Targeted Cancer Therapy

Question 1

MAB(s) targeting EGFR

Answer 1

Cetuximab, Panitumumab

Question 2

MAB(s) targeting VEGF

Answer 2

Bevacizumab

Question 3

MAB(s) targeting CD20

Answer 3

Rituximab, Ofatumumab

Question 4

MAB(s) targeting HER2

Answer 4

Trastuzumab

Question 5

MAB(s) targeting CTLA-4

Answer 5

Ipilimumab

Question 6

TKI inhibiting 26-S Proteasome

Answer 6

Bortezomib

Question 7

Trastuzumab mechanism of action?

Answer 7

1) Trastuzumab binds HER-2–> inhibition of stimulatory signal
2) inhibition of stimulatory signal–> down regulation of HER-2 receptors

Question 8

Ipilimumab mechanism of action?

Answer 8

Ipilimumab binds CTLA-4 on T cells–> prevents binding of inhibitory T-cell signals–> increase tumor surveillance

Question 9

Where is VEGFR most commonly seen upregulated?

Answer 9

Large, solid tumors that are beginning to outgrow their vasculature

Question 10

VEGF upregulation process

Answer 10

Under hypoxic conditions, HIF-1 is no longer degraded by the proteasome. Now it translocates to the nucleus and upregulates VEGF expression

Question 11

What Ig are MABs based on?

Answer 11

IgG

Question 12

Adverse effects seen in most all MABs

Answer 12

1) Infusion related reactions

2) Cardiomyopathy/CHF

Question 13

Trastuzumab toxicities

Answer 13

Cardiomyopathy (HER-2 found on the heart), Infusion reactions

Question 14

Cetuximab toxicities

Answer 14

Skin rash with sun exposure, Infusion reactions

Question 15

Panitumumab toxicities

Answer 15

Skin rash with sun exposure, Infusion reactions

Question 16

Bevacizumab toxicities

Answer 16

HTN, CHF, pulmonary hemorrhage, GI perforation

Question 17

Rituximab toxicities

Answer 17

B-cell depletion, lymphopenia, Infusion reactions

Question 18

Ofatumumab toxicities

Answer 18

Progressive leukoencephalopathy, neutropenia, Infusion reaction

Question 19

Bevacizumab indication(s)

Answer 19

Colorectal, Non-small cell Lung Cancer

Question 20

Cetuximab indication(s)

Answer 20

Colorectal, Head and Neck cancers

Question 21

Panitumumab indication(s)

Answer 21

Colorectal

Question 22

Rituximab indication(s)

Answer 22

Chronic Lymphocytic Leukemia, Non-Hodgkins Lymphoma

Question 23

Trastuzumab indication(s)

Answer 23

Breast cancer

Question 24

Ipilimumab indication(s)

Answer 24

Melanoma

Question 25

Ofatumumab indication(s)

Answer 25

Chronic Lymphocytic Leukemia

Question 26

Bortezomib indication(s)

Answer 26

Multiple Myeloma

Question 27

Where do all tyrosine kinase inhibitors work?

Answer 27

the highly-conserved ATP binding site

Question 28

Problem with target of tyrosine kinase inhibitors?

Answer 28

Only one target site, once it mutates, we’re fucked

Question 29

Are resistant mutations common with tyrosine kinase inhibitors?

Answer 29

Yes, after initial successful drug therapy, many mutated resistant clones emerge

Question 30

Drug-Drug interactions with tyrosine kinase inhibitors?

Answer 30

most are substrates for CYP3A4, variability in bioavailability

Question 31

Tyrosine kinase inhibitors causing Hand Foot Syndrome

Answer 31

Sunitinib, Sorafenib, Pazopanib, Vemurafenib

Question 32

Common adverse effects seen with tyrosine kinase inhibitors

Answer 32

endocrine problems; issues with glucose regulation, thyroid function, calcium homeostasis (PTH), child growth

Question 33

Cardiac issue(s) seen in tyrosine kinase inhibitor therapy

Answer 33

QT prolongation

Question 34

Issues in some patients with EGFR monoclonal antibody therapy?

Answer 34

Patients must be genotyped. Downstream mutations of the oncogenes BRAF and KRAS make patients much less likely to respond to EGFR therapy

Question 35

Describe the shotgun method of good cancer therapy

Answer 35

targeting multiple pathways at their critical “fragile points” with the indicated drugs (combo therapy)

Question 36

mTOR function

Answer 36

central regulation of cell proliferation, angiogenesis, and cell metabolism

Question 37

Mechanism of action of 26S proteasome in cell proliferation

Answer 37

IkB-alpha binds and inhibits transcriptional factor NfKB. In cancer, IkB-alpha is broken down and exponential rate so NfKB can translocate to the nucleus and instigate proliferation

Question 38

Action of Bortezomib?

Answer 38

Inhibits 26S proteasome thereby negating cell proliferation

Question 39

How are tyrosine kinase inhibitors administered?

Answer 39

Orally (because of small size)

Question 40

Bortezomib administration?

Answer 40

IV or SubQ, must be administered parenterally

Question 41

Protective effect of NSAIDs against cancer?

Answer 41

NSAIDs may have some protective effect against cancer; Prostanoids are seen to be elevated in most solid tumors