Targeted Cancer Therapy Flashcards
- 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
Cytotoxic Chemotherapy
- 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
Targeted Therapy
Clinical Application:
Non-small cell lung cancer (NSCLC) only
Erlotinib and Gefitinib
Mechanism of Action:
Small molecule inhibitor of intracellular kinase domain of EGFR (ERBB1)
Erlotinib and Gefitinib
Adverse Rx and Contraindications:
Serious, potentially lifethreatening: interstitial lung disease, GI perforations
Erlotinib and Gefitinib
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
Erlotinib Gefitinib
Clinical Application:
Metastatic colon cancer, metastatic NSCLC
Bevacizumab
Mechanism of Action:
Monoclonal Ab against VEGFA to inhibit angiogenic VEGF signaling pathway
Bevacizumab
Adverse Rx and Contraindications:
Hypertensive crisis, arterial thromboembolism; black box warning: GI perforations, wound healing complications, hemmorhage
Bevacizumab
Resistance due to VEGF gene amplification
Bevacizumab
Clinical Application:
Chronic Myeloid Leukemia (CML), Philadelphia chromosome positive (Ph+) ALL
Imitanib
Mechanism of Action:
Small molecule inhibitor of intracellular kinase domain of BCR-ABL
Imitanib
Adverse Rx and Contraindications:
Edema, myelosuppression, hepatotoxicity
Imitanib
Acquired resistance due to: i) up-regulation of MDR1, ii) amplification of BCR-ABL oncogene, iii) resistance mutations in kinase domain of BCR-ABL
Imitanib
Clinical Application:
Chronic Myeloid Leukemia (CML), Philadelphia chromosome positive (Ph+) ALL
Dasatinib and Ponatinib
Mechanism of Action:
Small molecule inhibitor of intracellular kinase domain of BCR-ABL
Dasatinib and Ponatinib
(and Imitanib)
Adverse Rx and Contraindications:
myelosuppression, thrombocytopenia, QT prolongation
Dasatinib only
Greater efficacy than imitanib; used for imitanibresistant BCR-ABL mutants with exception of T315I mutation
Dasatinib
Use what for T315I mutation
ponatinib
Clinical Application:
EGFR (aka ERBB1) overexpressed in metastatic colon cancer (EGFR+); ERBB1 overexpressed in head and neck cancer (EGFR+)
Cetuximab
Mechanism of Action:
Monoclonal Ab against ErbB1 extracellular domain to prevent stimulation by EGF
Cetuximab
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
Cetuximab
Patients must have wildtype (WT) K-RAS prior to therapy; ~50% of patients have primary resistance due to KRAS mutation – pharmacogenetic testing
Cetuximab
Clinical Applications:
HER2+ breast cancer
Lapatinib
Mechanism of Action:
Small molecule inhibitor of intracellular kinase domain of HER2
Lapatinib
Adverse Rx and Contraindications:
Cardiotoxicity, nephrotic syndrome, interstitial lung disease
Lapatinib
May be effective in trastuzumab-resistance cancers
Lapatinib
Clinical Application:
b Localized breast cancer with HER2 overexpression (HER2+), metastatic HER2+ breast cancer
Trastuzumab
Mechanism of Action:
Monoclonal Ab against HER2 extracellular domain to inhibit RASMAPK signaling pathway
Trastuzumab
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
Trastuzumab
Acquired resistance due to cleavage of extracellular domain of HER2 (“decoy” receptor);
This drug enhances cytotoxic chemo and reduces recurrence
Trastuzumab
