11. Targeted Therapies Flashcards
What are targeted cancer therapies?
Drugs or other substances blocking cancer growth by interference of specific molecules (targets) for tumor growth and progression
Able to focus on target specific for type of cancer
Avoidance of healthy cells = less ____ effects
Target expressed = increased ____
side effects
efficacy
Activity of Targeted Therapies Interference of cancer cell proliferation -- Ex: \_\_\_\_ against EGFR or BCR-ABL Modification of proteins that regulate gene expression or cellular function -- Ex: \_\_\_\_ Induction of apoptosis -- Ex: \_\_\_\_ Block angiogenesis -- Ex: \_\_\_\_ Enhancing activity of immune system -- Ex: \_\_\_\_, ipilimumab Improved delivery of other therapies -- Ex: \_\_\_\_ Cancer vaccines and gene therapy
* Induction of monoclonal ab via enhancing activity of the immune system * Can also be used to conjugate therapies to give an enhanced effect
tyrosine kinase inhibitors (TKIs) retinoids bortezomib bevacizumab rituximab tositumomab
LIST OF DRUGS!
Look at me!
Yay!
EGFR
____ rash, ____ toxicity
acneiform
pulmonary
Structure of a monoclonal antibody
\_\_\_\_ chains Heavy chains \_\_\_\_ bonds Antigen-binding fragment (\_\_\_\_) Crystallisable (or constant) fragment (\_\_\_\_)
• Can create monoclonal ab specific to \_\_\_\_ on cancer cells
light disulfide Fab Fc epitopes
Mechanisms of action
Immune-mediated effects
• ____ dependent cell lysis
• ____-dependent cell mediated cytotoxicity
Direct anti-proliferative/apoptotic effects
• ____ a ligand
• Block a ligand
• Interfere with cell ____
Interact or sensitize with other modalities
• Can interact with radioimmuno conjugates and the ____ conjugates
complement antibody mimic function ab-drug
Conjugated monoclonal antibodies
Can use antibodies as a delivery mechanism
– High concentration at targeted cell sites increases ____
– Specificity decreases dose-limiting side effects
Examples
____
Toxins
____
• The therapy is conjugated onto the monoclonal ab • The cell internalizes both the \_\_\_\_ and \_\_\_\_ via lysosomes ○ End up getting up a higher cxn of drug directly targeting specific cancer cells ○ Allows usage of toxic particles, toxins, and chemotherapies § Using mAb the toxicities decrease significantly
efficacy
radioactive particle
chemotherapy
receptor
monoclonal ab
• Mab will be chimeric, humanized or human mAb - used clinically
• Using murine protein - increasing risk of ____ and hypersensitivity reactions
○ Patient develops ab to that mouse ab; so if try to reinfuse the murine mAb:
§ Enhanced ____ response
§ Inactivation of the murine mAb
○ Not seen that often anymore
• Chimeric mAb
○ Human constant region - area that’s exposed to immune system and activate it
§ Less risk of patients having adverse reactions
○ Murine ____ region
• Humanized mAb
○ ____% human:10% mouse (vs. 70/30 for chimeric)
§ Further decreasing risk of adverse risk
• All human mAb
infusion
hypersensitivity
variable
90
• Variable prefix that is specific to the mAb • Target: ○ Immune system § \_\_\_\_ ○ Bone § \_\_\_\_ ○ Tumor § \_\_\_\_ ○ Circulatory system § \_\_\_\_ • Source: ○ Mouse § \_\_\_\_ ○ Human § \_\_\_\_ ○ Chimeric § \_\_\_\_ ○ Humanized § \_\_\_\_ ○ Chimeric/humanized hybrid § \_\_\_\_
l(im)
(o)s(o)
t(u)
c(ir)
o u xi zu xizu
Trastuzumab
____ monoclonal antibody
Denosumab
____ monoclonal antibody
Nivolumab
____ monoclonal antibody
Rituximab
____ monoclonal antibody
tumor-targeting humanized
bone-targeting human
immune system-targeting human
tumor-targeting chimeric
Small Molecule Inhibitors
• Small molecule inhibitors can target \_\_\_\_ within the receptor
tyrosine kinase
Tyrosine Kinase Inhibitors (TKI)
Single Tyrosine Kinase Inhibitor
Example
____ (EGFR)
Multi-Tyrosine Kinase Inhibitor
Example
____ (CRAF, BRAF, KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß)
erlotinib
sorafenib
EGFR inhibitors
Monoclonal antibodies
____
panitumumab
Small molecule inhibitors \_\_\_\_ gefitinib \_\_\_\_ osimertinib
cetuximab
erlotinib
afatinib
Intravenous EGFR-targeting monocolonal antibodies
Cetuximab (Erbitux) Indications: \_\_\_\_ cancer (KRAS negative, Head and neck cancer, Lung cancer) Side Effects \_\_\_\_-like rash (~80%) Premedication \_\_\_\_
Panitumumab (Vectibix) Indications: \_\_\_\_ cancer (KRAS negative) Side Effects: \_\_\_\_-like rash (90%) \_\_\_\_
• EGFR - acneiform rash, happens commonly when receiving mAb
colorectal
acne
diphenhydramine
colorectal
acne
diarrhea
Oral EGFR-targeting small molecule inhibitors
Erlotinib (Tarceva) Indications: \_\_\_\_, pancreatic cancer Side Effects: Interstitial lung disease (rare) Rash (~50%) -- Rash ≠ \_\_\_\_ Correlates with \_\_\_\_, can be managed pharmacologically \_\_\_\_
Osimertinib (Tagrisso) Indications: \_\_\_\_ progressed on EGFR TKI therapy -- \_\_\_\_ mutation Side effects \_\_\_\_ (<50%, decreased severity) Interstitial lung disease (3.3%) Cardiotoxicity \_\_\_\_ prolongation \_\_\_\_
• Rash is not as significant with these newer drugs
NSCLC
hypersensitivity
diarrhea
NSCLC T790M rash QTc cardiomyopathy
Rash
Ex: ____ inhibitors
Patient education
• Use of gentle cleansers and moisturizers
• Minimize ____ exposure
• ____
Treatment • Mild: \_\_\_\_ therapy --• \_\_\_\_ (macular) or antibiotics (pustular) • Moderate: topical/oral therapy --• \_\_\_\_ derivative (doxycycline/minocycline) • Severe: topical/oral therapy --• Oral \_\_\_\_ --• \_\_\_\_ reductions/discontinuation
• Rash usually occurs on face/trunk of body and occurs 4 weeks into therapy and continues for 6 to 8 weeks ○ \_\_\_\_ during that time ○ Using \_\_\_\_ medications will exacerbate the rash § Treatment: gentle moisturizer, and use of topical steroids and antibiotics (tetracycline derivatives - anti-inflammatory effects) ○ The rash is initially \_\_\_\_, but once it opens to the environment it is prone to infection
sun sunscreen steroids tetracycline steroid dose
improves
acne
sterile
• Not an allergy
• Short-lived
• Correlation between development and response to the ____
○ Seeing the rash is a ____ sign!
therapy
positive
HER2 Inhibitors
Monoclonal antibodies
____
ado-trastuzumab emtansine
____
Small molecule inhibitors
____
trastuzumab
pertuzumab
lapatinib
