Sweatman: Lung Cancer Drugs Flashcards
basis for treament of lung cancer: NSLC
- often able to resect surgically
- more targetted therapies
- histological subtype should always be reported
basis for tx. of SCLC
- usually mets at time of dx. therfore not surgically resectable most often
- 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
dx of NSCLC requires
explicit reporting if histo-subtype
EGFR mutations found in/not found in
found in adenocarcinomas
not found in Large cell, small cell, pure squamous carcinomas
Bevacizumab is associate with what side effect
ONLY PPROVED IN NON-SQUAMOUS NSCLC’S
high risk of bleeding in squamous lung cancers and therefore only
what are dirver mutaitons and passenger mutations
driver-> critical for cell-growth or survival
passenger-> mutations that accumulate not directly linked to survival or growth advantage
why are driver mutations important targets
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
DESCRIBE SYNTHETIC LETHALITY
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
HOW does egfr receptor work
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
GOF mutations in egfr result in
- receptor amplification
- mutation
- translocation
* self sufficiency in cell signalling–> anti-apoptotic
TKI’s work to
inhibit signal propagation from the dimerized TKR–> cell does not receive proliferation signal and undergoes apoptosis
mechanisms of reistance to TKI’s at the level of the EGFR
ALL OF WHICH LEAD TO SURVIVAL SIGNALS
- binding site mutation (small molecule no longer bind tkr)
- amplified met (AKA HGFR)–> compensatory trans-phosph
- HGF assuming independent role in the proliferativesignalling process
resistance to TKI’s regarding pro-apoptotic proteins
other than tki binding site mutations
- polymorphisms in apoptosis genes–> BIM
a. absence of pro-apoptotic gene BH3
bBAX and BAk downregulated while BCL2 and MCL1 are upregulated (anti-apoptotic)
TKI resistance downstream of EGFR
KRAS mutations
*negative response predictor in lung/colorectal cancer
BRAF mutations
mechanism of resistance that renders a tumor line unresponsive to TKI’s
KRAS and BRAF
*downstream of TKR/EGFR complex
targeted therapy most usful in compatting which lung cacinoma sub-type
adenocarcinoma
ALK stands for
anaplastic lymphoma kinase
EML4/ALK arises from what and does what?
fusion of these two genes translocation–> activates ras raf MEK/ERK pathway and promotes cell proliferation
anti-AML4/ALK drug
crozitinib
anti-vegf drug
bevacizumab
proliferation/ mets of solid tumurs requires…
formation of new vasculature
how does a tumur go about neo-vascularization
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
down sides to bevacizumab therapy
- reduce distribution of concurrent chemotherapy
- 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.
distribution of orally administered crozitinib (aml), erlotinib (egfr) and lapitinib (vegfr tki) is effected by
Must be absorbed in the gut and small intestines
metabolism depends on bioavailability and host pharmacogenetics
variations in germline (idiopathic) constitution of individual pt.’s can impact
response to treatment and toxicity-associated-off target effects
EML4/alk stands for
echinoderm microtubule associated like protein 4/anaplastic lymphoma kinase
EML4/alk inhibitor
crizotinib
egfr inhibitor
erlotinib
all mutations are more common in smokers except (4)
- EGFR (45%)
- EML4-ALK fusions
- HER 2 mutations
- hMSH2 expression
* all relatively more common in never smokers than smokers
methylation index in never-smokers relative to smokers
low in non-smokers
high in smokers
2 Most common mutations in adenocarcinoma pt.’s
KRAS (25%) and EGFR (23%)
regardinng genetic testing
60% actionable mutations IN AL ADENOCARCINOMAS
*histop-subtype now guides treatment accoridng to NCCO and ASCO guidelines
PREFERRED TEST FOR EGFR
DNA sequencing
Preferred test for EML4/alk
FISH
Peventative recommendation for lung cancer screening
55-80 yo with >30 pack year hx, who have quit in the past 15 yrs, –> LOW DOSE CT LUNG SCANS
*NOT YEARLY SCANS
TX PLAN FOR SCLC:
METS BY TIME OF DX–> CHEMOTHERAPY IS ONLY OPTION
TX. PLAN FOR NSCLC
SURGICAL RESECTION IF NO METS (VERY EARLY)
–>RADIATION USED IN ADJUVANT, NEOADJUVANT, OR MAINTAINENCE ROLE
NEOADJUVANT
GIVEN FIRS (REDUCE TUMOR BULK) TO SHRINK TUMOR SO IT CAN BE MORE READILY SURGICALLY EXCISED
ADJUVANT
GIVEN FOLLOWING SURGURY TO PREVENT RELAPSE GROWTH AND METASTASIS
METS USUALLY SPREAD TO
ADRENALS, LIVER, BRAIN, BONES
mets from which organs most prominently end up in the lungs
breast, colon, stomach, pancreas kidneys, skin prostate liver. thyroid
conventional chemo therapy guidelines for SCLC
Etoposide + cisplatin or carboplatin
a fuck ton of others which include
cisplatin
of cyclophoshamide to begin with
standard tx options for NSCLC
Cisplatin AND one of the following (commonly a taxane)
:Paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan or pemetrexed (maintainence)
permetrexed class
DHFRi–> methotrexate analog
NON-standard tx options for NSCLC
based on genetic markers–> TKI’s and VEGF inhbitors can be incorporated
when is bevacizumab indicated
patients with non-squamous histology, no brain mets, no hemoptysis
pemetrexed is indicated in
Maintainence therapy in patients with stable of responding disease following 4 cycles of non-pemetrexed-platinum combo therapy
MOA for carboplatin and Cisplatin
forms DNA intrstrand crosslinks and adducts
MOR for carboplatin and cisplatin
enhanced DNA repair enzymes
MOA for cyclophosphamide
pro-drug of active alkylating moeity
MOR for cyclophosphamide
increased glutathion DNA repair
MOA for docetaxel
microtubule stabalizer -> inhibits dpolymerization
MOR for docetaxel
???
MOA for etoposide
DNA topo II complex stabalizer–> prevents re-ligation of DNA during replication
MOA for gemcitabine
DNA pol. inhibitor via incorporation of triphosphate form during DNA synthesis
MOA for ifosfamide
intra and inter strand complex stabilizer
irinotecan MOA
DNA topo I complex stabalizer
paclitaxel MOA
microtubule stablizer inhibiting DEPOLYMERIZATION
pemetrxed MOA
DHFRi–> cell runs out of tetrahydrofolate and eventually thiamine
moa for topotecan
DNA topo I complex stabalizer
VIncristine/vinblastin MOA
inhibit microtubule polymerization, tubule disintegrate into spiral aggregates/protofilaments
toxicity for carboplatin
anemia, platinum allergy, increase hepatic enzymes BUN and creatinine elevation
cisplatin toxicity
renal , ototoxicity, tinitus and deafness
toxicity for cyclophosphamide
hemorrhagic cystitis–> mesna is antidote, secondary maligancies, pulmonary fibrosis, amenorrhea/infertility, anemia, renal compromise
toxicity with docetaxel
sensory neuropathy, CONTRAINDICATED IN LIVER DYSFUNCITON (INC ALK-PHOSPH, HILIRUIBIN, SGOT,SGPT)
increased mortality in NSCLC, edema
TXICITY WITH DOXORUBUCIN
CARDIOTOXICITY, CHF, HEPATIC DISEASE, SECONDARY MALIGNANCY, EXTRAVASATIONAL NECROSIS,
ETOPOSIDE TOXICITY
ALOPECIA, infection, hematologic toxicity
toxicity with gemcitabine
peripheral sensory neuropathy, alopecia
ifosfamide toxicity
alopecia, blood dyscrasias–>infection (leukopenia), neurotoxicity, hematuria and renal failure
irinotecan toxicity
weight loss, dirrhea
paclitaxel toxicity
taxane hypersensitivity,
toxicity with premetrexed
myelosupression and GI toxicitie (especially when combined with cisplatin) agaisnt NSCLC
elevted LFT’s and serum creatinine
toxicity of topotecan
GI, hyperbilirubinemia
Vinblastine and Vinorelbine toxcities
neurpathic toxicity (less with vinorelbine), neutropenia (vinobelrine)
fatal if given intracethcally
vinca alkaloids in the spinal cord
reversible inhibitor selective for EGFR (ERBb1)
erlotinib
erlotinib cannot be given with
food–> control for variability in bioavailabiltiy
cyp that metabolises erlotinib
CYP3A4>1A2
*smoking increases clearance
side effects of erlotinib (TARCEVA)
diarrhea common, organ failure kidney/liver (secondary to liver dysfunction)–> rash, hypertripchosis, and conjuctivitis
two TKi’s approved for tx of lung cancer
Afatinib and erlotinib
MOA for afatinib
covalent inhibitor (non reversible) of EGFR, ER2, HER4
MOR FOR AFATINIB
INHIBITOR AND SUBSTRATE FOR PGP PUMP
(p glycoprotein–> increases efflux from gut)
TAKE ON EMPTY STOMACH
SIDE EFFECTS OF AFATINIB
RASH AND DIRAHHEA INEVITBALE
LESS SE’S THAN ERLOTINIB
TKI RASH NECESSITATES
STEROIDS, ANTIMICROBIALS, COLLOID OATMEAL LOTIONS
*REDUCE DRUG DOSE, OR INTERMITTENTN/PERMANENT DISCONTINUATION MAY BE REQUIRED
describe Primary mutation in NSCLC
initially a good thing!!!)
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)
second mutation in TKI’s
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
MOA for crizotinib
reversible–>multi-kinase inhbitor including ALK and ROS1
metabolism of crizotinib
CYP3a4 and pgp substrate/inhbitor
toxicities of crizotinib
eye, liver
rash rare
QT prolong rare 2%
mutations conferring resistance to crizotinib
G2032R ROS1
–>OUTGROWTH OF TUMUR CLONES WITH INHERENT RESISTANCE
gatekeeper residue for ROS1
L2026
Bevacizumab
AVASTIN–> humanized MAB–> binds vegf–> prevents neovascularization signals in hypoxic microenvironment
administration of AVASTIN
iv infusion–> no first pass metabolism, excreted unchanged no known D-D interxns, long half life
toxicities of bevacizumab
thromboembolism, hemorrhage, fistula promotion (GI< VAGINAL, BRONCHOPULMONARY, proteinuria. HTN
VEGF oinhibition side efect LIFE THREATENING
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
PT’S WITH HIGHEST RISK OF BLEEDING FROM BEVACIZUMAB THERAPY
NSCLS (SQUAMOUS), RENAL CELL CARCINOMA, COLORECTAL CANCER
BEVACIZUMAB CONTRAINDICATED IN WHAT HISTO TYPE
SQUAMOUS
MOA FOR INCREASE BLEEDING RISK FOR BECAIZUMAB
CAUSES CENTRAL NECROSIS AND ENLARGES TUMOR CAVITY IN PT.;S WITH SQUAMOUS NSCLC–> IN COMBO WITH IMMATURE BV’S–> BLEEDING RISK IS GREATLY ICNREASED
GENETIC TESTIC IS EXTREMELY IMPORTANT FOR ______ BUT NOT FOR_____
ADENOCARCINOMA LOOKING FOR EGFR MUTATION–> BUT NOT FOR SQUAMOUS HISTOLOGY
EGFR MUTANTS ARE CANDIATES FOR
ERLOTINIB AND AFATINIB
AML4-alk mutations are candidates fro
crizotinib
