Gene Therapy Enhances Chemotherapy Tolerance and Efficacy in Glioblastoma Patients

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Charles S. Cobbs, MD

The Gregory Foltz, MD Endowed Director
Ben & Catherine Ivy Center for
Advanced Brain Tumor Treatment
Swedish Neuroscience Specialists

 

Recently, investigators at the Fred Hutchinson Cancer Institute in Seattle published interesting findings in the Journal of Clinical Investigation, a highly regarded translational research journal. The title of their article was “Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients”. www.fhcrc.org/en/news/releases/2014/08/gene-therapy-boosts-chemotherapy-tolerance.html   The aim of the research was to test a unique gene therapy approach that has the potential to overcome one of the key chemotherapy resistance mechanisms that we see in malignant brain tumors.

Frankly, this is a very complicated approach. In order to understand what the investigators did, one has to first understand that the reason that many patients do not respond to the standard chemotherapy drug temozolomide is that their tumor cells produce an enzyme with the acronym MGMT. When MGMT is functioning, it disables the DNA modification that temozolomide induces in the cancer cell DNA, which is the basis of the effect of temozolomide. Some patients, approximately 40% of patients with glioblastomas, have an inherent inactivation of the MGMT enzyme, and these patients are unable to inactivate temozolomide’s effects, and hence they have better response to the chemotherapy drug. In order to make the “nonresponsive” patient’s respond to temozolomide, they can be given another drug that is abbreviated as O6BG. However, this drug causes severe bone marrow toxicity due to its effects on bone marrow stem cells.

Thus, in order to give the patient this molecule which helps their brain tumor become sensitive to temozolomide, the investigators at the Fred Hutchinson Cancer Institute genetically engineered bone marrow stem cells that were resistant to the toxicity caused by O6BG.  With this complicated clinical regimen, they administered these genetically engineered, temozolomide resistant bone marrow cells to glioblastoma patients. The patients receiving this bone marrow stem cell protective regimen were able to tolerate the combination of temozolomide and O6BG to a greater degree than would have been expected. In a nutshell, this complicated treatment regim causing the severe bone marrow side effects. The authors should be congratulated for accomplishing this small study given the extremely difficult hoops required to administer this protocol to these patients.

Hopefully, this will improve our ability to treat patients better with temozolomide.  However, the brain tumor community should be advised that, even when temozolomide works under the best conditions, with patients who have sensitive tumors to temozolomide (i.e., MGMT. methylated tumors), the improvement in survival for glioblastoma is not more than an average of about 6-10 months. Nevertheless, these type of studies may lead to new ways of overcoming tumor resistance to chemotherapy which hopefully will improve survival for GBM patients.

 

 

 

 

 

 

 

 

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All content provided on this blog is for informational purposes only. The owner of this blog makes no representations as to the accuracy or completeness of any information on this site or found by following any link on this site. The owner will not be liable for any errors or omissions in this information nor for the availability of this information. The owner will not be liable for any losses, injuries, or damages from the display or use of this information.

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