Targeted Tx's Flashcards
What features characterize an ideal target for targeted cancer tx?
- crucial for cancer growth/survival,
- not sig expressed in vital organs/tissues,
- minimal/no tox in non-tumor cells,
- measurable in easily obtained samples,
- clinical response in majority of pts whose tumors express the target when target is interrupted/inhibited,
- target doesn’t have mutations/variants
Most common cancers that undergo endocrine tx’s?
breast cancers, prostate cancer, endometrial cancers, ovarian cancers
What’s tamoxifen used for?
Breast cancer
tamoxifen MOA
estrogen antagonist in breast cancer cells;
agonist effects on endometrium, bone, and lipids
T or F: Tamoxifen is appropriate for breast cancer in females only.
F
In males too
AEs of tamoxifen
flushing, hot flashes, edema (menopause-like sx’s), thromboembolic events, mood changes, arthralgia, weakness
What’s a major risk of taking tamoxifen?
Endometrial cancer
What’s second line endocrine tx for breast cancer?
Fulvestrant
Fulvestrant MOA
Estrogen receptor antagonist
When is fulvestrant used?
Advanced, hormone-receptor positive breast cancer
–>i.e. when breast cancer becomes tamoxifen-resistant or when it metastasizes
Aromatase inhibitor MOA
blocks estrogen PRODUCTION
Why are aromatase inhibitors only used in post-menopausal women?
bc it can’t overcome the amt of estrogen produced by the ovaries of pre-menopausal women
Name the two nonsteroidal, reversible inhibitors of aromatse
anastrozole, letrozole
Name the steroidal, irreversible aromatase inhibitor
exemestane
AEs of aromatase inhibitors?
hot flashes and flushing
HTN
Osteopenia/osteoporosis
weakness, arthralgia
fatigue
List the androgen deprivation tx’s used for prostate cancer
Luteinizing-hormone releasing hormone (LHRH) agonists
LHRH antagonist
abiraterone
androgen receptor blockers
What is NOT an effective tx for prostate cancer?
5-alpha-reductase inhibitors (e.g. finasteride, dutasteride)
Leuprolide and goserelin are examples of…
LHRH agonists
MOA of LHRH agonists (leuprolide and goserelin)
down-regulation of hypothalamus-pituitary axis
What’s important to know when starting LHRH agonist tx?
There’s an initial “flare” response
What can be Rx’ed to tx the initial flare from LHRH agonists?
bicalutamide for 14-30d
What LHRH antagonist is used for prostate cancer?
degarelix
MOA of degarelix?
blocks pituitary receptors > reduces LH and FSH secretion > rapid decrease in testosterone production
T or F: Degarelix causes an initial flare.
F
What’s abiraterone?
androgen biosynthesis inhibitor
MOA of abiraterone
Inhibits CYP17 > blocks androgen production in testes, adrenal glands, and tumour
What unique AE does abiraterone cause as a result of its MOA?
Reduces cortisol production > causes increased ACTH > causes accumulation of mineralocorticoids > HTN, hypokalemia, edema
What’s given in combo with abiraterone? Why?
Prednisone > prevents compensatory rise in ACTH
Name 4 androgen receptor blockers
Bicalutamide, flutamide, enzalutamide, apalutamide
Androgen deprivation tx’s: AEs
Urinary sx’s, gynecomastia, hot flashes, reduced libido and ED, fatigue, wt gain, loss of muscle mass, osteopenia/-porosis, MI/increased QT
Name the 5 classes of small molecule drugs (and the suffixes used in each drug class)
- tyrosine kinase inhibitors (-tinib)
- proteasome inhibitor (-zomib)
- cyclin-dependent kinase inhibitor (-ciclib)
- poly ADP-ribose polymerase inhibitor (-parib)
- mTOR (mammalian target of rapamycin) inhibitor (-irolimus)
Tyrosine kinase inhibitor MOA?
Intracellularly block signals from activated trans-membrane proteins by competing w/ ATP for the TK region of the trans-membrane receptor
Epidermal growth factors receptors - list them
HER1/2/3/4
Another name for HER1 receptors?
EGFR
What do the epidermal growth factors receptors do?
They ctrl cell differentiation, proliferation, and survival
Through which pathway do the epidermal growth factors receptors act?
Tyrosine kinase pathway (TKP)
4 EGFR inhibitors for non-small cell lung carcinoma:
- erlotinib
- gefitinib
- afatinib
- osimertinib
These two EGFR inhibitors target the EGFR tyrosine kinase cytosolic domain
erlotinib, gefitinib
This EGFR inhibitor targets EGFR, HER2, HER4, and HER3 (transphorylation of it)
afatinib
Which EGFR inhibitor isn’t used often?
osimertinib
Diarrhea is a huge AE of this EGFR inhibitor
afatinib
HER2 is overexpressed in what types of cancers?
15% of breast cancer cases, and some gastroesophageal cancers
AEs of HER2 agents?
rash, D, cardiotox, hepatotox
Specific HER-2 agents?
lapatinib
Name VEGF inhibitors
axitinib
What do VEGF inhibitors do?
Reduce/prevent angiogenesis of tumors
What kind of cancer is tx’ed w/ VEGF inhibitors?
Renal cell carcinoma
AEs of VEGF inhibitors?
HTN, bleeding, impaired wound healing
What do multikinase inhibitors target?
> 1 tyrosine kinase region in the cytoplasmic side of transmembrane protein receptors
What’re sunitinib and pazopanib?
multikinase inhibitors
sunitinib and pazopanib: how do they help tx cancer?
inhibit tumor growth, cellular proliferation, and angiogenesis
What’re sunitinib and pazopanib used to tx?
renal cell carcinoma
Unique AEs of sunitinib and pazopanib?
- hand foot skin rxn (HFSR) aka plantar palmar erythrodysethesia (PPE)
- discoloration of nails and/or hair (yellow or white)
Why is bleeding an AE of sunitinib and pazopanib?
Due to VEGF-inhibition activity
How do sorafenib and regorafenib work?
inhibit cellular proliferation and tumor angiogensis
What’s sorafenib used for?
hepatocellular carcinoma, renal cell carcinoma
What’s regorafenib used for?
Gastrointestinal Stromal Tumor (GIST), hepatocellular carcinoma
Unique AEs of sorafenib and regorafenib?
HFSR aka PPE
Severe rash, mild skin discoloration
What’s a “Philadelphia Chromosome”?
An oncogene that’s formed when the BCR portion of chromosome 22 fuses w/ the ABL portion of chromosome 9
The “Philadelphia chromosome” is found in this cancer
CML (chronic myelogenous leukemia)
List the BCR-ABL inhibitors
imatinib, dasatinib, nilotinib, bosutinib, ponatinib
What is wrong with the protein made by the BCR-ABL protein in CML (chronic myeloid leukemia)?
It’s an abnormal tyrosine kinase, hence the need for a tyrosine kinase inhibitor
List the tyrosine kinase inhibitors (classes):
EGFR inhibitors, HER2 inhibitors, VEGF inhibitors, multikinase inhibitors, BCR-ABL inhibitors
List the two cyclin dependent kinase (CDK) inhibitors
palbociclib, ribociclib
CDK inhibitors: what kind(s) of cancer are they used in?
Estrogen-receptor positive breast cancers
CDK inhibitors: MOA
Inhibit CDK (cyclin dependent kinase) > decrease breast cancer cell proliferation > induce senescence (i.e. it halts proliferation)
CDK inhibitors can be used synergistically with what type of chemotx?
anti-estrogen tx’s (e.g. estrogen receptor antagonists, aromatase inhibitors)
AEs of CDK inhibitors
Neutropenia, stomatitis, N, fatigue
Name a poly ADP-ribose polymerase (PARP) inhibitor
Olaparib
What proteins are responsible for repairing daily DNA damage?
PARP, BRCA1 and BRCA2
MOA of PARP inhibitors?
Inhibits PARP > DNA repair is prevented > cancer cell death
When would PARP inhibitors be used?
In cancers where BRCA1/2 is damaged/not working properly
AEs of PARP inhibitors
N/V, fatigue, anemia
Name the proteasome inhibitors
bortezomib, carfilzomib, ixazomib
Proteasome inhibitors are used in these types of cancers
hematologic cancers
What kind of cancers are tx’ed by proteasome inhibitors?
multiple myeloma, non-Hodgkin lymphoma
MOA of proteasome inhibitors
Damaged proteins and other substrates cannot be degraded by 20S proteasome > toxic metabolites buildup in cancer cell > cancer cell ruptures
Anaplastic lymphoma kinase gene mutation: most common pt population?
young pts who’re NON-smokers
ALK inhibitors: list them
crizotinib, alectinib, ceritinib
One of this ALK inhibitor’s AEs includes vision disorder
ceritinib
There’re 3 types of non-small cell lung cancer. What’re they?
squamous cell carcinoma, large cell carcinoma, adenocarcinoma
What kinds of mutations drive NSCLC adenocarcinoma and large cell carcinoma?
PD-L1, EGFR, AKL, ROS
BRAF kinase inhibitors: list them
vemurafenib, dabrafenib
BRAF kinase inhibitors: indication
melanoma ONLY
BRAF kinase inhibitor MOA:
Block BRAF kinase > stop cancer cells from growing
AEs of BRAF kinase inhibitors
alopecia, N, rash, photosensitivity, severe hypersensitivity, cutaneous squamous cell carcinoma
How do we reduce the risk of cutaneous squamous cell carcinoma when tx’ing pts w/ BRAF kinase inhibitors?
Combine the BRAF kinase inhibitor w/ MEK inhibitors
MEK inhibitors: AEs
acneiform rash, cardiotox’s, ocular tox
mTOR (mamallian target of rapamycin) - what is it?
serine/threonine protein kinase that ctrls cell cycle progression, cell proliferation, and angiogenesis
Name mTOR inhibitors
temsirolimus, everolimus
What kinds of cancers are tx’ed using mTOR inhibitors?
renal cell carcinoma, pNET (pancreatic neuroendocrine tumor), breast cancer (historical)
What’s the hedgehog pathway?
Cell differentiation and organ development pathway that’s active in vertebrate embryonic development
What role does the hedgehog pathway play in adults?
Tissue maintenance and repair only (or differentiation/organ development)
Inappropriate reactivation of the hedgehog pathway in adults is assoc w/ what kind of cancer?
basal cell skin cancer
Name a hedgehog pathway inhibitor
vismodegib (only one with “-gib” suffix)
AEs of vismodegib:
GI effects, loss of taste, alopecia, arthralgia
Which two targeted tx’s are assoc w/ alopecia?
hedgehog pathway inhibitors and BRAF inhibitors
hedgehog pathway inhibitor CI
pregnancy (teratogen)
Bruton’s tyrosine kinase (BTK) inhibitors: name them
ibrutinib, acalabrutinib
BTK inhibitors: used to tx which cancers?
chronic lymphocytic leukemia (CLL)
relapsed mantel cell lymphoma (MCL)
MOA of BTK inhibitors
Inhibition of B-cell receptor and cytokine receptor pathways > inhibits proliferation and survival of malignant B-cells
AEs of BTK inhibitors
arrhytmias, PR prolongation, tumor lysis syndrome, bleeding, Hep B reactivation
Phosphoinositide-3-kinase (PI3K) inhibitors: name it
idelalisib
MOA of idelalisib:
inhibits B-cell signaling > reduced B-cell migration to lymph nodes and bone marrow
ALSO induces malignant B-cell apoptosis
Idelalisib (a PI3K) is combined with this to tx CLL (chronic lymphocytic leukemia)
rituximab
idelalisib AE
GI, infections, rash, myelosuppression, pneumonia/pneumonitis, hepatotoxicity
BCL-2 inhibitors - name it
venetoclax
What is BCL-2?
B-cell lymphoma-2 = anti-apoptotic protein overexpressed in chronic lymphocytic leukemia (CLL) cells
Major AE of venetoclax (BCL-2 inhibitor)
Tumor lysis syndrome/hyperuricemia
Name the monoclonal antibody targets for cancer tx
CD20 antigen, EGFR (HER1), HER2, VEGF
Name the two anti-CD2- mabs
rituximab, obinutuzumab
MOA of anti-CD20 mabs (rituximab, obinutuzumab)
CD20 antigen found on malignant and nonmalignant B cells > mabs recruit other immune mediators enabling cell destruction and apoptosis
AEs of anti-CD20 mab tx?
infusion rxns (facial flushing, hypotension, fever, dyspnea, chest pain), tumor lysis syndrome, Hep B reactivation
CIs of anti-CD20 mab tx?
live vaccines 6mths before and after tx
anti-CD20 mab tx can cause tumor lysis syndrome - how to deal w/ this?
Premedicate w/ hydration and allopurinol
EGFR (HER1) mab drugs:
cetuximab, panitumumab
What’s cetuximab used for?
head and neck cancers
What’s panitumumab used for?
colorectal cancer
MOA of EGFR (HER1) mab drugs?
bind to extracellular ligands > stops intracellular tyrosine kinase pathways
Major AE assoc w/ EGFR mab drugs
Significant Mg2+ level drop
This EGFR mab drug is assoc w/ interstitial pneumonitis
panitumumab
Name the HER2 mab drugs
trastuzumab, pertuzumab
MOA of trastuzumab
blocks HER-2 dimerization > reduces cell replication
MOA of pertuzumab
blocks HER-2 heterodimerization > reduces cell replication
trastuzumab is also used in these cancers
GI cancers that overexpress HER2
Name the VEGF mab drugs
bevacizumab, ramicirumab,
bevacizumab MOA:
binds all circulating VEGF > prevents activation of VEGF receptors
bevacizumab is used for what types of cancers
advanced colorectal cancer, NSCLC, glioblastoma, gynecologic cancers
bevacizumab: AEs
HTN, bleeding, cerebral infarction, MI, proteinuria
ramicirumab MOA:
binds to VEGF receptor 2 specifically
What’s ramicirumab used for?
advanced gastric cancer and gastroesophageal adenocarcinomas
Name 3 antibody-drug conjugates
DM1, trastuzumab emtansine, brentuximab vedotin, and ibritumomab tiuxetan,
DM1 MOA
microtubule inhibitor
Name two other microtubule inhibitors
taxanes and vinca alkaloids
Why isn’t DM1 used anymore for cancer tx?
Too toxic
How is DM1 given nowadays?
As trastuzumab emtansine
T or F: trastuzumab emtansine is given at the same dose as DM1
F
It would kill the pt; half the dose is given
MOA of trastuzumab emtansine
trastuzumab brings emtansine to cancer cell > emtansine (containing DM1) gets taken up > causes tumor cell death
What kind of cancer is tx’ed w/ brentuximab vedotin
refractory Hodgkin dz and refractory anaplastic lg cell lymphoma
What kind of cancer is tx’ed w/ ibritumomab tiuxetan?
relapsed refractory follicular lymphoma
