Oncology 3 Flashcards
What is the role of epidermal growth factor receptors?
regulate cell differentiation, proliferation, and survival
What are the four EGFR receptors?
HER1
HER2
HER3
HER4
Through which pathway does EGFR act?
tyrosine kinase pathways
What are growth factors?
chemicals produced by the body that control cell growth
-some tell cells what type of cells they should become
-some make cells grow and divide into new cells
-some tell cells to stop growing or to die
How do growth factors work?
by binding to receptors on the cell surface
-this sends a signal to the inside of the cell, which sets off a chain of complicated chemical reactions
What is the difference between mAbs and TKIs in terms of where they act at the cell?
mAbs work extracellularly
TKIs work intracellularly
In which cancer is EGFR gene commonly overexpressed or mutated?
non-small cell lung cancer
-EGFR mutation present in 10-15% of patients (30-40% of Asian pts)
What is the role of the following growth factors?
-EGF
-VEGF
-PDGF
-FGF
epidermal growth factor (EGF):
-controls cell growth
vascular endothelial growth factor (VEGF):
-controls blood vessel development
platelet derived endothelial growth factor (PDGF):
-controls blood vessel development and cell growth
fibroblast growth factor (FGF):
-controls cell growth
What are cancer growth blockers?
a targeted drug that blocks the growth factors that trigger cancer cells to divide and grow
What are the types of cancer growth blockers?
tyrosine kinase inhibitors
proteasome inhibitors
mTOR inhibitors
Hedgehog pathway blockers
Provide the correct naming for small molecule drugs.
-tinib: TKI
-zomib: proteasome inhibitor
-ciclib: CDK inhibitor
-parib: PARP inhibitor
-irolimus: mTOR inhibitor
Which TKI was the pioneer?
imatinib
What is the MOA of TKIs?
block chemical messengers (enzymes) called tyrosine kinases
-TKs help to send growth signals in cells, so blocking them stops the cell growing and dividing
What is a multi-TKI?
TKIs that block more than one type of TK
Which TKI does not end in “-tinib”?
pazopanib
What are examples of multi-TKIs?
sorafenib
sunitinib
vandetinib
cabozantinib
lenvantinib
pazopanib
regorafenib
True or false: the therapeutic use and toxicities of multi-TKIs are the same
false
some targets may overlap but therapeutic use and toxicities are different
What are the TKI-EGFR inhibitors for NSCLC?
erlotinib
gefitinib
afatinib
osimertinib
Differentiate the TKI-EGFR inhibitors based on target.
erlotinib:
-EGFR TK cytosolic domain
gefitinib:
-EGFR TK cytosolic domain
afatinib:
-EGFR, HER2, HER4, HER3 transphorylation
osimertinib:
-EGFR, HER2, HER3, ACK1, BLK
Differentiate the TKI-EGFR inhibitors based on drug interactions.
erlotinib: CYP 3A4, PPI
gefitinib: CYP 3A4, 2D6
afatinib: P-gp
osimertinib: CYP 3A4, QT
Differentiate the TKI-EGFR inhibitors based on adverse effects.
erlotinib and gefitinib:
-rash, sun sensitivity, diarrhea
afatinib:
-rash, diarrhea, paronychia
osimertinib: milder ADR
-cardiomyopathy, vision disturbance
Which TKI-EGFR inhibitor is used for the T790M mutation?
osimertinib
Which cancer are ALK fusion genes sometimes present in?
~5% of patients with NSCLC
-more common in young pts who are non-smokers
What is the MOA of ALK inhibitors?
block an enzyme called anaplastic lymphoma kinase
-only work in cancer cells that have an overactive version of ALK
Which cancer are ALK inhibitors often used in?
some people with advanced NSCLC
What are examples of TKI-ALK inhibitors?
alectinib
brigatinib
ceritinib
crizotinib
lorlatinib
Which TKI-ALK is often first line for advanced NSCLC (ALK+)?
alectinib
What is a PK advantage of alectinib?
better CNS penetration if brain metastases
What are the side effects of ALK inhibitors?
most commonly GI toxicities (NVD)
some lab abnormalities
-elevated AST and ALT
less common: pneumonitis
What are examples of TKIs that target HER2?
lapatinib
neratinib
pyrotinib
tucatinib
Which blood vessel related process is unregulated in many tumors?
angiogenesis
-tumor growth, invasion, and metastasis
What is the master regulator of angiogenesis?
VEGF
What has emerged as potent anti-tumor weapons against multiple solid tumors?
VEGFR-associated multi-targeted TKIs
What is the use of axitinib?
metastatic renal cell cancer
What are the adverse effects of axitinib?
hypertension
bleeding
impaired wound healing
What are the drug interactions of axitinib?
substrate of CYP 3A4
acid blockers
What are the targets of sunitinib and pazopanib?
VEGF
PDGFR
c-KIT
What are the uses of sunitinib and pazopanib?
both: metastatic renal cell carcinoma
sunitinib:
-GI stromal tumor
-pancreatic neuroendocrine tumor
What are the adverse effects of sunitinib and pazopanib?
nausea, diarrhea
hand foot skin reaction (palmar erythrodysesthesia)
discoloration of nails or hair
hypothyroidism
HTN, QT prolongation, decreased LVEF
bleeding
What are the drug interactions of sunitinib and pazopanib?
substrates of CYP 3A4
What are the uses of sorafenib and regorafenib?
sorafenib:
-metastatic hepatocellular carcinoma
regorafenib:
-GIST
-hepatocellular carcinoma
What are the adverse effects of sorafenib and regorafenib?
GI (less severe than sunitinib)
HFSR (more common than sunitinib)
severe rash, mild skin discolouration
hypertension
bleeding
metabolic and electrolyte abnormalities
cardiotoxicity & QT
What are the drug interactions of sorafenib and regorafenib?
substrates of 3A4
sorafenib inhibits 2B6, 2C8
What are the indications for lenvatinib?
thyroid cancer
hepatocellular carcinoma
renal cell carcinoma
endometrial cancer
-advanced endometrial with pembrolizumab
What do most people with CML have?
abnormal chromosome called the Philadelphia chromosome
What causes the development of the Philadelphia chromosome?
ABL1 gene on chromosome 9 breaks off and sticks to a gene called the BCR gene on chromosome 22
-produces a new gene called BCR-ABL1, known as a fusion gene
What is an example of a BCR-ABL inhibitor?
imatinib
What are the targets of imatinib?
BCR-ABL kinase
PDGF
c-KIT
What are the adverse effects of imatinib?
edema
hepatotoxicity
bone marrow suppression
What are the drug interactions of imatinib?
CYP 3A4
What are around half of melanomas caused by?
a mutation in a gene called BRAF
What is the issue with BRAF inhibitors?
they quickly develop resistance
What is the MOA of BRAF inhibitors?
they target the faulty BRAF gene
-blocking the BRAF protein to slow or stop the growth of the cancer
What are examples of BRAF inhibitors?
vemurafenib
dabrafenib
encorafenib
What are BRAF inhibitors used in combination with for melanomas?
MEK inhibitors
What are the adverse effects of BRAF inhibitors?
cutaneous toxicities
-maculopapular rash (common)
-phototoxic reactions (wear sunscreen)
-squamoproliferative lesions
-alopecia
Describe the interplay of BRAF and MEK.
the BRAF protein can affect other proteins, such as MEK, which makes cancer cells divide and grow in an uncontrolled way
What is the MOA of MEK inhibitors?
they block the MEK protein, which slows down the growth of cancer cells
What are examples of MEK inhibitors used for melanoma?
trametinib
cobimetinib
binimetinib
What are the usual BRAF and MEK inhibitor combinations for melanoma?
dabrafenib with trametinib
vemurafenib with cobimetinib
encorafenib with binimetinib
Why are BRAF inhibitors and MEK inhibitors combined in melanoma?
synergistic and delays onset of drug resistance
-tolerability is also improved
What are the adverse effects of MEK inhibitors?
fewer cutaneous squamous cell carcinomas
acneiform rash
cardiotoxicities
ocular toxicity
What are the drug interactions of MEK inhibitors?
trametinib: none significant
cobimetinib: substrate of 3A4
What are proteasomes?
tiny, barrel shaped structures found in all cells
-they help break down proteins the cell doesnt need into smaller parts
-the cell can then use them to make new proteins that it does need
What is bortezomib?
a proteasome inhibitor used to treat multiple myeloma
What is the MOA of proteasome inhibitors?
cause a buildup of unwanted proteins in the cell, which makes the cancer cells die
What are examples of proteasome inhibitors?
bortezomib (sc)
carfilzomib (IV)
ixazomib (po)
What are proteasome inhibitors used for?
multiple myeloma
What are the adverse effects of proteasome inhibitors?
neutropenia
thrombocytopenia
peripheral neuropathy
diarrhea
reactivation of Hep B or Herpes zoster
What is recommend to combat the increased risk of herpes zoster or herpes simplex reactivation with proteasome inhibitors?
antiviral prophylaxis
-valacyclovir for seropositive pts
How can bortezomib-induced peripheral neuropathy be curtailed?
adjustments in route (SC rather than IV) and scheduling (weekly vs more frequent)
-less common and less severe with carfilzoimb and ixazomib
What can repair DNA strand breaks?
single-stranded breaks: PARP
double-stranded breaks: BRCA1, BRCA2
What happens if PARP enzymes are inhibited?
cancer cells lose one of the major mechanisms to repair single-stranded DNA breaks, which decreases their viability
What are cancer cells with mutated BRCA genes less able to do?
repair dsDNA breaks, thus more likely to die
-because ssDNA breaks left unrepaired by the PARP inhibition will turn into dsDNA breaks during DNA replication
-inhibitors of PARP can stop the growth of cancer, particularly cancers that have mutated BRCA genes
Which cancers are PARP inhibitors used for?
gynecological
breast
prostate
specifically cancers with BRCA mutation
What are the ovarian cancer indications for PARP inhibitors?
niraparib:
-advanced or recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer and who are in response to platinum-based chemo
olaparib:
-recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer with BRCA-mutation and who are in response to platinum-based chemo
What are the breast cancer indications for PARP inhibitors?
olaparib:
-early stage, high risk BRCA mutated, HER2 negative as adjuvant tx, continues for 1yr
What are the prostate cancer indications for PARP inhibitors?
olaparib:
-metastatic castration resistant prostate cancer with BRCA or ATM mutations
niraparib/abiraterone:
-combination production for metastatic castration resistant prostate cancer with BRCA mutation with prednisone
How is progression through different phases of the cell cycle controlled?
by a group of proteins called cyclins
What occurs when there is dysregulation in CDK4 and CDK6?
allows cancer cells, despite their genetic damage, to progress through the G1 checkpoint to the S phase of the cell cycle
What are CDK4/6 inhibitors used for?
adjuvant and metastatic breast cancer
Which cancer is CDK often overexpressed in?
breast
Which therapies are CDK inhibitors synergistic with?
anti-estrogen therapies
What are examples of CDK4/6 inhibitors?
abemaciclib
-continuous
palbociclib
-3 wks on 1 wk off
ribociclib
-3 wks on 1 wk off
What are the adverse effects of abemaciclib?
neutropenia (23%, less)
diarrhea (85%, the downside)
increased ALT/AST
alopecia
increased creatinine
VTE/PE
pneumonitis
What are the adverse effects of palbociclib?
neutropenia (55%)
diarrhea (26%)
alopecia
VTE/PE
pneumonitis
What are the adverse effects of ribociclib?
neutropenia (61%)
diarrhea (35%)
increased ALT/AST
alopecia
VTE/PE
QT prolongation
pneumonitis
What are the drug interactions of the CDK inhibitors?
abemaciclib:
-3A4 substrate, P-gp substrate
palbociclib:
-3A4 substrate, weak inhibitor
ribociclib:
-3A4 substrate, moderate inhibitor, QT
