Targeting CD38 Inhibits Glioma and Melanoma Progression in Vivo

It is well established that in many cases tumor microenvironment promotes tumor progression. Among the tumors where their microenvironment supports tumor expansion are glioma and melanoma.

CD38 is a proinflammatory ectoenzyme that catalyzes the formation of the calcium-mobilizing metabolites adenosine diphosphoribose (ADPR), cyclic ADPR (cADPR), and nicotinic acid adenine dinucleotide phosphate from its substrates nicotinamide adenine dinucleotide (NAD) and NAD phosphate. CD38 is also the major constitutively active NAD-degrading enzyme expressed in mammalian cells, thereby regulating NAD homeostasis.

In previous studies using CD38 deficient mice (Cd38^-/-) we showed that loss of CD38 in the glioma microenvironment attenuated glioma progression in vivo in a mouse model of glioma progression (GL261 glioma cells implanted into C57BL/6J mice brains). This effect was probably mediated via an inhibitory effect on microglia, the main constitute of the glioma microenvironment. Having demonstrated the effect of loss of CD38 on glioma we next examined whether such condition can inhibit also melanoma progression. To this end we used two different mouse models of melanoma progression: B16 or Ret melanoma cells implanted subcutaneously into C57BL/6J mice. Our results showed that loss of CD38 also inhibited melanoma progression in these mouse models. Furthermore, fibroblasts seem to be involved in the effect of loss of CD38 on the melanoma microenvironment. Collectively these results suggest that targeting CD38 may be a new potential therapeutic approach for treating tumors in which tumor microenvironment promotes tumor progression. To further test this possibility we identified a new small molecule CD38 inhibitor, K-rhein. Treatment of glioma- or melanoma-bearing WT mice with K-rhein substantially inhibited tumor expansion of both tumor types and this effect was CD38 dependent since the inhibitor did not affect tumors progression in Cd38^-/- mice.