Chapter 8 anticancer - kinase and growth factor receptor inhibitors

Question 1

Helpful hint for drug names -mab and -ib

Answer 1

• drugs ending with -mab are monoclonal antibodies (large proteins that do not pass through glomeruli in kidney [therefore LONG serum half life]; therefore most monoclonal antibodies are adminsitered IV about every 2-3 weeks; risk is cannot stop serious side effect
• -ib endings are small molecule inhibitors (typically oral meds and many been optimized to require only day dosing!)

Question 2

imatinib (gleevec)
dasatinib (sprycel)
nilotinib (Tasigna)
bosutinib (bosulif)
pnatinib (iclusig)

Answer 2

• BCR-ABL tyrosine kinase inhibitors
• translocation between chromosome 9 and 22 makes a chimeric chromosome (philadelphia chromosome, Ph+) w/ a novel fusion protein called BCR-Abl (tyrosine kinase that drives cancer
• these agents inihbit ABL kinase and some are used for cancers in which upstream mutations inc activity of ABL (GIST or gastrointestinal stromal tumors)
• can inhibit kinases other than BCR-ABL to varying degrees
• e.g chronic myelogenous leukemia
• drug resistance is common

Question 3

gefitinib (iressa)
erlotinib (tarceva)
laptinib (tykerb)
vandetanib (caprelsa)
neratinib (nerlynx)
osimertinib (tagrisso)
dacomitinib (vizimpro)

Answer 3

Epidermal growth factor (EGRF) inhibitor
* bind to tyrosine kinase extracellular domain of EGFR to block EGFR activity (normally for epithelial tissue growth, development + homeostasis)
* EGFR mutations or amplifications drive lung, breast, brain and other cancers
* often prescribed when the above mutations or amplifications are happening
* can inhibit other kinases (oral)

Question 4

cetuximab (erbitux)
pantiumumab (vectibix)
necitumumab (portrazza)

Answer 4

monoclonal antibodies that block EGFR ((normally for epithelial tissue growth, development + homeostasis)) => mutations + amplification

IV every 2-3 weeks, very specific to above

Question 5

sunitinib (sutent)
sorafenib (nexavar)
axitinib (inlyta)
cabozantinib (cometriq)
ponatinib (iclusig)
regorafenib (stivarga)
vandetanib (capreisa)
pazopanib (votrient)
levatinib (lenvima)

Answer 5

• vascular endothelila growth factor (VEGF) receptor inhibitor
• bind to VEGF receptor and block tyrosine kinase activity that is required for generated new blood vessels
• all of them inhibit other kinases

qd PO

Question 6

bevacizumab (avastin, mvasi)
ramucirumab (cyramza)

Answer 6

• monoclonal antibodies that block VEGFR (vascular endothelial growth factor recptor inhibitor)

IV 2-3 weeks d/t half-life

stop these drugs 4 weeks prior to major surgery and for about 4 weeks after surgery

Question 7

ziv-afliberept (zaltrap)

Answer 7

recombinant humanized protein that antagonizes VEGF-A + B and placental growth factor

effects
* severe bleeding
* GI perforation
* delayed wound healing d/t on-target activity

Question 8

dabrafenib (taflinlar)
trametinib (mekinist)
vemurafenib (zelboraf)
ibrutinib (imbruvica)
ruxolitnib (jakafi)
afatinib (gilotrif)
ceritinib (zykadia)
idelalisib (zydelig)
nintedanib (ofev)
alectinib (alecensa)

Answer 8

multikinase inhibitors
* dirty kinase inhibitors — block multiple signaling pathways that are all important for cancer
* many of these pathways are also important for noncancercous cells so finding a therapeutic window in which drugs kill cancer cell at an well tolerated dose is difficult

Question 9

olaratumab (lartruvo)

Answer 9

• monoclonal antibody that blocks PDGFRa (Platelet derived growth factor receptor alpha)
• elevated of this level l/t poor prognosis in sarcoma
• other cancers — PDGFRa muations, fusions or amplifications are observed

indication:
* standard chemo agent for sarcoma (rare cancers that develop in the bones and soft tissues, including fat, muscles, blood vessels, nerves, deep skin tissues and fibrous tissues.)

Question 10

Vemurafenib (zelboraf)
encorafenib (braftovi)

MAPK inhibitor

Answer 10

• BRAF inhibitor inhibitors
• used for melanoma and other tumors w/ BRAFv600 mutation
• has cancer specificity to target mutated forms

Effects
* rash
* photosensitivity
* alopecia
* cutaneous squamous cancer
* fatigue

Question 11

trametinib (mekinist)

MAPK inhibitor

Answer 11

• mitogen-activated exctracellular signal-regualted kinase (MEK) inhibitor
• approved for use alone in selected patients w/ BRAF V600E or V600k mutation
• also approved for use with combination – such as BRAF inhbiitor for cancers that have BRAF mutations

effects
* edema
* diarrhea (can be bloody)

Question 12

binimetinib (mektovi)
cobimetinib (cotellic)

MAPK inhibitor

Answer 12

MEK kinase inhibitors used in combination with encorafenib (BRAF inhibitor) for cancers with BRAF V600E or V600K mutation

Question 13

Copanlisib (aliqopa)

idelalisib (zydelig)

PI3K/AKT/mTOR pathway inhibitors

Answer 13

PI3Ka (phosphoinositide 3-kinase alpha) or delta (PI3Kd) inhibitor
* blocks b-receptor-mediated signaling
* bloks CXCR12-mediated malignant B cell chemotaxis

idelaisib only delta inhibitor
effects for idelalisib: hepatoxic (monitor ALT and AST)

Question 14

duvelisib (copiktra)

PI3K/AKT/mTOR pathway inhibitors

Answer 14

• delta or gamma inibhitor (PI3Kd or “Y)

effects:
1) serious infection
2) colitis
3) pneumonitis (inflammation of lung tissue; however pneumonitis caused by an infection is known as pneumonia)

• assess risk-benefit ratio

Question 15

everolius (afinitor)
temsirolimus (torisel)
sirolimus (rapamune)

PI3K/AKT/mTOR pathway inhibitors

Answer 15

• mammalian target of rapamycin (mTOR) inhibitors
• central to mutiple cancer causing or cancer promoting tyrosine kinase pathways

indication
* renal carcinoma
* everolimus —- tumors w/ tuberous sclerosis (involves overactivity of the mTOR pathway)

Question 16

Ibrutinib (imbruvica)
acalabrutinib (calquence)

other tyrosine kinase inhibitors

Answer 16

• Bruton’s tyrosine kinase (BTK) inhibitor
• BTK needed for b cell development
• this inhibitor affects both normal and cancerous b cells — also used for chronic graft versus host disease

effects
* diarrhea
* thrombocytopenia
* neutropenia
* edema
* fatigue/dizziness/anxiety

Question 17

mindostaurin (rydapt)
gilteritinib (xospata)
crenolanib

other tyrosine kinase inhibitor

Answer 17

FLT3 kinase inhibitor
* FLT3 tyrosine kinase regulates
1) proliferation and survival of hematopoietic stem (multipotent primitive cells that can develop into all types of blood cells) and progenitor cells
2) FOR ACUTE MYELOGENOUS LEUKEMIA ( cancer of the blood and bone marrow. It is the most common type of acute leukemia in adults. ), 1/3 of pts with this condition have mutated FL3
* these inhibitors – reduce peripheral blasts (AML progenitor cells); have little effect okn blasts located in bone marrow
* as a result remissions happen rarely

Question 18

crizotinib (xalkori)
brigatinib (alunbrig)
lorlatinib (lorbrena)
alectinib (alecensa)

other tyrosine kinase inhibitor

Answer 18

ALK tyrosine kinase inhibitors
* ALK tyrosine kinase plays a role in brain development
* also in small intestine and testes
* Fusions involving ALK and other genes cause non-small cell lung cancer + anaplastic large cell lymphomas (ALK inhibitors can target these mutations)

effects
* edema
* irregular heart beat
* dizzizness

Question 19

Larotrectinib (vitrakvi)

other tyrosine kinase inhibitor

Answer 19

oral selective tropmysoin receptor kinase (TRK) inhibitor

indication:
* solid tumors with neurtrophic TRK (NTRK)-fusion proteins

• NTRKS are receptors for neurotrophic growth factors (autophosphorylation and activatio nof downstream MAPK pathway)