SX-007, a small molecule TGF-β receptor I kinase inhibitor, prolongs animal survival in the syngeneic SMA560 glioma model

6033 Many cancers overexpress transforming growth factor beta (TGF-β), a protein that plays a major role in tumor progression by regulating cell proliferation, angiogenesis, metastasis and immunosupression. Glioblastoma multiformae (GBM) is one such cancer. TGF-β secretion may play a role in the highly invasive nature of the disease and appears to be responsible for the suppressed immune system in GBM patients. The therapeutic potential of SX-007, an orally bioavailable small molecule TGF-β RI kinase inhibitor (IC50=33 nM), was investigated in the SMA560 model, a syngeneic murine model of glioma. SMA560 cells were implanted into the right striatum of male VM/Dk mice. Dosing began three days after implanting tumor cells and continued until the end of the study. The efficacy of SX-007 was assessed at 5, 20 and 40 mg/kg po qd in the SMA560 model. Maximal efficacy was observed at 20 mg/kg (median survival=24 days). Increasing dosing from 20 mg/kg once to twice daily did not result in improved survival benefit. From each study, approximately 20% of animals from the groups dosed with 20 mg/kg SX-007 remained alive at the end of the study (Day 35). These long-term survivors appear to be disease-free. In a separate study, the animals were sacrificed at Day 15 and brain tissue removed to verify that SX-007 reached the site of action. The levels of phosphorylated Smad 2/3 and transcription of TGF-β related genes (most notable, PAI-1) were reduced in tumors from compound-treated animals confirming an inhibition of TGF-β signaling. In addition, there was increased CD3+ T-cell infiltration into the tumor and a concomitant increase in caspase-3 staining in the brain tissue of compound-treated animals as measured by immunohistochemistry demonstrating a functional consequence of inhibiting TGF-β signaling. SX-007 can modulate TGF-β signaling pathway in vivo and treatment with SX-007 is associated with an improvement in animal survival. Survival benefit is due, at least in part, to a reversal of the immune suppressed state allowing for rejection of the tumor. Thus SX-007 may be useful in the treatment of glioblastoma.