DIPG/DIPT Discussion

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Friday, August 21, 2009

Tyrosine Kinase Inhibitors

Kinases are cellular enzymes that have specific jobs. One group of kinases is the tyrosine kinases, and their job is to phosphorylate proteins. In other words, these enzymes take a phosphate group from a chemical molecule called ATP and transfer it to a tyrosine of one of the cell’s proteins. This placing of the phosphate molecule on the protein then becomes a signal for the cell to do something. In the case of tyrosine kinases, it seems that the signal affects the cell’s normal growth, metabolism, adhesion, and motility. If not properly controlled, however, these tyrosine kinases can cause uncontrolled cellular growth and thus be a factor in the development of cancer.

The approximately 90 different tyrosine kinases known today can be divided into two groups: those associated with receptors on the cell surface (also called transmembrane receptor-linked kinases), and those within the cytoplasm of the cell. There are 58 receptor tyrosine kinases (RTKs) which have been grouped into 20 families. Of the 20 families several names recurrently come up in the literature with DIPGs. Examples are VEGF, EGFR and PDGFR. (See http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase)

Tyrosine kinases have been a focus for anticancer drug development because over-active RTKs have led to the uncontrolled growth of tumors. Many of these RTKs are affected by genetic mutation or over-expression, leading to cancerous growth. Two different classes of drugs are currently being developed to target different RTKs: small molecule inhibitors and monoclonal antibodies. The web references below provide information on investigations for each class of drugs.

Small Molecule Inhibitors. These tend to be orally administered and have been used in several different trials which included children with DIPGs. Here are some examples of small molecule references:

1. Gefitinib and Radiation Therapy in Treating Children With Newly Diagnosed Gliomas (www.clinicaltrial.gov/ct2/show/NCT00042991?term=iressa+children+St+Jude&rank=5
2. Erlotinib Alone or in Combination With Radiation Therapy in Treating Young Patients With Refractory or Relapsed Malignant Brain Tumors or Newly Diagnosed Brain Stem Glioma (http://www.clinicaltrial.gov/ct2/show/NCT00360854?term=Tarceva+brainstem&rank=2)
3. Vandetanib and Radiation Therapy in Treating Young Patients With Newly Diagnosed Diffuse Brainstem Glioma (http://www.clinicaltrial.gov/ct2/show/NCT00472017?term=vandetanib+St+Jude&rank=1)
4. A recently opened multi-TKI trial: Pazopanib Hydrochloride in Treating Young Patients With Solid Tumors That Have Not Responded to Treatment (www.clinicaltrial.gov/ct2/show/NCT00929903?term=pazopanib+brain+tumor&rank=2)
5. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer. 2009 Jan;9(1):28-39 (http://www.ncbi.nlm.nih.gov/pubmed/19104514?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pub med.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedreviews&logdbfrom=pubmed)

Monoclonal Antibodies. Intravenous monoclonal antibodies, such as Avastin and Cetuximab, are currently being investigated in the treatment of DIPG both on and off trial.

Here is a recently completed trial for Cetuximab: Study of Erbitux™ (Cetuximab) in Pediatric Patients With Refractory Solid Tumors (www.clinicaltrial.gov/ct2/show/NCT00110357?term=Cetuximab+pediatric&rank=1)

And two more references on Tyrosine Kinase inhibitors in general:

Tyrosine kinase – Role and significance in Cancer. Int J Med Sci. 2004; 1(2): 101–115. (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1074718)

Different drug names, targets, pharmaceutical companies and mechanism of action are given in a chart at the bottom of this Wikipedia page: http://en.wikipedia.org/wiki/Tyrosine_kinase_inhibitor

This is a rapidly evolving field. It is helpful to have some knowledge of this field in considering the options for treating DIPG.