Medulloblastomas are the most frequent malignant brain tumors in children. Sorafenib (Nexavar, BAY43-9006), a multikinase inhibitor, blocks cell proliferation and induces apoptosis in a variety of tumor cells. Sorafenib inhibited proliferation and induced apoptosis in two established cell lines (Daoy and D283) and a primary culture (VC312) of human medulloblastomas. In addition, sorafenib inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) in both cell lines and primary tumor cells. The inhibition of phosphorylated STAT3 (Tyr 705 ) occurs in a dose-and time-dependent manner. In contrast, AKT (protein kinase B) was only decreased in D283 and VC312 medulloblastoma cells and mitogenactivated protein kinases (extracellular signal-regulated kinase 1/2) were not inhibited by sorafenib in these cells. Both D-type cyclins (D1, D2, and D3) and E-type cyclin were down-regulated by sorafenib. Also, expression of the antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was decreased and correlated with apoptosis induced by sorafenib. Finally, sorafenib suppressed the growth of human medulloblastoma cells in a mouse xenograft model. Together, our data show that sorafenib blocks STAT3 signaling as well as expression of cell cycle and apoptosis regulatory proteins, associated with inhibition of cell proliferation and induction of apoptosis in medulloblastomas.These findings provide a rationale for treatment of pediatric medulloblastomas with sorafenib. [Mol Cancer Ther 2008;7(11):3519 -26]

Pemetrexed (ALIMTA) is a folate anti-metabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multi-kinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to Class III RTKs such as PDGFRβ and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors.

Object. Bone grafts used in anterior cervical fusion (ACF) may subside postoperatively. The authors reviewed a recent series in which instrument-assisted ACF was performed to determine the degree of subsidence with respect to fusion length, use of segmental screws, and patient smoking status, age, and sex. Methods. Charts and implant records were reviewed for all 70 patients who underwent instrument-assisted ACF during a 2-year period. The procedures, grafting materials, plate types/lengths, and patient smoking status were recorded. The immediate postoperative and follow-up lateral radiographs were analyzed. The plate lengths and lengths of the fused segments were measured in a standardized fashion. The mean intraoperative and follow-up fusion segment lengths were 54.3 and 51.9 mm, respectively. Greater subsidence occurred in multilevel fusions than in single-level fusions. There were noticeable changes in the position of plates or screws on 14 of 70 follow-up x-ray films. No new neurological deficits related to graft subsidence occurred, and the reoperation rate was 3%. There was no statistical relation between subsidence and the following variables: segmental fixation, smoking status, sex, age, or dowel size when corrected for length of the plate. Hardware migration correlated significantly with plate length in cases of two- and three-level fusions. Conclusions. The length of a fusion segment decreases in the immediate weeks following instrument-assisted ACF. Construct length is the most important determinant of subsidence. When designing multilevel cervical constructs, consideration of the effects of graft subsidence may help to avoid hardware-related complications.