Reducing Toxicity of Chemotherapy For Brain Cancer

This article was co-written with Dr. Boro Dropulic, President and CSO of Lentigen Corporation (see: http://www.lentigen.com)

Glioblastoma Mulitiforme (GBM), a form of brain cancer, is a highly debilitating, most often fatal disease, with many patients dying within a year after diagnosis.  The current mode for treatment of GBM is a combination of radiation and chemotherapy which extends life, but it is not a cure. The chemotherapy uses a drug called Temozolomide (TMZ), or Tedomar, which can effectively kill GBM cancer cells.  However, the drug cannot be used at desired higher dose levels because of its toxicity to the blood-forming  stem cells which help create a major part of our immune system. As a result, often before the TMZ can kill off the GBM, the patient's immune system is so highly compromised that they die of the cancer or other diseases. 

Evidence that higher doses of TMZ could dramatically help treat GBM comes from recent evidence that cancer stem cells can be killed more effectively by higher or denser dosing with TMZ. The question is how to protect the bone marrow stem cells of the immune system, so that the TMZ has time to kill the cancer? In other words, how to we get to using higher doses of TMZ without destroying the blood forming (hematopoietic) marrow stem cells (HSC)? 

Lentigen is close to Phase I clinical testing of LG631, a Lentiviral vector that delivers a gene payload (MGMT - methylguanine-DNA-methyltransferase) into HSCs to make them resistant to the toxic effects of TMZ.  The goal is to develop this therapy into an effective treatment for GBM by protecting HSCs with LG631 so that physicians can treat patients with higher and denser doses of TMZ, so as to more effectively treat the disease.  The excitement for this clinical trial is supported by preclinical work performed in multiple top research institutions in the US, including validation of the protection of HSCs in the presence of high TMZ levels in multiple animal models, including mice, dogs and non-human primates.  Lentigen hopes to start this clinical trial later this year.

TMZ is in the family of chemotherapies called alkylating agents, many of which have similar off-target effects of killing off major parts of the patients' immune systems (HSC's), and if successful with GBM, Lentigen anticipates this opening up opportunities to use the same therapeutic approach with these other alkylating agents.