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Pulmonology > Sweatman: Lung Cancer Drugs > Flashcards

Sweatman: Lung Cancer Drugs Flashcards

1
Q

basis for treament of lung cancer: NSLC

A
  1. often able to resect surgically
  2. more targetted therapies
  3. histological subtype should always be reported
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2
Q

basis for tx. of SCLC

A
  1. usually mets at time of dx. therfore not surgically resectable most often
  2. demonstrate a high sucseptibility to tx. but usually a relaps in 8 mos with a more lethal form of cancer causing deaht in 4mos on average
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3
Q

dx of NSCLC requires

A

explicit reporting if histo-subtype

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4
Q

EGFR mutations found in/not found in

A

found in adenocarcinomas

not found in Large cell, small cell, pure squamous carcinomas

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5
Q

Bevacizumab is associate with what side effect

A

ONLY PPROVED IN NON-SQUAMOUS NSCLC’S

high risk of bleeding in squamous lung cancers and therefore only

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6
Q

what are dirver mutaitons and passenger mutations

A

driver-> critical for cell-growth or survival

passenger-> mutations that accumulate not directly linked to survival or growth advantage

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7
Q

why are driver mutations important targets

A

drugs targetting newly critical driver enzymes can be highly effective agents because cancer cells are often times become reliant on these pathways at the expense of other previously critical cell-survival pathways (OVERDEPENDENCE MECHANISMS)
*TARGETTING PASSENGER MUTATIONS DOES NOTHING

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8
Q

DESCRIBE SYNTHETIC LETHALITY

A

IN A NORMAL CELL–> YOU MUST INACTIVATE 2 MUTATIONS A+B IN ORDER TO COMPROMISE CELL VIABILITY–> INACTIVATION OF A SINGLE GENE DOES NOT KILL CELL–> REMAMINING GENE ACTS IN A COMPENSATORY MANNER
*SYNTHETIC L;ETHALITY IN A CANCER CELL WITH A MUTATED GENE A NOW MAKES THE CELL VULERABLE BECAUSE B IS NOW A SOLE TARGET TO KILL THE CELL–> A CANNOT COMPENSATE

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9
Q

HOW does egfr receptor work

A

egf–egfr= dimerization and tyrosine residue trans-phophorylation–> signals to the nucleus–> cell growth and proliferation–> avoidance of apoptosis
GOF in this pathway=some cancers

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10
Q

GOF mutations in egfr result in

A
  1. receptor amplification
  2. mutation
  3. translocation
    * self sufficiency in cell signalling–> anti-apoptotic
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11
Q

TKI’s work to

A

inhibit signal propagation from the dimerized TKR–> cell does not receive proliferation signal and undergoes apoptosis

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12
Q

mechanisms of reistance to TKI’s at the level of the EGFR

ALL OF WHICH LEAD TO SURVIVAL SIGNALS

A
  1. binding site mutation (small molecule no longer bind tkr)
  2. amplified met (AKA HGFR)–> compensatory trans-phosph
  3. HGF assuming independent role in the proliferativesignalling process
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13
Q

resistance to TKI’s regarding pro-apoptotic proteins

other than tki binding site mutations

A
  1. polymorphisms in apoptosis genes–> BIM
    a. absence of pro-apoptotic gene BH3
    bBAX and BAk downregulated while BCL2 and MCL1 are upregulated (anti-apoptotic)
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14
Q

TKI resistance downstream of EGFR

A

KRAS mutations
*negative response predictor in lung/colorectal cancer
BRAF mutations

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15
Q

mechanism of resistance that renders a tumor line unresponsive to TKI’s

A

KRAS and BRAF

*downstream of TKR/EGFR complex

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16
Q

targeted therapy most usful in compatting which lung cacinoma sub-type

A

adenocarcinoma

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17
Q

ALK stands for

A

anaplastic lymphoma kinase

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18
Q

EML4/ALK arises from what and does what?

A

fusion of these two genes translocation–> activates ras raf MEK/ERK pathway and promotes cell proliferation

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19
Q

anti-AML4/ALK drug

A

crozitinib

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20
Q

anti-vegf drug

A

bevacizumab

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21
Q

proliferation/ mets of solid tumurs requires…

A

formation of new vasculature

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22
Q

how does a tumur go about neo-vascularization

A

sensing HIF1–> releasing VEGF in hypoxic states (HIF1 is not destroyed by VWF in truly hypoxic states(–. goes to nucleus and causes transcription of VEGF->neovascularization

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23
Q

down sides to bevacizumab therapy

A
  1. reduce distribution of concurrent chemotherapy
  2. induce accumulation of more aggressive cells (with increased capacity to spread to other organs)
    * applies a major selective pressure on 2-independent cell population–> can make them more resistant to tx.
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24
Q

distribution of orally administered crozitinib (aml), erlotinib (egfr) and lapitinib (vegfr tki) is effected by

A

Must be absorbed in the gut and small intestines

metabolism depends on bioavailability and host pharmacogenetics

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25
Q

variations in germline (idiopathic) constitution of individual pt.’s can impact

A

response to treatment and toxicity-associated-off target effects

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26
Q

EML4/alk stands for

A

echinoderm microtubule associated like protein 4/anaplastic lymphoma kinase

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27
Q

EML4/alk inhibitor

A

crizotinib

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28
Q

egfr inhibitor

A

erlotinib

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29
Q

all mutations are more common in smokers except (4)

A
  1. EGFR (45%)
  2. EML4-ALK fusions
  3. HER 2 mutations
  4. hMSH2 expression
    * all relatively more common in never smokers than smokers
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30
Q

methylation index in never-smokers relative to smokers

A

low in non-smokers

high in smokers

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31
Q

2 Most common mutations in adenocarcinoma pt.’s

A

KRAS (25%) and EGFR (23%)

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32
Q

regardinng genetic testing

A

60% actionable mutations IN AL ADENOCARCINOMAS

*histop-subtype now guides treatment accoridng to NCCO and ASCO guidelines

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33
Q

PREFERRED TEST FOR EGFR

A

DNA sequencing

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34
Q

Preferred test for EML4/alk

A

FISH

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35
Q

Peventative recommendation for lung cancer screening

A

55-80 yo with >30 pack year hx, who have quit in the past 15 yrs, –> LOW DOSE CT LUNG SCANS
*NOT YEARLY SCANS

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36
Q

TX PLAN FOR SCLC:

A

METS BY TIME OF DX–> CHEMOTHERAPY IS ONLY OPTION

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37
Q

TX. PLAN FOR NSCLC

A

SURGICAL RESECTION IF NO METS (VERY EARLY)

–>RADIATION USED IN ADJUVANT, NEOADJUVANT, OR MAINTAINENCE ROLE

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38
Q

NEOADJUVANT

A

GIVEN FIRS (REDUCE TUMOR BULK) TO SHRINK TUMOR SO IT CAN BE MORE READILY SURGICALLY EXCISED

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39
Q

ADJUVANT

A

GIVEN FOLLOWING SURGURY TO PREVENT RELAPSE GROWTH AND METASTASIS

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40
Q

METS USUALLY SPREAD TO

A

ADRENALS, LIVER, BRAIN, BONES

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41
Q

mets from which organs most prominently end up in the lungs

A

breast, colon, stomach, pancreas kidneys, skin prostate liver. thyroid

42
Q

conventional chemo therapy guidelines for SCLC

A

Etoposide + cisplatin or carboplatin

a fuck ton of others which include
cisplatin
of cyclophoshamide to begin with

43
Q

standard tx options for NSCLC

A

Cisplatin AND one of the following (commonly a taxane)

:Paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan or pemetrexed (maintainence)

44
Q

permetrexed class

A

DHFRi–> methotrexate analog

45
Q

NON-standard tx options for NSCLC

A

based on genetic markers–> TKI’s and VEGF inhbitors can be incorporated

46
Q

when is bevacizumab indicated

A

patients with non-squamous histology, no brain mets, no hemoptysis

47
Q

pemetrexed is indicated in

A

Maintainence therapy in patients with stable of responding disease following 4 cycles of non-pemetrexed-platinum combo therapy

48
Q

MOA for carboplatin and Cisplatin

A

forms DNA intrstrand crosslinks and adducts

49
Q

MOR for carboplatin and cisplatin

A

enhanced DNA repair enzymes

50
Q

MOA for cyclophosphamide

A

pro-drug of active alkylating moeity

51
Q

MOR for cyclophosphamide

A

increased glutathion DNA repair

52
Q

MOA for docetaxel

A

microtubule stabalizer -> inhibits dpolymerization

53
Q

MOR for docetaxel

A

???

54
Q

MOA for etoposide

A

DNA topo II complex stabalizer–> prevents re-ligation of DNA during replication

55
Q

MOA for gemcitabine

A

DNA pol. inhibitor via incorporation of triphosphate form during DNA synthesis

56
Q

MOA for ifosfamide

A

intra and inter strand complex stabilizer

57
Q

irinotecan MOA

A

DNA topo I complex stabalizer

58
Q

paclitaxel MOA

A

microtubule stablizer inhibiting DEPOLYMERIZATION

59
Q

pemetrxed MOA

A

DHFRi–> cell runs out of tetrahydrofolate and eventually thiamine

60
Q

moa for topotecan

A

DNA topo I complex stabalizer

61
Q

VIncristine/vinblastin MOA

A

inhibit microtubule polymerization, tubule disintegrate into spiral aggregates/protofilaments

62
Q

toxicity for carboplatin

A

anemia, platinum allergy, increase hepatic enzymes BUN and creatinine elevation

63
Q

cisplatin toxicity

A

renal , ototoxicity, tinitus and deafness

64
Q

toxicity for cyclophosphamide

A

hemorrhagic cystitis–> mesna is antidote, secondary maligancies, pulmonary fibrosis, amenorrhea/infertility, anemia, renal compromise

65
Q

toxicity with docetaxel

A

sensory neuropathy, CONTRAINDICATED IN LIVER DYSFUNCITON (INC ALK-PHOSPH, HILIRUIBIN, SGOT,SGPT)
increased mortality in NSCLC, edema

66
Q

TXICITY WITH DOXORUBUCIN

A

CARDIOTOXICITY, CHF, HEPATIC DISEASE, SECONDARY MALIGNANCY, EXTRAVASATIONAL NECROSIS,

67
Q

ETOPOSIDE TOXICITY

A

ALOPECIA, infection, hematologic toxicity

68
Q

toxicity with gemcitabine

A

peripheral sensory neuropathy, alopecia

69
Q

ifosfamide toxicity

A

alopecia, blood dyscrasias–>infection (leukopenia), neurotoxicity, hematuria and renal failure

70
Q

irinotecan toxicity

A

weight loss, dirrhea

71
Q

paclitaxel toxicity

A

taxane hypersensitivity,

72
Q

toxicity with premetrexed

A

myelosupression and GI toxicitie (especially when combined with cisplatin) agaisnt NSCLC
elevted LFT’s and serum creatinine

73
Q

toxicity of topotecan

A

GI, hyperbilirubinemia

74
Q

Vinblastine and Vinorelbine toxcities

A

neurpathic toxicity (less with vinorelbine), neutropenia (vinobelrine)

75
Q

fatal if given intracethcally

A

vinca alkaloids in the spinal cord

76
Q

reversible inhibitor selective for EGFR (ERBb1)

A

erlotinib

77
Q

erlotinib cannot be given with

A

food–> control for variability in bioavailabiltiy

78
Q

cyp that metabolises erlotinib

A

CYP3A4>1A2

*smoking increases clearance

79
Q

side effects of erlotinib (TARCEVA)

A

diarrhea common, organ failure kidney/liver (secondary to liver dysfunction)–> rash, hypertripchosis, and conjuctivitis

80
Q

two TKi’s approved for tx of lung cancer

A

Afatinib and erlotinib

81
Q

MOA for afatinib

A

covalent inhibitor (non reversible) of EGFR, ER2, HER4

82
Q

MOR FOR AFATINIB

A

INHIBITOR AND SUBSTRATE FOR PGP PUMP
(p glycoprotein–> increases efflux from gut)
TAKE ON EMPTY STOMACH

83
Q

SIDE EFFECTS OF AFATINIB

A

RASH AND DIRAHHEA INEVITBALE

LESS SE’S THAN ERLOTINIB

84
Q

TKI RASH NECESSITATES

A

STEROIDS, ANTIMICROBIALS, COLLOID OATMEAL LOTIONS

*REDUCE DRUG DOSE, OR INTERMITTENTN/PERMANENT DISCONTINUATION MAY BE REQUIRED

85
Q

describe Primary mutation in NSCLC

initially a good thing!!!)

A

primary mutation opens the theraputic window–> compromises in ATP affinity and icnreases in initial sensitivity to erlotinib/afitinib
*in frame deletion of chromosome 19
Point mutation in Leu-858 with ARginine (L858R)

86
Q

second mutation in TKI’s

A

closes therputic window–> conferse resistance
usually a T790M mutations–> outgrowth of pre-existing clones that are inherently resistant
*restores atp affinity to nar WT levels

87
Q

MOA for crizotinib

A

reversible–>multi-kinase inhbitor including ALK and ROS1

88
Q

metabolism of crizotinib

A

CYP3a4 and pgp substrate/inhbitor

89
Q

toxicities of crizotinib

A

eye, liver
rash rare
QT prolong rare 2%

90
Q

mutations conferring resistance to crizotinib

A

G2032R ROS1

–>OUTGROWTH OF TUMUR CLONES WITH INHERENT RESISTANCE

91
Q

gatekeeper residue for ROS1

A

L2026

92
Q

Bevacizumab

A

AVASTIN–> humanized MAB–> binds vegf–> prevents neovascularization signals in hypoxic microenvironment

93
Q

administration of AVASTIN

A

iv infusion–> no first pass metabolism, excreted unchanged no known D-D interxns, long half life

94
Q

toxicities of bevacizumab

A

thromboembolism, hemorrhage, fistula promotion (GI< VAGINAL, BRONCHOPULMONARY, proteinuria. HTN

95
Q

VEGF oinhibition side efect LIFE THREATENING

A

severe bleeding–>PROTHROMBOTIC AND LOSS OF VASCULAR INTEGRITY-> vasculature is now inhibited from forming proper edothelial matrix and is much more likley to bleed
*GI perfortion, and impaired wound healing

96
Q

PT’S WITH HIGHEST RISK OF BLEEDING FROM BEVACIZUMAB THERAPY

A

NSCLS (SQUAMOUS), RENAL CELL CARCINOMA, COLORECTAL CANCER

97
Q

BEVACIZUMAB CONTRAINDICATED IN WHAT HISTO TYPE

A

SQUAMOUS

98
Q

MOA FOR INCREASE BLEEDING RISK FOR BECAIZUMAB

A

CAUSES CENTRAL NECROSIS AND ENLARGES TUMOR CAVITY IN PT.;S WITH SQUAMOUS NSCLC–> IN COMBO WITH IMMATURE BV’S–> BLEEDING RISK IS GREATLY ICNREASED

99
Q

GENETIC TESTIC IS EXTREMELY IMPORTANT FOR ______ BUT NOT FOR_____

A

ADENOCARCINOMA LOOKING FOR EGFR MUTATION–> BUT NOT FOR SQUAMOUS HISTOLOGY

100
Q

EGFR MUTANTS ARE CANDIATES FOR

A

ERLOTINIB AND AFATINIB

101
Q

AML4-alk mutations are candidates fro

A

crizotinib

Pulmonology (10 decks)

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