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Wk 5 Targeted Anti-cancer therapy Flashcards

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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
3 VEGF mAbs, only need to know 1
1. Bevacizumab* 2. Ramucirumab 3. ziv-aflibercept
24
4 VEGF mAbs toxicities
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
25
What are VEGFR TKIs?
multi-targeted tyrosine kinase inhibitors of VEGFR, PDGFR, FGFR, c-kit, MET, etc don't need to know names, yet -Regorafenib
26
How are VEGFR TKIs administered?
orally -spec dosing for w/ or w/o food
27
Where are VEGFR TKIs metabolized?
Liver -drug interactions w/ CYP3A4
28
6 VEGFR TKI toxicities
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
What is hand-foot skin rxn and rash?
Looks like chemical irritant
30
What is EGFR?
Epidermal growth factor receptors (HER1) and HER2 -membrane receptors -ex RAS/RAF/MEK/ERK pathway -ex PI3K/AKT pathway
31
MOA of EGFR mAbs
Binds EGFR (HER1, c-ErbB-1), competitively inhibits EGF binding
32
What is Cetuximab?
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
4 EGFR mAb toxicities
1. infusion rxns 2. Acneiform rash * 3. Hypomagnesemia 4. Diarrhea
34
MOA EGFR TKIs
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
EGFR TKI toxicities
1. Acneiform rash - use moisturizers, maybe topical steroids, tetracycline antibiotics 2. diarrhea 3. N/V 4. fatigue 5. interstitial lung disease
36
What is HER2?
1. member EGFR family 2. receptor protein tyrosine kinase 3. heterodimerizes w/ other EGFRs 4. Affect RAS/RAF or PI3K/AKT pathways
37
What happens to HER2 w/ cancer?
Gets amplified and overexpressed -> cell proliferation, cell growth and resistance to pro-apoptotic stimuli
38
What cancers have HER2 amplification/overexpression?
Breast Ovarian Lung Gastric Oral cancers
39
MOA Trastuzumab
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
HER2 directed therapy toxicities
1. Cardiotoxicity -LVEF decline (monitored and mostly reversible) -heart failure 2. infusion reactions
41
What is BCR-ABL and what are drugs that Inhibit it (BCR-ABL TKIs)?
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
MOA Imatinib
Blocks ATP binding pocket and tyrosine kinase activity in BCR-ABL protein
43
Factors in choosing BCR-ABL TKIs
1. choose 1st gen (Imatinib) or 2nd gen first 2. cost 3. mutational analysis 4. compliance
44
BCR-ABL TKI toxicities
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
Whatdrug categories fall under immunotherapy?
1. Anti-PD1 2. Anti-PDL1 3. Anti-CTLA4 4. CAR T
46
Normal process of tumor cells attacked by immune system
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 3. T cells proliferate and migrate to the tumor 4. T cells release apoptosis-inducing proteins
47
How do tumor cells stop the immune system from killing them?
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
How do tumor cells stop the immune system from killing them?
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
MOA Nivolumab
=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
What are 6 immune-related adverse events (IRAE's)?
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
What is CAR T?
=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
What are CAR T Therapy drugs approved for?
1. ALL 2. NHL - know Axicabtagene ciloleucel 3. MM avg cost over $400k
53
CAR T Toxicities
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
What agents target Cytokine Release Syndrome?
Rescue agents: 1. Tocilizumab Siltuximab
55
What agents target Cytokine Release Syndrome?
Rescue agents: 1. Tocilizumab Siltuximab
56
BRAF Inhibitors
=type of kinase inhibitor that targets BRAF (intracellular enzyme) -inhibits growth in melanomas by inhibiting kinase activity of mutated BRAF (V600E) -Dabrafenib
56
BRAF Inhibitors
=type of kinase inhibitor that targets BRAF (intracellular enzyme) -inhibits growth in melanomas by inhibiting kinase activity of mutated BRAF (V600E) -Dabrafenib
57
BRAF inhibitor toxicities
1. edema 2. hand-foot 3. rash 4. hepatotoxicity 5. secondary skin cancers 6. basal cell/squamous cell carcinoma
58
BRAF inhibitor toxicities
1. edema 2. hand-foot 3. rash 4. hepatotoxicity 5. secondary skin cancers 6. basal cell/squamous cell carcinoma
59
MEK inhibitors
MEK is downstream of BRAF, so often combined w/ BRAF inhibitors
60
4 other types of kinase inhibitors
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
7 Small molecule inhibitors
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
PARP inhibitors
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
MOA proteasome inhibitors
inhibit chymotrypsin-like activity at the 26S proteasome, disrupting protein homeostasis
64
MOA mTOR inhibitors
antiproliferative and antiangiogenic properties
65
MOA histone deacetylase inhibitors
causes accumulation of acetyl groups -> alters chromatin structure and transcription factor activation
66
MOA Rituximab
=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
Rituximab side effects
1. infusion rxns 2. viral infections (increased due to killing of B-cells)
68
CD52 inhibitor MOA
CD52 present on surface of B and T lymphocytes -binding -> ADCC
69
MOA CD30 antibody drug conjugate
binds to CD30, forms a complex that's internalized in cell and releases MMAE (microtubule inhibitor)

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