Rx for Lung Cancer- Sweatman Flashcards
Name 3 mechanisms of resistance to TKIs
1) Drug binding site mutation (highly conserved ATP binding site)
2) Compensatory Tyrosine phosphorylation by MET
3) MET assumes an independent role in the proliferative signaling process
What are the 2 common downstream mutations in the EGFR/Tyrosine Kinase complex pathway?
Constitutive activation of KRAS or BRAF
What effect does downstream mutation have on drug therapy?
It renders it useless
What is the effect of the EML4-ALK oncogene?
Activation of MEK/ERK, subsequent proliferation
Who is the EML4-ALK mutation seen in?
Non-smokers and those with adenocarcinomas
What is the mechanism for VEGF release?
Hypoxia is sensed by the cell–> induces HIF-1–>HIF-1 translates to the nucleus–>VEGF is transcribed–>Angiogenesis
What TKI is used against EML4-ALK?
Crizotinib
What TKI is used against EGFR?
Erlotinib
What is the gold standard CONVENTIONAL chemo treatment for SCLC?
Etoposide + cisplatin or carboplatin
When is Erlotinib first line therapy?
Treatment of locally advanced or metastatic NSCLC after failure of at least one prior chemo regimen
Mechanism of 6-Mercaptopurine, 6-Thioguanine, and Methotrexate therapy?
Inhibits purine ring synthesis; the first 2 interrupt elongation after incorporation into the strand; MTX is a DHFR antagonist
Mechanism of Hydroxyurea?
Inhibits ribonucleotide reductase
Mechanism of 5-Fluorouracil?
Inhibits dTMP synthesis
Mechanism of Cytarabine?
Inhibits DNA synthesis (antimetabolite)
Mechanism of Bleomycin?
Acts as molecular scissors to cut DNA strands
Mechanism of the Anthracyclines?
Intercalate DNA; also produces free radicals (where the cardiomyopathy comes from)
Mechanism of the alkylating agents, Nitrosureas, and Platinum drugs?
Cross-link DNA
Mechanism of L-aspariginase?
Inhibits protein synthesis
Mechanism of Taxanes and Vincas?
Inhibit microtubule function; Taxanes stabilize and Vincas prevent formation
Unique toxicities of the platinum drugs?
Ototoxicity and Nephrotoxicity
Unique toxicity of cyclophosphamide and ifosfamide? What is given with it to prevent this?
Hemorrhagic cystitis (more so cyclophosphamide); mesna protects the bladder
Unique toxicities seen in the taxanes and vincas? What clinical finding helps you diagnose this?
Peripheral neuropathy; loss of deep tendon reflex
Unique toxicity of the anthracylcines (doxorubicin, daunorubicin, and idrarubicin)? What is given to protect against it?
Cardiomyopathy–>CHF; co-administer with dexrazoxane
What are some downsides to oral therapy (TKIs)?
Interactions with CYP, P-gp efflux pumps, first-pass metabolism, and drug drug interactions
Are TKIs used for NSCLC or SCLC?
NSCLC
Name the common ADEs of TKIs
1) EGFR antagonists cause skin rash
2) All TKIs cause GI symptoms like nausea, vomiting, diarrhea (EGFR important in maintenance of GI cells)
3) Endocrine dysfunction and QT prolongation
Why are there so many ADEs associated with TKIs?
The target is very nonspecific and it plays an important homeostatic role in multiple tissues throughout the body
What is the definition of a pharmacodynamic change? what are some examples?
A change in the level of drug in the body; protein binding, efflux pumps
What is the definition of pharmacokinetic change?
Alteration of the molecular target
What is the role of CTLA-4?
plays an important role in T cell activation at initial antigen presentation
What is PD1?
Don’t you mean PD-L1? What a fucking douche
What is the significance of PD-L1 expression by cancer cells?
It binds T-cells and tells the lymphocyte it is a friendly cell; evades the immune system
What is Nivolumab?
A recently approved drug; only for metastatic disease after platinum drug based therapy
Mechanism of action of Bevacizumab?
Inhibits VEGF–> inhibits angiogenesis
What are a couple life threatening toxicites of Bevacizumab?
Thromboembolism, fistula formation, hemorrhage
Why does Bevacizumab cause nephrotoxicity?
Because VEGF plays an important homeostatic role in maintaing the glomerular basement membrane
Why is bevacizumab not recommended for treatment of squamous cell lung carcinoma?
Because it commonly causes fatal hemorrhage
