Justin's Biologic/Targeted Therapy + 2018 Flashcards
Which is not a growth factor target for treatment? (EGFR, VEGF, MTOR)
mTOR: mammalian target of rapamycin, is the major regulator of growth in animals and controls most anabolic and catabolic processes in response to nutrients and nutrient-induced signals
Everolimus (rapamycin analog) binds to FKBP-12 which interacts with mTORC1, inhibiting downstream signaling–G1-S cell cycle arrest.
mTORC1: controls translation, supresses autophagy, regulates transcription and response to DNA damage
Which factor leads to poor outcomes in treatment of ovarian cancer with Her2neu (Trastuzumab)?
A No amplification of ERBB2
B mutation of ERBB2
C mutation of ERBB1
D amplification of ERBB1
No amplification of ERBB2–trastuzumab won’t help unless this is amplified
Trastuzumab: directed against the juxtamembranous portion of the extracellular domain of Her2/Neu; it prevents Her2 dimerization, increases endocytosis and down-regulation of the receptor; leads to cell cycle arrest by release of p27kip1; inhibits MMP mediated cleavage and shedding of extracellular receptor domain; immune activation
RESISTANCE: alterations in downstream signaling cascades (loss of PTEN); hetero-dimerization with IGF-1; receptor epitope masking
What is the function of Gefitinib (Iressa)?
**TEST QUESTION **
selective EGFR tyrosine kinase inhibitor (first described)
It binds to ATP binding pocket of the intracellular EGFR tyrosine kinase domain and prevents ATP binding and transphosphorylation of activated EGFR dimers.
limited benefit in gyn cancers
What does not interact with imatinib?
A EGFR
B ckit
C ABL
D PDGFR
EGFR
Imatinib inhibits Bcr-Abl fusion protein tyrosine kinase (produced by CML cells that contain Philadelphia chromosome); also inhibits receptor tyrosine kinases for PDGF and c-kit tyrosine kinase which is activated in GIST tumors; inhibits proliferation and induces apoptosis in cells that over-express these onco-proteins.
Downstream: Ras/MAPK; Src/Pax/Rak/Rac; PI/PI3K/AKT/BCL2; JAK/STAT
What is the specific mechanism of action of Bevacizumab (Avastin)?
binds specifically to all isoforms of VEGF-A (THE LIGAND, NOT THE RECEPTOR) and prevents binding of the ligand to the receptors VEGFR-1,2 on the surface of endothelial cells.
bev inhibits the growth of new vessels, triggers the regression of newly formed vessels and results in normalization of the tumor vasculature
VEGFR-2 is though to be mainly responsible for signaling in angiogenesis
Mechanism of action of PARPi?
(Duplicate Qs)
**TEST QUESTION **
inhibition of PARP results in ssDNA breaks that degenerate into dsDNA breaks in HR-deficient cells (ie BRCA mutations and HRD).
ssDNA breaks usually repaired by BER (need PARP).
also cause PARP trapping (inhibition of autoPARylation) PARP1,2 become trapped in DNA damage sites and block recruitment of DNA repair proteins to DNA damage site.
PARP traping leads to myelosuppression
Bevacizumab response correlated with which molecular pathways?
Ras/MAPK and PI3K/AKT/mTOR
Where is Her2 (ERBB2) primarily expressed?
Epithelial cells
Where is EGFR expressed?
Epithelial and stromal cells
What protein and gene does Trastuzumab target?
protein: HER2, receptor tyrosine-protein kinase erbB-2, HER2/Neu
gene: ERBB2
Which PARP do PARPi target?
Mostly PARP-1 but also gets 2; RUCAPARIB only one that also targets 3 (per B&H)…olaparib does do all 3 but stronger at 1,2
Niraparib, Veliparib–PARP-1,2
Olaparib, Rucaparib–PARP-1,2,3
What causes elevated Cr with Rucaparib use?
inhibition of renal transporters MATE1 and MATE2-K
Which PARPi’s are most likely to cause elevated liver enzymes?
(Duplicate Qs)
Rucaparib > Niraparib
rucaparib (serum enzmes elevated in 67%) vs niraparib 34%
What are the EGFR Inhibitors?
**TEST QUESTION **
small molecule: gefitinib, erlotinib
monoclonal Ab: cetuximab, panitumumab
EGFR belongs to erbB/Her family (ERBB1)
Where do growth factors act?
A Cytosol
B nucleus
C extracellular
extracellular / cell surface
Growth factors can act on specific cell surface receptors that subsequently transmit their growth signals to other intracellular components and eventually result in altered gene expression.
