Summary of the technology
The aim of this proposal is to recapitulate the effect of CD38 deficiency on glioma by the development of drugs which will act as CD38 inhibitors. CD38 is a NAD glycohydrolase and ADP-ribosyl cyclase. The extracellular enzymatic domain of CD38 uses NAD+ to catalyze the formation of the calcium mobilizing metabolites [ADP ribose (ADPR), cyclic ADPR and nicotinic acid adenine dinucleotide phosphate] involved in cellular Ca2+ mobilization. Despite being an attractive target for drug therapy for glioma (and other disorders), effective drugs which inhibit CD38 have not yet been developed. Recently several natural anthocyanines that inhibit CD38 at low ?M concentrations were identified. However, these CD38 inhibitors are not selective towards CD38, and as such are likely to cause additional and undesired side effects. The aim of this proposal is to use these lead compounds for the development of specific and potent CD38 inhibitors that will have great potential of becoming anti-glioma drugs.
Project ID : 2-2011-175
Description of the technology
Drug Treatments Targeting Glioma Microenvironment: CD38 inhibitor as a Potential Therapeutic Approach for Glioma Treatment
Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas, Glioblastoma multiforme (GBM), there is no successful treatment. Thus, there is an urgent need to develop new therapeutic approaches to treat glioma. It has been demonstrated that the tumor microenvironment plays an essential role in glioma progression, hence, glioma tumors' microenvironment is a promising new conceptual target for the development of novel therapeutic approaches.
The majority of glioma microenvironments consistof infiltrating microglia.Wepreviously reported that CD38 regulates the microglia "activation" state in vitro and that CD38 deficiency in mice impairs the microglia-associated recovery of mice from head trauma, suggesting that CD38 deficiency abrogates microglia activation both in vitro and in vivo.
In view of these results and the important role of the tumor microenvironment in glioma expansion we reasoned that inhibition of CD38 will reduce glioma expansio. We have demonstrated that CD38 deficiency in the tumor microenvironment reduces glioma progression and prolongs the life span of glioma-bearing mice.