Chemotherapy V

Question 1

Define targeted therapy

Answer 1

Refers to a new generation of cancer drugs designed to interfere with a specific molecular target (typically a protein) that is believed to have a critical role in tumor growth or progression

Question 2

Main target of targeted therapy

Answer 2

Main target of targeted therapy Tyrosine kinase

Question 3

Two types of Tyrosine Kinase

Answer 3

• Transmembrane protein with a ligand brining extracellular domain and a catalytic intracellular kinase domain (receptor)
• Non membrane tyrosine domain (non-receptor)

Question 4

Dysregulation of Tyrosine Kinase

Answer 4

• Common mechanism of TK activation is the fusion of a partner protein with TK due to chromosomal translocation causing TK oligomerization in the absence of ligand binding or other signals
• Mutation that disrupts autoregulation
• increased or aberrant expression of a receptor TK

Question 5

How is pharmacologic inhibition of tyrosine kinase achieved

Answer 5

1. Small molecule inhibition of the catalytic activity of the kinase
2. Antibodies against the receptor tyrosine kinases or a ligand of the receptor tyrosine kinase

Question 6

Class of Imatinib mesylate

Answer 6

Tyrosine kinase inhibitor

Question 7

Macromolecular target of Imatinib mesylate

Answer 7

Bcr-Abl fusion protein (9,22 translocation)

c-kit (constitutive phosphorylation)

Question 8

MOA of Imatinib mesylate

Answer 8

Inhibits critical signaling pathways in the cancer cell that are constitutively active
-Binds in the Bcr-Abl ATP pocket to shut down proliferation

Question 9

Metabolism of Imatinib mesylate

Answer 9

Metabolized in the liver by the CYP3A4 system and excreted into the feces by the hepatobiliary system

Avoid coadministration with inducers (St. John’s Wort) and inhibitors of the pathway-other drugs and grapefruit juice

Question 10

SEs of Imatinib mesylate

Answer 10

Superficial edema, nausea, muscle cramps, abdominal pain, musculoskeletal pain, rash, diarrhea, anemia, neutropenia, thrombocytopenia
Rarely, CHF

Question 11

Administration of Imatinib mesylate

Answer 11

Oral administration

Chronic, daily

Question 12

Consideration of patients with hypothyroid taking Imatinib mesylate

Answer 12

Monitor thyroid function

Imatinib may increase the clearance of thyroid hormone and the dose of thyroid medication may have to be increased

Question 13

Uses of Imatinib mesylate

Answer 13

Chronic myelogenous leukemia (Bcr-Abl oncogene addiction dependence for cell survival)
GI stromal tumor (c-kit)

Question 14

Outcome of Imatinib therapy

Answer 14

Resistance will develop and therapy is not known to be curative at the present time
Eradicate Bcr-Abl cells from detection

Question 15

Other compounds in the same class as Imatinib mesylate

Answer 15

Dasatinib and nilotinib (useful in imatinib resistant disease)

Question 16

Class of Cetuximab

Answer 16

Epidermal growth factor receptor (EGFR) inhibitor

Question 17

Macromolecular target of Cetuximab

Answer 17

EGFR

Question 18

MOA of Cetuximab

Answer 18

Overexpression of EGFR receptors leads to increased signaling and affects cell growth and division and metastases and invasion
Also can sensitize cell to effect of chemotherapy and can be used as a radiation therapy sensitizer

Question 19

SEs of Cetuximab

Answer 19

Hypersensitivity reactions
Rash (seen in most targeted therapy) 
Diarrhea
Hypomagnesemia
Infusion reactions 
Tichomegaly: long eye lashes

Question 20

Administration of Cetuximab

Answer 20

Chimeric monoclonal antibody administered IV weekly or every other week usually in combination with chemotherapy

Question 21

Uses of Cetuximab

Answer 21

1. Lung CA and head and neck CA (patients not selected based on EGFR expression or kras mutational status)
2. Colo-rectal cancer (metastatic): perform k-ras mutational analysis on tumor (wildtype responds)
   If k-ras/ n-ras is mutated (independent of EGFR), patient will not respond to cetuximab

Question 22

Class of Panitumumab

Answer 22

Fully humanized monoclonal antibody
In same class as Cetuximab

Question 23

Class of Erlotinib

Answer 23

Small molecule inhibitor of the tyrosine kinase domain associated with EGFR

Question 24

Macromolecular target of Erlotinib

Answer 24

Tyrosine kinase domain associated with EGFR

Question 25

MOA of Erlotinib

Answer 25

Inhibition of critical cell signaling pathways

Question 26

Metabolism of Erlotinib

Answer 26

Metabolized by CYP3A4- avoid coadministration with inducers

Question 27

SEs of Erlotinib

Answer 27

Rash, nausea, anorexia and fatigue, nail changes

Question 28

Administration of Erlotinib

Answer 28

Oral

Question 29

In what case must mutational analysis be done on the tumor before using Erlotinib

Answer 29

Non-small cell lung cancer should have mutational analysis done on the tumor - if there are activating mutations observed the treatment of choice is ertolinib

Question 30

Uses of Erlotinib

Answer 30

Lung CA (esp adenocarcinomas non-small cell with EGFR activating mutations), head and neck CA, pancreas cancer (in combo with gemcitabine)

Question 31

Effect of EGFR activating mutations

Answer 31

Make cancer cell more sensitive to TK inhibitors

Question 32

Prototype patients with EGFR activating mutations

Answer 32

Prototype patients with EGFR activating mutations Adenocarcinoma, bronchoalveolar Women Asian Never smokers

Question 33

Class of Bevacizumab

Answer 33

Inhibitor of vascular endothelial growth factor (VEGF)

Question 34

Macromolecular target of Bevacizumab

Answer 34

Vascular endothelial growth factor ligand

Question 35

MOA of Bevacizumab

Answer 35

Binds to VEGF ligand and decreases the growth of primary cancers and metastatic cancers due to impaired vasculature formation in the tumor

Question 36

SEs of Bevacizumab

Answer 36

Infusion reactions, proteinuria, HTN, arterial clots, bleeding, perforation of the colon, reversible posterior leukoencephalopathy syndrome is rare (seizures, headache, mental status changes, visual changes and findings on MR of the brain)

Question 37

Administration of Bevacizumab

Answer 37

IV | Must be combined

Question 38

Uses of Bevacizumab

Answer 38

Lung CA and metastatic colorectal cancer

Question 39

List the VEGF inhibitors

Answer 39

Bevacizumab Sorafenib Pazopanib Sunitinib

Question 40

Oral VEGF inhibitors

Answer 40

Sorafenib Pazopanib Sunitinib

Question 41

SEs of oral VEGF inhibitors

Answer 41

``` Rash Hand-foot syndrome HTN Reversible posterior leukoencephalopathy syndrome Perforation of the GI tract CHF ```

Question 42

Uses of oral VEGF inhibitors

Answer 42

Renal cell cancer (clear cell variety)

Question 43

Use of Sorafenib

Answer 43

Renal cell cancer (clear cell variety) | Hepatocellular cancer

Question 44

Use of Sunitinib

Answer 44

Renal cell cancer (clear cell variety) Pancreatic neuroendocrine cancer GI stromal tumors

Question 45

Effect of VEGF inhibitors

Answer 45

None are curative

Question 46

Class of Trastuzumab

Answer 46

Monoclonal antibody

Question 47

Macromolecular target of Trastuzumab

Answer 47

Extracellular domain of epidermal growth factor receptor | Her-2/neu

Question 48

MOA of Trastuzumab

Answer 48

Binds to the extracellular domain of the epidermal growth factor receptor and decreases signaling pathways

Question 49

SEs of Trastuzumab

Answer 49

1. Fever, nausea, vomiting, infusion reactions, diarrhea, cough, headache, fatigue, shortness of breath, back pain, rash and muscle pain; allergic reactions 2. Heart failure (high if also given doxorubicin) - asymptomatic decline in EF (NOT CUMULATIVE and reversible)

Question 50

Administration of Trastuzumab

Answer 50

IV weekly

Question 51

Uses of Trastuzumab

Answer 51

Breast cancer in combo with chemo when Her2/neu + | Stomach and gastroesophageal junction cancer in combo with chemo when Her2/neu +

Question 52

MOA of lapatinib

Answer 52

Small molecule tyrosine kinase inhibitor of Her-2 family

Question 53

MOA of pertuzumab

Answer 53

Monoclonal antibody binds to Her-2

Question 54

Use of Crizotinib

Answer 54

Patients with ALK-anaplastic lymphoma kinase rearrangements had adenocarcinoma, tended to be younger and had little or no exposure to smoke 60% response rate 33% stable disease Perform mutational analysis on lung cancer patients for ALK rearrangement

Question 55

Use of Vemurafenib

Answer 55

40-60% of patients with melanoma have an actvating mutation in the gene encoding for BRAF (V600E) -> constitutively active phosphorylation and downstream signaling Inhibits mutated BRAF

Question 56

MOA of Asparaginase

Answer 56

- Bacterial product | - Hydrolyzes L-asparagine -> tumor cells lack asparagine synthetase and protein synthesis is inhibited

Question 57

Toxicities of Asparaginase

Answer 57

Immunologic sensitization and depletion of asparagine pools Allergic reactions Clotting and bleeding (conc. of clotting factors and AT II dec.) Pancreatitis, hyperglycemia and mental status changes Liver enzyme abnormalities

Question 58

Use of Asparaginase

Answer 58

ALL

Question 59

MOA of hydroxyurea

Answer 59

Analog of urea that inhibits DNA synthesis by inhibiting ribonucleotide reductase

Question 60

Administration of hydroxyurea

Answer 60

Oral

Question 61

Main use of hydroxyurea

Answer 61

Treatment of high WBC counts in patients with AML and chronic granulocytic leukemia with blast crisis

Question 62

SEs of hydroxyurea

Answer 62

Leukemia blasts in high #s can cause sludging in the vasculature leading to thromboses Nausea and vomiting Low blood counts Rash

Question 63

MOA of All trans retinoic acid (tretinoin)

Answer 63

Induces terminal differentiation of the leukemic cells

Question 64

Use of All trans retinoic acid (tretinoin)

Answer 64

Combination with chemo for patients with acute promyelocytic leukemia (APL, M3)

Question 65

SEs of All trans retinoic acid (tretinoin)

Answer 65

Dry skin and dry mucus membranes | Retinoic acid syndrome consisting of fever, weight gain, pulmonary infiltrates and pleural or pericardial effusions

Question 66

Use of Arsenic Trioxide

Answer 66

Treatment of relapsed APL (acute promyelocytic leukemia)

Question 67

SEs of Arsenic Trioxide

Answer 67

Fatigue, QT prolongation | Syndrome similar to retinoic acid syndrome