Chemo IV: Targeted Therapies Flashcards
What are tyrosine kinases? Where might they be found in the cell? How are they involved in cancer?
They transfer a P from ATP to tyrosine in polypeptides
Found as receptor-type (in the membrane) or non-receptor
Constitutive activation of a TK enzyme can disrupt autoregulation and lead to unchecked cell growth, survival, and drug resistance
Imatinib
MOA
Binds and inhibits the BCR-ABL protein product (from a t(9;22))
Inhibits a driver mutation pathway
May also block c-KIT pathway
Imatinib
Indications
CML (BCR ABL t(9;22))
Gastrointestinal stromal tumors (c-KIT)
Imatinib
Metabolism and its implications
Metabolized in liver by CYP3A4 system
Avoid giving Imatinib with GFJ (inhibitor of CYP) or St John’s wort (inducer of CYP)
Imatinib
AEs
Muscle cramps Superficial edema (periorbital, extremity)
Increased clearance of T4/T3 in patients on thyroid replacement therapy (Monitor TSH levels)
Cetuximab
MOA
Monoclonal Ab to EGFR
Cetuximab
Indications
Metastatic lung cancer
Colon cancer
Head and neck cancer
Cetuximab
AEs
RASH
Diarrhea
Hypomagnesemia
Trichomegaly
Cetuximab
Contraindications
If KRAS, NRAS, or both are mutated, the patient will NOT respond to Cetuximab
Erlotinib
MOA
Small molecule inhibitor of tyrosine kinase domain assoc with EGFR
Inhibits autophosphorylaion and leads to lower signal transduction downstream
Erlotinib
Metabolism
CYP3A4
Prototypical patient with EGFR Activating Mutations
Adenocarcinoma, bronchoalveolar carcinoma
Asian woman
Never smoker
Bevacizumab
MOA
VEGF inhibitor
Prevents signaling for new blood vessel formation in tumors
Bevacizumab
Indications
Prolongs survival in metastatic colorectal cancer and metastatic lung cancer
Sorafenin, Pazopanib, Sunitinib
MOA
VEGF receptor TK inhibitors
Trastuzumab
MOA
Binds extracellular domain of EGFR receptor Her2/neu
Trastuzumab
AEs
Fever, nausea, vomit, diarrhea
Cough, HA, SOB, back pain
Very few get clinical heart failure (risk is highest when receiving concurrent anthracycline)
- Not dose dependent
- Reversible heart failure
Vemurafenib
MOA
Inhibits mutated BRAF
Use in melanomas
L-asaparaginase
MOA and Indication
Depletes asparagine pools
Since leukemia cells cannot synthesize asparagine, the cells will die
Used in ALL
Hydroxyurea
MOA and Indication
Inhibits DNA synthesis by inhibiting ribonucleotide reductase
Used in AML (and used to increase HbF in sickle cell anemia)
All-trans retinoic acid
MOA and Indication
Used in APL (t(15;17))
Induces terminal differentiation of leukemic cells in APL
Arsenic Trioxide
MOA and Indication
Treatment for relapsed APL, when all-trans retinoic acid didn’t work
Causes QT prolongation
