Targeted Cancer Therapy

Question 1

• Injury to cancer cells and normal cells (with high mitotic index or high growth fraction)
• Side effects/toxicity can be cumulative and may lead to long term sequelae (e.g. heart failure, hearing loss, infertility, pulmonary fibrosis, secondary cancers)
• Prominent dose-limiting side effects
• Prominent multi-drug resistance

Answer 1

Cytotoxic Chemotherapy

Question 2

• Specifically target tumor over normal cells; in general, fewer side effects at normal cells
• Fewer cumulative side effects/ sequelae
• Fewer dose-limiting side effects
• Less chance of drug resistance – No, resistance can occur

Answer 2

Targeted Therapy

Question 3

Clinical Application:

Non-small cell lung cancer (NSCLC) only

Answer 3

Erlotinib and Gefitinib

Question 4

Mechanism of Action:

Small molecule inhibitor of intracellular kinase domain of EGFR (ERBB1)

Answer 4

Erlotinib and Gefitinib

Question 5

Adverse Rx and Contraindications:

Serious, potentially lifethreatening: interstitial lung disease, GI perforations

Answer 5

Erlotinib and Gefitinib

Question 6

Patients eligible for treatment must have exon 19 deletion mutation or L858R point mutation in ERBB1; patients with WT ERBB1 tend to be nonresponders Acquired resistance due to T790M mutation in ErbB1, or amplification of MET oncogene leading to alternative activation of RAS-MAPK pathway

Answer 6

Erlotinib Gefitinib

Question 7

Clinical Application:

Metastatic colon cancer, metastatic NSCLC

Answer 7

Bevacizumab

Question 8

Mechanism of Action:

Monoclonal Ab against VEGFA to inhibit angiogenic VEGF signaling pathway

Answer 8

Bevacizumab

Question 9

Adverse Rx and Contraindications:

Hypertensive crisis, arterial thromboembolism; black box warning: GI perforations, wound healing complications, hemmorhage

Answer 9

Bevacizumab

Question 10

Resistance due to VEGF gene amplification

Answer 10

Bevacizumab

Question 11

Clinical Application:

Chronic Myeloid Leukemia (CML), Philadelphia chromosome positive (Ph+) ALL

Answer 11

Imitanib

Question 12

Mechanism of Action:

Small molecule inhibitor of intracellular kinase domain of BCR-ABL

Answer 12

Imitanib

Question 13

Adverse Rx and Contraindications:

Edema, myelosuppression, hepatotoxicity

Answer 13

Imitanib

Question 14

Acquired resistance due to: i) up-regulation of MDR1, ii) amplification of BCR-ABL oncogene, iii) resistance mutations in kinase domain of BCR-ABL

Answer 14

Imitanib

Question 15

Clinical Application:

Chronic Myeloid Leukemia (CML), Philadelphia chromosome positive (Ph+) ALL

Answer 15

Dasatinib and Ponatinib

Question 16

Mechanism of Action:

Small molecule inhibitor of intracellular kinase domain of BCR-ABL

Answer 16

Dasatinib and Ponatinib

(and Imitanib)

Question 17

Adverse Rx and Contraindications:

myelosuppression, thrombocytopenia, QT prolongation

Answer 17

Dasatinib only

Question 18

Greater efficacy than imitanib; used for imitanibresistant BCR-ABL mutants with exception of T315I mutation

Answer 18

Dasatinib

Question 19

Use what for T315I mutation

Answer 19

ponatinib

Question 20

Clinical Application:

EGFR (aka ERBB1) overexpressed in metastatic colon cancer (EGFR+); ERBB1 overexpressed in head and neck cancer (EGFR+)

Answer 20

Cetuximab

Question 21

Mechanism of Action:

Monoclonal Ab against ErbB1 extracellular domain to prevent stimulation by EGF

Answer 21

Cetuximab

Question 22

Adverse Rx and Contraindications:

Infusion rxn, renal failure, interstitial lung disease; black box warning: cardiopulmonary arrest and sudden death in head and neck cancer patients

Answer 22

Cetuximab

Question 23

Patients must have wildtype (WT) K-RAS prior to therapy; ~50% of patients have primary resistance due to KRAS mutation – pharmacogenetic testing

Answer 23

Cetuximab

Question 24

Clinical Applications:

HER2+ breast cancer

Answer 24

Lapatinib

Question 25

Mechanism of Action:

Small molecule inhibitor of intracellular kinase domain of HER2

Answer 25

Lapatinib

Question 26

Adverse Rx and Contraindications:

Cardiotoxicity, nephrotic syndrome, interstitial lung disease

Answer 26

Lapatinib

Question 27

May be effective in trastuzumab-resistance cancers

Answer 27

Lapatinib

Question 28

Clinical Application:

b Localized breast cancer with HER2 overexpression (HER2+), metastatic HER2+ breast cancer

Answer 28

Trastuzumab

Question 29

Mechanism of Action:

Monoclonal Ab against HER2 extracellular domain to inhibit RASMAPK signaling pathway

Answer 29

Trastuzumab

Question 30

Adverse Rx and Contraindications:

Hypersensitivity (infusion) reaction, nephrotic syndrome, interstitial lung disease; black box warning: cardiomyopathy, fatal infusion rxn in the form of acute respiratory syndrome

Answer 30

Trastuzumab

Question 31

Acquired resistance due to cleavage of extracellular domain of HER2 (“decoy” receptor);

This drug enhances cytotoxic chemo and reduces recurrence

Answer 31

Trastuzumab