Chem V: Targeted Therapy Flashcards
What does it mean by targeted therapy?
Targeted therapy refers to a new generation of CA drugs designed to interfere with a specific molecular target (ie - protein) that is thought to have a critical role in tumor growth or its progression.
This is different from conventional, more empirical approach that uses a cytotoxic chemotherapy approach, since it identifies appropriate targets based on the understanding of hte molecular changes underlying a specific acancer
One of the main targets in targeted therapy of CA is tyrosine kinase.
What type of protein is typrosine kinase? (2 types)
How do tyrosine kinase work?
What is the main function to TKs?
There are two types of tyrosine kinases:
- TRANSMEMEBRANE PROTEIN - ligand binding extracellular domain and a catalytic intracellular kinase domain = RECEPTOR
- NON-MEMBRANE tk = non-receptor
Transfer of PHOSPHATE from ATP –> TYROSINE in polypetides
Regulate: cellular proliferation, survival, differentiation, function and motility, metastases and invasion
How can tyrosine kinase by inhibited? (2)
- small molecule inhibition of the catalytic activity of the kinase
-
antibodies against the receptor tyrosine kinase or ligand of the receptor tyrosine kinase
* some drugs inhibit a specific TK while others may target multiple TKs*
But how can a TK be invovled in cancer??
How can TK promote tumors?
- Dysregulation
One of the ways that TK is activated is via the fusion of a partner protein with TK due to chromosomal translocation –> TK oligomerization in the absence of ligand binding or other signals
MUTATIONS that DISRUPT autoregulation of kinase
–> INC or aberrant expression of a receptor TK, since there is a loss of checks and balances = constitutes autoregulation / unchecked TK –> continual UNCHECKED growth.
Aberrant TK activation can INC cell survival, proliferation and drug resistance –> INC angiogenesisi, invasiveness and metastatic potential
What type of TK inhibitors are available? (2 types)
- Small molecule TK recetor inhibitors
includes: imatinib, erlotinib - Monoclonal antibodies
includes: trastuzumab, cetuziman, bevacizumab
What is BCR -ABL ‘s role in TK activity?
Ckit?
BCR - ABL transolcation –> BCR-ABL protein –> contitute TK autophosphorylation which signals for cell to continue to divide
BCR-ABL unqieu to CML [oncogene addition-dependnt for cell survival on TK signaling pathway] –> phosphorylation, not controlled
C-Kit: normally needed to signal; with mutant CKit process is contitute, thus regulation is loss – gene expression continues
Imatinib Mesylate
MOA + target
Major uses (2)
Other drugs in this class? (2)
Imatinib is a tyrosine kinase inhibitor
By binding to the BCR-ABL ATP binding pocket - blocks phosphorylation, inhibiting critical signaling pathways in the cancer cell that are otherwise constitively active
Also, inhibits Ckit
uses: CML, gastrointestinal stromal tumors (c-kit target)
BUT: resistance will eventually develop and this therapy is not know to be curative at the present time!
Others: dasatanib, nilotinib
What should be avoided when taking imatinib?
What are the side effects? (9)
What needs to be monitored?
Imatinibi is metabolized by the liver by CYP3A4, and excreted into the feces via the biliary system thus it is important to avoid coadministration with INDUCERS of the CYP3A4 pathway [St. John’s Wort - anti-depressant herbal therapy] and INHIBTORS of the CYP3A4 pathway [grapefruit juice, and other drugs]
Side Effects: superficial EDEMA [legs, periorbital], nausea, muscle cramps, abdominal pain, rash, diarrhea, anemia, neutropenia, thrombocytopenia
MONITOR: TSH LEVELS
imatinib also increases clearance of thyroid homrone in hypothyroid patients taking thyroid replacement therapy!
Cetuximab
MOA? What is its target …..
What is its role in chemotherapy?
What is its main uses (3):
Cetuximan = monoclonal antibody against EGFR (inhibitor)
[EGFR = epidermal growth factor receptor; overexpression of EGFR receptors leads to increased signaling and affects cell growth and division, metastases and invasion]
Cetuximab can also SENSITIZE CELLS TO THE EFFECTS OF CHEMOTHERAPY AND CAN BE USED AS A RADIATION THERAPY SENSITIZER
Main uses:
Metastatic lung CA (no mutaiton analysis required)
Metastatic colon-rectal CA **perform K-ras and n-ras mutational analysis on tumor. If k-ras and n-ras are both wildtype, pt may respond to cetuximab; if they are mutated, pt will not respond to cetuximab and thus its use not indicated**
Head and neck cancers receiving radiation treatment (not selected on the basis of EGFR expression)
Cetuximab side effects (5)
Side effects: rash, diarrhea, hypomagnesemia, infusion reactions, trichomegally (long lashes)
- most TK inhibitors have some type of skin manifestation/toxicity*
- You can give prophylaxis antibiotics before starting medication, dose reduction and discourage the use of alcohol based creams*
Erlotinib:
MOA?
Uses?
is mutational analysis required?
Small molecule inhibitor of tyrosine kinase domain associated with EGFR
- makes cancer cells more sensitive to TKI*
- Should be used for: lung, head and neck CA*
- pt with EGFR activation mutations +*
adenocarcinomas, bronchoalveolar CA
Women, Asian background, never smoked
** perform mutational analysis on non-small cell lung cancers for EGFR activating mutations, esp of the adenocarinoma, to see if they have EGFR mutation **
If the patient w/ non-small cell lung cancer has an activating mutation - treatment of choice in a patient with metastatic dz is erlotinib and is SUPERIOR TO CHEMOTHERAPY!
Side effects? (4)
Any dose reduction/changes?
Rash, nausea, anorexia, fatigue
Metabolized by CYP3A4, thus careful with drugs that inhibit / induce cyp. - avoid coadministration with induces (St. John’s Wort) and inhibitors of the pathway (other drugs and grapefruit juice)
oral administration
Bevacizumab:
MOA + target molecule
Uses: (2)
What is one important thing to know about the administration of Bevacizumab?
Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF)
Monoclonal antibody that binds to VEGF LIGAND and presumably decreases the growth of primary and metastatic cancers due to impaired vasculature formation in the tumor, mby prventing signaling for new blood vessel formation in tumors
Significant prolongation of survival in pt with..
metastatic lung cancer and metastatic colon cancer
- when combined with chemotherapy*
- NOT active as a single agent*
What are the major side effects of bevacizumab? (7)
Infusion reactions, proteinuria, HTN, arterialclots, bleeding, perforation of the colon, reversible posterior leukoencephalopathy syndrome (rare - seizures, h/a, mental status change, visual changes, findings on MR of the brain)
What are 3 other VEGF receptor TK inhibitors that are similar to bevacizumab?
What are their similaries? (3)
What are some of the differences? (3)
What is one difference of Sunitnib? (2)
What is one difference of sorafenib?
Sorafenib, pazopanib, sunitinib
Similarities: all metabolized by CYP3A4, oral administration, could use in renal cell cancer
Difference: although they have similar toxicities, these drugs also have hand foot syndrome, rashes and CHF (uncommong)
Sunitnib - also used for: pancreatic neuroendocrine CA, GI stromal tumor
Sorafenib - also used for hepatocellular CA
