?

A

ATP

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2
Q

What is the role of tyrosine kinases?

A

critical for intracellular signal transduction
-often mutated in cancer cells -> unrestrained signaling (growth signaling or apoptosis)

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2
Q

What is the role of tyrosine kinases?

A

critical for intracellular signal transduction
-often mutated in cancer cells -> unrestrained signaling (growth signaling or apoptosis)

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3
Q

What are 2 tyrosine kinases in cancers?

A

EGFR family
BCR-ABL

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4
Q

What are Ser/Threonine kinases?

A

Raf/MEK/MAPK

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5
Q

What is the role of Imatinib in CML?

A

Blocks the binding of ATP to BCR-ABL tyrosine kinase

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5
Q

What is the role of Imatinib in CML?

A

Blocks the binding of ATP to BCR-ABL tyrosine kinase
=tyrosine kinase inhibitor (TKI)

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6
Q

6 mechanisms of TKI resistance

A
  1. intracellular target mutation
  2. overproduction of cell receptors
  3. gene amplification (ex. many copies of BCR-ABL instead of 1)
  4. overexpression of growth factor (ligand)
  5. pathway modifications to bypass where blocking w/ drug
  6. increased efflux of drug or decreased uptake
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7
Q

Characteristics of monoclonal antibodies (mAbs)

A

-large
-grown in living cells (biologic)
-recognition domains that target extracellular domains

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8
Q

What are 7 types of mAbs?

A
  1. tumor-spec IgG
  2. Angiogenesis inhibition
  3. checkpoint blockade
  4. radioimmunotherapy
  5. antibody-drug conjugate therapy
  6. bispecific antibody therapy
  7. CAR T-cell
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9
Q

3 mechanisms of mAbs

A

recognize receptor on target cell then:
1. attack it
2. recruit immune processes like complement cascade, monocytes or macrophages
3. directly act at lipid bilayer to poke hole in tumor cell

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10
Q

How does VEGF work?

A

VEGF secreted by tumor cell, binds VEGFR on norm endothelial cells to try to recruit more BV growth

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11
Q

Checkpoint blockers

A
  1. PD1 (Nivolumab)
  2. CTLA4 (Ipilimumab)
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12
Q

Radioummunotherapy

A

Radiotherapy bound to mAbs that can then bind the cancer cell

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13
Q

Antibody-drug conjugate therapy

A

drug bound to Ab that can bind cancer cell
=immunoconjugates

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14
Q

CAR T cells

A
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15
Q

-mab

A

=monoclonal antibody

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16
Q

-ib

A

= small molecule w/ inhiBItory properties

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17
Q

3 Monoclonal antibody target names

A
  1. -ci(r)- = circulatory system
  2. -li(m) = immune system
  3. -t(u)- = tumor
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18
Q

3 mAb source naming

A
  1. -ximab = chimeric human-mouse
  2. -zumab = humanized mouse
  3. -mumab = fully human
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19
Q

4 small molecule names

A
  1. -tinib - TKI
  2. -zomib = proteasome inhibitor
  3. -ciclib - cyclin-dependent kinase inhibitor
  4. -parib = poly ADP-ribose polymerase inhibitor (PARP)
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20
Q

What kinds of inhibitors are VEGFs?

A

mAbs and TKIs

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21
Q

MOA of Bevacizumab

A

Targets free floating VEGF
(vaso-endothelial growth factor) to keep it from binding VEGFR on normal cells and recruit angiogenesis

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22
Q

PK of Bevacizumab

A

IV, long t1/2 (large molecule)
-usually combined w/ chemo
(similar to other VEGF mAbs)

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23
Q

3 VEGF mAbs, only need to know 1

A
  1. Bevacizumab*
  2. Ramucirumab
  3. ziv-aflibercept
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24
Q

4 VEGF mAbs toxicities

A
  1. *hemorrhage - GI perforations and delayed wound healing w/ decreased angiogenesis (would withhold for a month if having surgery)
  2. hypertension
  3. arterial thrombotic events
  4. proteinuria/nephrotic syndrome
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25
Q

What are VEGFR TKIs?

A

multi-targeted tyrosine kinase inhibitors of VEGFR, PDGFR, FGFR, c-kit, MET, etc

don’t need to know names, yet

-Regorafenib

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26
Q

How are VEGFR TKIs administered?

A

orally
-spec dosing for w/ or w/o food

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27
Q

Where are VEGFR TKIs metabolized?

A

Liver
-drug interactions w/ CYP3A4

28
Q

6 VEGFR TKI toxicities

A
  1. Hemorrhagic events - GI perforations, delayed wound healing
  2. hypertension
  3. hand-foot skin rxn & rash
  4. QT prolongation
  5. hypothyroidism
  6. fatigue/N/V/D
29
Q

What is hand-foot skin rxn and rash?

A

Looks like chemical irritant

30
Q

What is EGFR?

A

Epidermal growth factor receptors (HER1) and HER2
-membrane receptors
-ex RAS/RAF/MEK/ERK pathway
-ex PI3K/AKT pathway

31
Q

MOA of EGFR mAbs

A

Binds EGFR (HER1, c-ErbB-1), competitively inhibits EGF binding

32
Q

What is Cetuximab?

A

EGFR mAbs
IV admin, long t1/2
-combined w/ chemo
-KRAS wildtype in colorectal cancer

-if patient is KRAS mutated, need a diff med b/c path is already always turned on intracellularly and EGFR is upstream

33
Q

4 EGFR mAb toxicities

A
  1. infusion rxns
  2. Acneiform rash *
  3. Hypomagnesemia
  4. Diarrhea
34
Q

MOA EGFR TKIs

A
  1. Inhibit EGFR (HER1/ErbB-1) tyrosine kinase activity
  2. NSCLC: exon 19 deletions or exon 21 substitution
    - Erlotinib (metab induced by smoking)
  3. Oral
  4. CYP3A4 metabolism/interactions
35
Q

EGFR TKI toxicities

A
  1. Acneiform rash - use moisturizers, maybe topical steroids, tetracycline antibiotics
  2. diarrhea
  3. N/V
  4. fatigue
  5. interstitial lung disease
36
Q

What is HER2?

A
  1. member EGFR family
  2. receptor protein tyrosine kinase
  3. heterodimerizes w/ other EGFRs
  4. Affect RAS/RAF or PI3K/AKT pathways
37
Q

What happens to HER2 w/ cancer?

A

Gets amplified and overexpressed -> cell proliferation, cell growth and resistance to pro-apoptotic stimuli

38
Q

What cancers have HER2 amplification/overexpression?

A

Breast
Ovarian
Lung
Gastric
Oral cancers

39
Q

MOA Trastuzumab

A

Acts as competitive inhibitor to growth factors on HER2 receptor, so acts as a TKI
-extracellular (larger molecule than smaller ones that act intracellularly)

40
Q

HER2 directed therapy toxicities

A
  1. Cardiotoxicity
    -LVEF decline (monitored and mostly reversible)
    -heart failure
  2. infusion reactions
41
Q

What is BCR-ABL and what are drugs that Inhibit it (BCR-ABL TKIs)?

A

BCR-ABL = mutated fusion protein (t9;22) that results in constitutive tyrosine kinase activity (instead of needing activation)
Imatinib = first small molecule inhibitor of the BCR-ABL protein kinase

42
Q

MOA Imatinib

A

Blocks ATP binding pocket and tyrosine kinase activity in BCR-ABL protein

43
Q

Factors in choosing BCR-ABL TKIs

A
  1. choose 1st gen (Imatinib) or 2nd gen first
  2. cost
  3. mutational analysis
  4. compliance
44
Q

BCR-ABL TKI toxicities

A
  1. myelosuppression
  2. N/D
  3. Hepatotoxicity - most common non-hematologic
  4. Fluid retention/edema (mostly dasatinib)
  5. Arterial thrombotic events (ponatinib)
  6. Pancreatic toxicity (nilotinib)
  7. QT prolongation
45
Q

Whatdrug categories fall under immunotherapy?

A
  1. Anti-PD1
  2. Anti-PDL1
  3. Anti-CTLA4
  4. CAR T
46
Q

Normal process of tumor cells attacked by immune system

A
  1. tumor releases antigens
  2. antigens detected by APCs
  3. APCs present antigens to T cells via interaction of CD28 receptor on T cell w/ ligands on APC -> T cell activation
  4. T cells proliferate and migrate to the tumor
  5. T cells release apoptosis-inducing proteins
47
Q

How do tumor cells stop the immune system from killing them?

A

Via PD-1 and PD-L1 or PD-L2 inhibition
-these are immune system checkpoint receptors that inhibit T cell response by acting like healthy cells and avoid getting killed

48
Q

How do tumor cells stop the immune system from killing them?

A

Via PD-1 and PD-L1 or PD-L2 inhibition
-these are immune system checkpoint receptors that inhibit T cell response by acting like healthy cells and avoid getting killed

49
Q

MOA Nivolumab

A

=anti-PD-1
-PD-1 is a T-cell receptor that turns off activated T-cells thereby controlling the druation and intensity of an immune response
-Nivolumab keeps T cell activated
-used in many tumor types, more effective if tumor has upregulated PD-L1 expression

50
Q

What are 6 immune-related adverse events (IRAE’s)?

A

Autoimmune/inflammatory side effects:
1. breaking of tolerance to self-antigens
2. toxicities (~60%), grade 3 or 4 (severe) ~10-15%
3. diarrhea: tx = high dose steroids
4. dermatologic (pruritus or rash)
5. Endocrine (hyper-, hypo- thyroid, hypopituitarism, hypophysitis, adrenal insufficiency)
6. hepatic

  • more common w/ CTLA4 inhibitors vs PD-1 inhibitors
51
Q

What is CAR T?

A

=chimeric antigen receptor modified T-cell
-take person’s own T cells, modify them w/ specific antigen
-designed to recognize spec antigens on tumor cells -> T cell activation and proliferation -> destruction of malignant cells
-currently designed to target B-cells CD19
-considered “living drug,” persist long time

52
Q

What are CAR T Therapy drugs approved for?

A
  1. ALL
  2. NHL - know Axicabtagene ciloleucel
  3. MM

avg cost over $400k

53
Q

CAR T Toxicities

A
  1. Cytokine Release Syndrome (CRS) - T-cell mediated release of IL-6, TNF, INF, etc (like sepsis)
    -progressive, usually w/in 2-7 days, end organ damage possible, possibly life threatening
  2. Neurotoxicity: T-cell mediated cyotkine release. concomitant w/ CRS or independent. Progressive or spontaneous, possibly life threatening.
54
Q

What agents target Cytokine Release Syndrome?

A

Rescue agents:
1. Tocilizumab
Siltuximab

55
Q

What agents target Cytokine Release Syndrome?

A

Rescue agents:
1. Tocilizumab
Siltuximab

56
Q

BRAF Inhibitors

A

=type of kinase inhibitor that targets BRAF (intracellular enzyme)
-inhibits growth in melanomas by inhibiting kinase activity of mutated BRAF (V600E)
-Dabrafenib

56
Q

BRAF Inhibitors

A

=type of kinase inhibitor that targets BRAF (intracellular enzyme)
-inhibits growth in melanomas by inhibiting kinase activity of mutated BRAF (V600E)
-Dabrafenib

57
Q

BRAF inhibitor toxicities

A
  1. edema
  2. hand-foot
  3. rash
  4. hepatotoxicity
  5. secondary skin cancers
  6. basal cell/squamous cell carcinoma
58
Q

BRAF inhibitor toxicities

A
  1. edema
  2. hand-foot
  3. rash
  4. hepatotoxicity
  5. secondary skin cancers
  6. basal cell/squamous cell carcinoma
59
Q

MEK inhibitors

A

MEK is downstream of BRAF, so often combined w/ BRAF inhibitors

60
Q

4 other types of kinase inhibitors

A
  1. ALK inhibitors
  2. CDK (cyclin dependent kinase) inhibitors
  3. BTK (Bruton’s tyrosine kinase) inhibitor (highly active in cell malignancies)
  4. PI3K inhibitor - active in indolent lymphomas and CLL
61
Q

7 Small molecule inhibitors

A
  1. PARP inhibitors
  2. Proteosome inhibitors
  3. mTOR inhibitors
  4. Histone deacetylase inhibitors
  5. CD20 inhibitors
  6. CD52 inhibitor
  7. CD30 antibody drug conjugate
62
Q

PARP inhibitors

A

induce synthetic lethality in BRCA1 and BRCA2 deficient tumor cells by causing irrepairable double-stranded DNA breaks
-one repair mechanism already missing due to mutation, PARP inhibitor knocks out other repair mechanism to -> apoptosis

63
Q

MOA proteasome inhibitors

A

inhibit chymotrypsin-like activity at the 26S proteasome, disrupting protein homeostasis

64
Q

MOA mTOR inhibitors

A

antiproliferative and antiangiogenic properties

65
Q

MOA histone deacetylase inhibitors

A

causes accumulation of acetyl groups -> alters chromatin structure and transcription factor activation

66
Q

MOA Rituximab

A

=CD20 inhibitor
-CD20 on B-cells regulate cell cycle initiation
-inhibition ->
1. activation of complement-dependent B-cell cytotoxicity (ADCC)
2. antibody-dependent cell-mediated cytotoxicty
3. apoptosis

67
Q

Rituximab side effects

A
  1. infusion rxns
  2. viral infections (increased due to killing of B-cells)
68
Q

CD52 inhibitor MOA

A

CD52 present on surface of B and T lymphocytes
-binding -> ADCC

69
Q

MOA CD30 antibody drug conjugate

A

binds to CD30, forms a complex that’s internalized in cell and releases MMAE (microtubule inhibitor)

MCC (44 decks)

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