Pharmacology - Cancer IV Lecture AND Cancer Clinical Cases Lecture Flashcards
What are the two major groups of targeted therapy?
Two major groups of targeted therapeutics
Small molecule inhibitors
Monoclonal antibodies
“tinib”
tyrosine kinase inhibitor
small molecule inhibitor
“zomib”
proteasome inhibitor
small molecule inhibitor
“tu”
tumor
mab
“parib”
PARP inhibitor
small molecule inhibitor
“ci”
“ci” circulatory system
mab
“li”
“li” immune system
mab
What is the Ph chromosome of CML?
Ph: reciprocal translocation between chromosomes 9 and 22 t(9;22).
The t(9;22) translocation fuses the BCR gene with ABL gene to generate Bcr-Abl fusion protein.
What was the first line CML treatment?
Imatinib (Gleevec) Start with 400 mg once a day oral everyday. • Expectation after three months: – Complete hematologic response – Some cytogenetic response – Molecular response i.e. reduction in BCR-ABL transcripts by about 90% • Expectation after 18 months: – Complete hematologic response – Complete cytogenetic response – Major molecular response
What is the mechanism of resistance and relapse after Imatinib treatment for CML?
Imatinib
Mechanism of Relapse and Resistance
• Intrinsic Resistance: patients with persistent Bcr- Abl kinase activity.
• Could be due to:
– Mutations in Bcr-Abl kinase making it insensitive to this drug.
– Drug unable to reach its target because of enhanced binding to other proteins in circulation and/or drug efflux.
• Relapse after initial response: reactivation of Bcr- Abl kinase.
– Mutations in Abl kinase domain. Interfere with drug binding. Mutant kinase less sensitive to drug. Many mutations; T315I mutation noteable.
– Bcr-Abl amplification.
• Some who relapse show persistent inhibition of Bcr-Abl kinase.
– additional molecular abnormalities besides Bcr-Abl?
What are the first-line Next Generation TKIs for treatment of CML?
Nilotinib
Dasatinib
Bosutinib (Bosulif): Second-line
Ponatinib (Iclusig): Second-line; T315I mutant
T/F: Nilotinib and Dasatinib and Bosutinib are not effective against CML with T3151 mutation.
True
What are the side effects of Nilotinib?
Nilotinib • Myelosuppression: thrombocytopenia, neutropenia and anemia • QT Prolongation • Sudden Deaths • Elevated Serum Lipase • Hepatotoxicity • Electrolyte Abnormalities
Contraindicated for people with Long QT syndrome
Pulmonary Arterial Hypertension is a unique side effect of what CML first line TKI?
Dasatinib
Side Effects
• Myelosuppression: thrombocytopenia, neutropenia and anemia
• Bleeding
• Fluid Retention
• Cardiac Problems: abnormal heart rate etc.
• Pulmonary Arterial Hypertension (PAH)
Other Side Effects
• Diarrhea, headache, cough, skin rash, fever, nausea, tiredness, vomiting, muscle pain, weakness, infections
MOA - Bosutinib
- Also an ATP competitive inhibitor of Bcr-Abl.
- Second-line agent for CML patients resistant or intolerant to other TKIs.
- Active against most BCR-ABL mutants with clinical resistance to other TKIs. Ineffective against T315I.
**Same MOA as Ponatinib
What are some major side effects of Bosutinib?
GI toxicity
Renal toxicity
Hepatic toxicity
What is the boxed warning on Ponatinib for?
• VASCULAR OCCLUSION
– Arterial and venous thrombosis and occlusions associated with fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease
• HEART FAILURE
• HEPATOTOXICITY
What are the major side effects of Ponatinib?
GI perforation
Tumor Lysis Syndrome
Cardiac Arrhythmias
What is the BRAF mutation?
• BRAF gene encodes a serine threonine kinase.
• Mutations in BRAF gene in ~45%-50% (some literature
says 40-60%) of cutaneous melanomas.
• Less common in acral, mucosal and uveal types.
• BRAFV600E mutation in the kinase activation domain is the most common. Results in constitutive activation of BRAF kinase.
• BRAFV600K is the second most common mutation.
What has been the mainline treatment for metastatic melanoma until very recently?
Dacarbazine
MOA Vemurafenib
Inhibits BRAF kinase.
Used for unresectable stage III and IV or metastatic melanomas that harbor BRAFV600 mutations.
What is the main contraindication for giving Vemurafenib?
• Should not be given to melanomas harboring wild type BRAF.
QT syndrome also an issue
What cancer is Dabrafenib used to treat?
Considered as a next generation agent.
• Indication: unresectable stage III and IV or metastatic
melanomas that harbor BRAFV600E mutation.
What is the main contraindication for giving Dabrafenib?
Should not be given to melanoma harboring wild type BRAF.
