Pharm: Targeted Drugs for Cancers Flashcards
When you see a drug ending in “-ib” think:
It inhibits something
What is the drug that targets VEGF in treating colorectal cancer and non-small cell lung cancer (NSCLC)?
Bevacizumab
What is the drug that targets EGFR in treating colorectal and head & neck cancers?
Cetuximab
What is the drug that targets EGFR in colorectal cancer only?
Panitumumab
What is the drug that targets CD20 in treatment of chronic lymphocytic leukemia (CLL) and non-hodgkin’s lymphoma (NHL)?
Rituximab
What drug targets HER-2 in treating breast cancer?
Trastuzumab
What drug targets CTLA-4 in treating melanoma?
Ipilimumab
What other drug targets CD20 in treating chronic lymphocytic leukemia (CLL)?
Ofatumumab
Which drug is a 26-S Proteosome inhibitor used to treat multiple myeloma?
Bortezomib
Which drug is a hedgehog pathway inhibitor used to treat basal cell carcinoma?
Vismodegib
EGFR/HER1 (growth factor receptor) oncogenes are associated with which tumor types?
glioblastoma
lung
breast cancer
HER2/Neu (growth factor receptor) is an oncogene associated with which tumor types?
Breast
ovarian
gastric cancer
K-Ras (signal transduction) is an oncogene associated with which tumor type?
multiple tumor types
B-Raf (signal transduction) is an oncogene associated with which tumor type?
Multiple tumor types, melanomas
p53 and RB are tumor suppressor genes associated with which cellular function?
cell cycle regulation
PTEN is a tumor suppressor gene associated with which cellular function?
signal transduction, adhesion signaling
PTEN is a tumor suppressor gene associated with which tumor types?
glioblastomas
prostate
breast
BRCA1/2 are tumor suppressor genes associated with what cellular function?
DNA ds-break repair
BRCA1/2 are tumor suppressor genes associated with which types of tumors?
breast
ovarian
VHL is a tumor suppressor gene associated with which cellular function?
Ubiquitin ligase
VHL is a tumor suppressor gene associated with which tumor types?
kidney
others
p16/CDKN2 is a tumor suppressor gene associated with which cellular functions?
Cell cycle regulator
p16/CDKN2 is a tumor suppressor gene associated with which tumor types?
melanoma
pancreatic
esophageal
This drug is an immunostimulant because it binds to CTLA-4, inhibiting it from binding to B7 in place of CD28. If CTLA-4 was allowed to bind to B7, this would inhibit the secondary signal of activation of T cells, causing them to become anergic.
Ipilimumab
Which drug produces a rapid and sustained depletion of B-cells lasting for several months by binding to CD20 on B cells?
Rituximab
Is VEGF particularly important for solid tumors or liquid tumors more, and why?
Solid tumors. For recruitment of blood vessels as they outgrow their vascular supply.
Which protein, under conditions of low oxygen, stops being degraded by the 26S proteosome pathway and translocates to the nucleus to promote upregulation and expression of VEGF?
hypoxia inducible factor (HIF-1)
What characteristic of mAbs makes them potential poor penetrators of large, solid tumors?
Large molecular weight
Current mAbs are based on which immunoglobulin isotype?
IgG
Describe the ADEs associated with antibody drugs.
How can you overcome these effects?
infusion related rxns: anaphylaxis, angioedema, and pulmonary toxicity.
Overcome with: pre-medicate with antihistamines and/or corticosteroids before resumption of infusions.
Left ventricular dysfunction and CHF; HTN
Depletion of cell populations in blood where target is expressed in component of this tissue.
List mechanisms of resistance to tyrosine kinase inhibitors.
kinase over-expression
binding site mutations (do not affect kinase function, shift drug dose-response curves right for inhibitors)
Describe a complication associated with use of tyrosine kinase inhibitors.
Because RTKs are present everywhere in the body, off-target effects are expected.
Explain the relationship of tyrosine kinase inhibitors with CYP.
Most TK inhibitors are substrates for CYP3A4 and a few are inhibitors of other isoforms. Therefore, the potential for drug-drug interaction cannot be overstated.
A common theme amongst the RTK inhibitors is their ability to disrupt _______ function through “off-target” effects. Therefore these things should be monitored in a pt:
endocrine function.
monitor: thyroid function, bone density, PTH, 25-OH Vit. D
child growth & pubertal development
Women who may become pregnant should be counseled about the known averse effects of KIs on fetal development.
Monitor diabetics for blood glucose levels
List the tyrosine kinase inhibitors known to have the ADE thyroid dysfunction commonly.
Sorafenib
Sunitinib
Imatinib
List the common ADEs of tyrosine kinase inhibitors.
rash, fatigue, N/V, dyspnea, stomatitis, anorexia, blood dysplasias, QT prolongation, Hand-foot syndrome
Mutations of which downstream proteins in intracellular signaling are important in determining if treatment with tyrosine kinase inhibitors will be efficacious and why?
KRAS & BRAF
If the pt has downstream mutations of KRAS of BRAF, they are likely to continue constitutive expression of EGFR signaling, even when EGFR is inhibited by TKIs.
List the 6 major resistance mechanisms of tumors to TKIs.
Decreased intracellular drug levels
Increased plasma protein binding
MDR-1 mediated efflux
Genomic amplification of kinase
Clonal evolution of kinase-independent mechanism
Mutations of ATP-binding site affecting drug binding or kinase activity
What is the best way to overcome the compensatory downstream recruitment of secondary tyrosine kinases that may render targeted primary RTK inhibition useless?
Shotgun approach- multiple drugs targeting multiple pathways and critical fragile points, concurrently. Administered with a shotgun.
mTOR is a central regulator of these three cell functions:
cell proliferation
angiogenesis
cell metabolism
How can mTOR be inhibited, mechanistically?
-don’t name exact drugs
small molecular weight molecules that form a three-way complex involving inhibitor, FKBP-12, and mTOR.
BIG picture, what does mTOR regulate that mediates cell proliferation, angiogenesis, and cell metabolism?
Protein synthesis
Which two mTOR inhibitors are approved for the tx of advanced renal cell cancer?
temsirolimus & everolimus
Are the mTOR inhibitors suitable for all tumor types?
No, that goes for pretty much all anticancer drugs though.
The ____________ is another intracellular target of anticancer drugs whose function is to degrade proteins which have been targeted by ubiquination.
26S proteasome
Generally speaking, what is wrong with the 26S proteasome that causes cancer?
The 26S proteasome is overactive, cleaving inhibitors of cell signaling and transcriptional regulation. This transcription of proteins that are necessary for cellular proliferation is constitutive, and then BOOM CANCER.
How does Bortezomib work?
It inhibits the proteasomal activity of the 26S proteasome, allowing IkB-alpha to remain bound (inhibiting) to NfkB, preventing the transcriptional regulation of NfkB, and thus proliferation.
What are the major ADEs of Bortezomib use?
Cardiotoxicity, hepatotoxicity
