Molecular Targeted Therapy

Question 1

Imatinib MOA

Answer 1

binds to Bcr-Abl at ATP binding site, blocking its tyrosine kinase activity; Bcr-Abl fusion protein created by t(9;22)

Question 2

Imatinib TU

Answer 2

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)

Question 3

Imatinib Toxicity

Answer 3

minimal - nausea, vomiting, myalgia, arthralgia, myelosuppression

Question 4

Imatinib Intrinsic Resistance

Answer 4

mutations in Bcr-Abl making it insensitive; enhanced binding to proteins in circulation and/or drug efflux

Question 5

Imatinib relapse after initial response

Answer 5

1. mutations in Abl kinase making it less sensitive
2. Bcr-Abl amplification
3. persistent inhibition of Bcr-Abl; other molecular abnormalities take over

Question 6

Second Generation TKIs

Answer 6

nilotinib and dasatinib

Question 7

all trans-retinoic acid (RA) MOA

Answer 7

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

Question 8

all trans-RA TU

Answer 8

APL (acute promyelocytic leukemia)

Question 9

all trans-RA Tox

Answer 9

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

Question 10

all-trans RA resistance

Answer 10

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

Question 11

trastuzumab (herceptin) MOA

Answer 11

humanized mAb against HER2 (Erb-B2) growth factor receptor; prevents transduction of proliferation and survival signals

Question 12

trastuzumab TU

Answer 12

HER2 positive breast cancer; works best in combination with paclitaxel or doxorubicin

Question 13

trastuzumab Tox

Answer 13

hypersensitivity reaction
cardiotoxicity (ventricular dysfunction and CHF)
can enhance cardiotoxic effects of doxorubicin

Question 14

cetuximab (erbitux) MOA

Answer 14

competes with ligands for binding to EGFR and inhibits its TK activity, blocking growth promoting and survival signals

Question 15

cetuximab TU

Answer 15

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

Question 16

rituximab MOA

Answer 16

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

Question 17

rituximab TU

Answer 17

non-Hodgkins lymphoma (particularly follicular lymphomas - relapsed or refractory)

Question 18

cetuximab Tox

Answer 18

allergic rxn, cardiac events, skin problems, renal failure, PE, hypomagnesemia, hypocalcemia, hypokalemia

Question 19

rituximab Tox

Answer 19

hypotension, flushing, fever and chills, asthenia, nausea, hypersensitivity rxn

Question 20

vemurafenib MOA

Answer 20

BRAF inhibitor; blocks its constitutive activity to decrease cell proliferation and survival

Question 21

vemurafenib TU

Answer 21

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

Question 22

vemurafenib Tox

Answer 22

arthralgia, fatigue, photosensitivity, alopecia, nausea, diarrhea
cutaneous squamous cell carcinoma, keratoacanthoma
QT prolongation, enhancing risk of ventricular arrhythmias
new primary cutaneous melanoma

Question 23

vemurafenib contraindications

Answer 23

wt BRAF melanomas, electrolyte abnormalities, long QT syndrome, pts on durgs that will cause QT prolongation

Question 24

dabrafenib MOA and TU

Answer 24

BRAF inhibitor for BRAF mutation positive metastatic melanoma

Question 25

dabrafenib Tox

Answer 25

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

Question 26

trametinib MOA and TU

Answer 26

inhibits MEK (extracellular signal-related kinase) in BRAF mutation positive metastatic melanoma

Question 27

trametinib Tox

Answer 27

``` cardiomyopathy retinal pigment epithelial detachment retinal vein occlusion interstitial lung disease serious skin toxicity normal side effects may inhibit fertility in females ```

Question 28

ipilimumab (yervoy)

Answer 28

CTLA-4 inhibitor, expected to stimulate immune system; approved for melanoma

Question 29

IL-2

Answer 29

modulate immune system; used to treat melanoma