Pharm: Targeted Drugs for Cancers

Question 1

When you see a drug ending in “-ib” think:

Answer 1

It inhibits something

Question 2

What is the drug that targets VEGF in treating colorectal cancer and non-small cell lung cancer (NSCLC)?

Answer 2

Bevacizumab

Question 3

What is the drug that targets EGFR in treating colorectal and head & neck cancers?

Answer 3

Cetuximab

Question 4

What is the drug that targets EGFR in colorectal cancer only?

Answer 4

Panitumumab

Question 5

What is the drug that targets CD20 in treatment of chronic lymphocytic leukemia (CLL) and non-hodgkin’s lymphoma (NHL)?

Answer 5

Rituximab

Question 6

What drug targets HER-2 in treating breast cancer?

Answer 6

Trastuzumab

Question 7

What drug targets CTLA-4 in treating melanoma?

Answer 7

Ipilimumab

Question 8

What other drug targets CD20 in treating chronic lymphocytic leukemia (CLL)?

Answer 8

Ofatumumab

Question 9

Which drug is a 26-S Proteosome inhibitor used to treat multiple myeloma?

Answer 9

Bortezomib

Question 10

Which drug is a hedgehog pathway inhibitor used to treat basal cell carcinoma?

Answer 10

Vismodegib

Question 11

EGFR/HER1 (growth factor receptor) oncogenes are associated with which tumor types?

Answer 11

glioblastoma
lung
breast cancer

Question 12

HER2/Neu (growth factor receptor) is an oncogene associated with which tumor types?

Answer 12

Breast
ovarian
gastric cancer

Question 13

K-Ras (signal transduction) is an oncogene associated with which tumor type?

Answer 13

multiple tumor types

Question 14

B-Raf (signal transduction) is an oncogene associated with which tumor type?

Answer 14

Multiple tumor types, melanomas

Question 15

p53 and RB are tumor suppressor genes associated with which cellular function?

Answer 15

cell cycle regulation

Question 16

PTEN is a tumor suppressor gene associated with which cellular function?

Answer 16

signal transduction, adhesion signaling

Question 17

PTEN is a tumor suppressor gene associated with which tumor types?

Answer 17

glioblastomas
prostate
breast

Question 18

BRCA1/2 are tumor suppressor genes associated with what cellular function?

Answer 18

DNA ds-break repair

Question 19

BRCA1/2 are tumor suppressor genes associated with which types of tumors?

Answer 19

breast

ovarian

Question 20

VHL is a tumor suppressor gene associated with which cellular function?

Answer 20

Ubiquitin ligase

Question 21

VHL is a tumor suppressor gene associated with which tumor types?

Answer 21

kidney

others

Question 22

p16/CDKN2 is a tumor suppressor gene associated with which cellular functions?

Answer 22

Cell cycle regulator

Question 23

p16/CDKN2 is a tumor suppressor gene associated with which tumor types?

Answer 23

melanoma
pancreatic
esophageal

Question 24

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.

Answer 24

Ipilimumab

Question 25

Which drug produces a rapid and sustained depletion of B-cells lasting for several months by binding to CD20 on B cells?

Answer 25

Rituximab

Question 26

Is VEGF particularly important for solid tumors or liquid tumors more, and why?

Answer 26

Solid tumors. For recruitment of blood vessels as they outgrow their vascular supply.

Question 27

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?

Answer 27

hypoxia inducible factor (HIF-1)

Question 28

What characteristic of mAbs makes them potential poor penetrators of large, solid tumors?

Answer 28

Large molecular weight

Question 29

Current mAbs are based on which immunoglobulin isotype?

Answer 29

IgG

Question 30

Describe the ADEs associated with antibody drugs. | How can you overcome these effects?

Answer 30

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.

Question 31

List mechanisms of resistance to tyrosine kinase inhibitors.

Answer 31

kinase over-expression | binding site mutations (do not affect kinase function, shift drug dose-response curves right for inhibitors)

Question 32

Describe a complication associated with use of tyrosine kinase inhibitors.

Answer 32

Because RTKs are present everywhere in the body, off-target effects are expected.

Question 33

Explain the relationship of tyrosine kinase inhibitors with CYP.

Answer 33

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.

Question 34

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:

Answer 34

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

Question 35

List the tyrosine kinase inhibitors known to have the ADE thyroid dysfunction commonly.

Answer 35

Sorafenib Sunitinib Imatinib

Question 36

List the common ADEs of tyrosine kinase inhibitors.

Answer 36

rash, fatigue, N/V, dyspnea, stomatitis, anorexia, blood dysplasias, QT prolongation, Hand-foot syndrome

Question 37

Mutations of which downstream proteins in intracellular signaling are important in determining if treatment with tyrosine kinase inhibitors will be efficacious and why?

Answer 37

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.

Question 38

List the 6 major resistance mechanisms of tumors to TKIs.

Answer 38

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

Question 39

What is the best way to overcome the compensatory downstream recruitment of secondary tyrosine kinases that may render targeted primary RTK inhibition useless?

Answer 39

Shotgun approach- multiple drugs targeting multiple pathways and critical fragile points, concurrently. Administered with a shotgun.

Question 40

mTOR is a central regulator of these three cell functions:

Answer 40

cell proliferation angiogenesis cell metabolism

Question 41

How can mTOR be inhibited, mechanistically? | -don't name exact drugs

Answer 41

small molecular weight molecules that form a three-way complex involving inhibitor, FKBP-12, and mTOR.

Question 42

BIG picture, what does mTOR regulate that mediates cell proliferation, angiogenesis, and cell metabolism?

Answer 42

Protein synthesis

Question 43

Which two mTOR inhibitors are approved for the tx of advanced renal cell cancer?

Answer 43

temsirolimus & everolimus

Question 44

Are the mTOR inhibitors suitable for all tumor types?

Answer 44

No, that goes for pretty much all anticancer drugs though.

Question 45

The ____________ is another intracellular target of anticancer drugs whose function is to degrade proteins which have been targeted by ubiquination.

Answer 45

26S proteasome

Question 46

Generally speaking, what is wrong with the 26S proteasome that causes cancer?

Answer 46

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.

Question 47

How does Bortezomib work?

Answer 47

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.

Question 48

What are the major ADEs of Bortezomib use?

Answer 48

Cardiotoxicity, hepatotoxicity