Molecular Targeted Therapy Flashcards
Imatinib MOA
binds to Bcr-Abl at ATP binding site, blocking its tyrosine kinase activity; Bcr-Abl fusion protein created by t(9;22)
Imatinib TU
first-line therapy for CML; also approved for unresectable and metastatic GI stromal tumors (most common mesenchymal tumor of GI tract; KIT and PDGFRA mutations)
Imatinib Toxicity
minimal - nausea, vomiting, myalgia, arthralgia, myelosuppression
Imatinib Intrinsic Resistance
mutations in Bcr-Abl making it insensitive; enhanced binding to proteins in circulation and/or drug efflux
Imatinib relapse after initial response
- mutations in Abl kinase making it less sensitive
- Bcr-Abl amplification
- persistent inhibition of Bcr-Abl; other molecular abnormalities take over
Second Generation TKIs
nilotinib and dasatinib
all trans-retinoic acid (RA) MOA
induces terminal differentiation of malignant promyelocytes in APL; PML-RAR(alpha) fusion protein from t(15;17) cannot induce normal differentiation at physiological RA conc.and possibly acts as an oncoprotein
all trans-RA TU
APL (acute promyelocytic leukemia)
all trans-RA Tox
if used alone, 1/3 pts develop ‘leukocyte activation syndrome’ = inc white count; fever, resp distress, weight gain, pleural or pericardial effusion, occasional renal failure
***can avoid this by giving corticosteroids with RA Tx
other side effects = skin and lip dryness, nausea, headache, arthralgias, bone pain
all-trans RA resistance
induction of cytochrome P450 to enhance RA catabolism; alterations in level of cytosolic RA binding protein II (CRBP II) that could affect RA transport to target
trastuzumab (herceptin) MOA
humanized mAb against HER2 (Erb-B2) growth factor receptor; prevents transduction of proliferation and survival signals
trastuzumab TU
HER2 positive breast cancer; works best in combination with paclitaxel or doxorubicin
trastuzumab Tox
hypersensitivity reaction
cardiotoxicity (ventricular dysfunction and CHF)
can enhance cardiotoxic effects of doxorubicin
cetuximab (erbitux) MOA
competes with ligands for binding to EGFR and inhibits its TK activity, blocking growth promoting and survival signals
cetuximab TU
colorectal (w/ irinotecan or FOLFIRI), squamous cell carcinoma of head and neck; works best in combination with cisplatin or other chemo drugs
FOLFIRI = leucovorin, 5-FU, irinotecan
rituximab MOA
binds to CD20 antigen (which is present on all B cells); eliminates CD20 positive follicular lymphoma by: direct activation of apoptosis, complement activation, cell-mediated cytotoxicity
rituximab TU
non-Hodgkins lymphoma (particularly follicular lymphomas - relapsed or refractory)
cetuximab Tox
allergic rxn, cardiac events, skin problems, renal failure, PE, hypomagnesemia, hypocalcemia, hypokalemia
rituximab Tox
hypotension, flushing, fever and chills, asthenia, nausea, hypersensitivity rxn
vemurafenib MOA
BRAF inhibitor; blocks its constitutive activity to decrease cell proliferation and survival
vemurafenib TU
BRAF mutation positive metastatic melanoma; BRAF is a serine threonine kinase downstream of RAS and RTKs, most commonly mutated at V600 in cutaneous melanomas not associated with sun damage
vemurafenib Tox
arthralgia, fatigue, photosensitivity, alopecia, nausea, diarrhea
cutaneous squamous cell carcinoma, keratoacanthoma
QT prolongation, enhancing risk of ventricular arrhythmias
new primary cutaneous melanoma
vemurafenib contraindications
wt BRAF melanomas, electrolyte abnormalities, long QT syndrome, pts on durgs that will cause QT prolongation
dabrafenib MOA and TU
BRAF inhibitor for BRAF mutation positive metastatic melanoma
dabrafenib Tox
cutaneous squamous cell carcinoma, keratoacanthoma, melanoma
serious febrile drug rxn
uveitis, iritis
hyperglycemia
hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodyesthesia, rash, back pain, cough, constipation, myalgia, nasopharyngitis
may inhibit fertility in men
trametinib MOA and TU
inhibits MEK (extracellular signal-related kinase) in BRAF mutation positive metastatic melanoma
trametinib Tox
cardiomyopathy retinal pigment epithelial detachment retinal vein occlusion interstitial lung disease serious skin toxicity normal side effects may inhibit fertility in females
ipilimumab (yervoy)
CTLA-4 inhibitor, expected to stimulate immune system; approved for melanoma
IL-2
modulate immune system; used to treat melanoma
