CXCR7 Program in Glioblastoma Multiforme

CCX662, a highly potent and selective small molecule compound targeting CXCR7, is currently in preclinical development for the treatment of glioblastoma multiforme, or GBM, and is expected to enter a Phase I clinical trial in the second half of 2012. We are developing drugs that target CXCR7 and combine an anti-angiogenic approach to stopping the blood supply to cancerous cells with anti-tumor activity via direct attack of tumor cells. Our current efforts are primarily focused on the development of CCX662 for the treatment of GBM. CCX662 may qualify for orphan drug status, which may provide a faster path to regulatory approval.

Our most recent data support the notion that CXCR7 is causally connected to tumor growth regulation. This is coupled with clear evidence from immunohistochemistry staining of primary human tumor tissues which revealed clear evidence of CXCR7 expression. In contrast to standard chemotherapies which can be highly toxic, our compounds are designed to selectively target CXCR7 in an effort to halt cancer progression while minimizing detrimental effects, such as generalized immunosuppression or cytotoxicity.

We believe that we are the first to provide clear evidence that CXCR7 expression can directly control tumor growth in vivo. We and others have shown that CXCR7 regulates several important biological processes including cell survival, cell adhesion, trans-endothelial migration, tumor development and metastatic growth in secondary organs, in a variety of in vivo and in vitro models. CXCR7 is expressed on many human tumor cells but not on most healthy cells. In our tumor model systems we found that reduction or inhibition of CXCR7 by genetic and pharmacological means reduces or abolishes tumor formation in vivo, and that the introduction of CXCR7 into a "naïve" background is both necessary and sufficient for that tumor to grow aggressively in vivo. CXCR7 is highly expressed in human GBM and in GBM-associated blood vessels.

We and others have demonstrated, using various aggressive GBM models, that CXCR7 inhibition is effective at preventing tumor growth, particularly when utilized in combination with radiation. Recent discoveries support a role for CXCR7 in preventing apoptosis, or programmed cell death, of human GBM cells. Separate observations indicate that recruitment of bone-marrow derived cells from blood into irradiated GBM/brain in a model system is critical for tumor re-vascularization after irradiation and is dependent on CXCL12, the main chemokine ligand for CXCR7.

We believe that CCX662 represents a promising novel therapeutic for the treatment of GBM and other types of cancer. Preclinical studies support not only the anti-tumor efficacy of this drug but also an excellent safety profile, a reflection of its highly targeted and specific activity profile, which is fundamentally different from many other cytotoxic drugs in development or on the market.