Chem V: Targeted Therapy Flashcards Preview

MSY2 Viruses > Chem V: Targeted Therapy > Flashcards

Flashcards in Chem V: Targeted Therapy Deck (24):

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: 

1. TRANSMEMEBRANE PROTEIN - ligand binding extracellular domain and a catalytic intracellular kinase domain = RECEPTOR

2. 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)

1. small molecule inhibition of the catalytic activity of the kinase

2. 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?

1. 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)

1. Small molecule TK recetor inhibitors

includes: imatinib, erlotinib


2. Monoclonal antibodies

includes: trastuzumab, cetuziman, bevacizumab


What is BCR -ABL 's role in TK activity?



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



imatinib also increases clearance of thyroid homrone in hypothyroid patients taking thyroid replacement therapy!



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]



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






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



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



MOA + target


Uses: (3)

What is a special condition of its uses

Trastuzumab monoclonal antibody that targets the extracellular domain of EGFR receptor, Her-2/neu --> binding the domain, decreases the signaling pathways of EGFR receptor


Used for: breast cancer in combination with chemotherapy when the breast cancer overexpresses Her-2/neu; stomach and gastroesophageal junction cancer in combo with chemtherapy when the cancer overexpresses Her-2/neu



Side effects of trastuzumab: (13)


Which side effects requires special monitoring? how frequently is this seen in people taking trastuzumab? is it dose dependent ie) does it require dose adjusment? is this reaction seen with any other drug - how does it differ?

fever, n/v, diarrhea, cough, h/a, sob, back pain, rash, muscle pain, allergic reactions and infusion reactions, CARDIO TOXICITY


Carditoxicity is seen in 1-4% of pt tha thave clinical heart failure

Up to 34% of patients have decline in cadiac fxn

Greatest risk when taking anthracycline / doxorubicin concurrently

NOT DOSE DEPENDENT! but reversible although potential for problems later unknown

**serial monitor of cardiac ejection fraction is required**

[different from that seen in anthracycline; trastuzumab cardiac dysfunction manifest as ASYMPTOMATIC DECLINE IN EJECTION FRACTION, NOT CUMULATIVE! thus pt can be rechallenged with drug vs this cannot be done with doxyrubicin/anthracycline]

Stop until EJ gets better again 



What is the main use?

What is the treatmetn response?


What is something particularly important about its administration?

Crizotinib is an ALK inhibitor


Main use is in patients with ALK-anaplastic lymphoma kinse rearragements that develop adenocarcinoma

These pt tend to be younger, had little or no exposure to smoke

Tx response --> 60% response rate, 33% stable dz

**must perform mutational analysis on lung cancer patients for ALK rearragement




What is its main use? 


Are mutational analysis needed? 

Vemurafenib inhibits mutated BRAF


Patients with melanoma that have an activating mutation in the gene coding for BRAF

mutation--> constitutively active phosphorylation and downstream signaling 


Mutational analysis in melanoma CA for V600E mutaiton in BRAF



Which targets in particular require mutational analysis? (5)



non-small cell lung CA

Colon CA

malignant melanoma

Clear Cell Kidney CA

Liver CA


What is the role of L-asparaginase in cancer treatment?


What is its use? 


Side effects (5)

L-asparaginase is a bacterial product that hydrolyzes L-asparagine -->

L-asparaginase rapidly depletes asparagine pools 

Leukemia cells LACK ASPARAGINE SYNTHEASE and thus cannot synthesize asparagine -- this "cellular defect" --> DEC PROTEIN SYNTHESIS


Useful for: acute lymphoblastic leukemia


Side Effects: allergic rxns, liver enzyme elevations, clotting (due to a derease in antithrombin-3 levels), pancreatitis, elevated glucose, mental status changes




What is the role of hydroxyurea in cancer treatment?


Side effects (4)

Hydroxyurea is an analog of urea that inhibits DNA synthesis by inhibiting ribonucleotide reductase


Use: treatment of WBC counts in pt with AML and chronic granulocytic leukemia with blast crisis. Blast could cause leukostasis and that could lead to strokes/ sludging in the vascultature that lead to thomboses. ONCE THE COUNT IS CONTROLLED other treatmetn can be given


Side effects: N/V, low blood counts, rash


What is the role of all-trans retinoic acid (tretinoin) in cancer treatment? 



Side effects?

What is the retinoic acid syndrome?

Treatment of choice in combination with chemotherapy for pt with acute promyelocytic leukemia (APL, M3)


The drug induces terminal differentiation of the leukemic cells


Side effects: Mucocutaneous toxicity, retinoic acid syndrome [fever, wt gain, lung infiltrates and pleural or periocardial effusions] 




What is the role of arsenic trioxide in cancer treatment?


side effects (4)

Treatment of choice for REPLASED APL


Side Effects: fatigue, wt gain, retinoic acid syndrome, QT prolongation (must monitor!! risk for torsade)