Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86

BACKGROUND: The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer. We previously reported the synthesis of kinase inhibitors with potent activity against RET. Herein, we have further investigated the effect of the lead compound SPP86 on RET mediated signaling and proliferation. Based on these observations, we hypothesized that SPP86 may be useful for studying the cellular activity of RET. METHODS: We compared the effects of SPP86 on RET-induced signaling and proliferation in thyroid cancer cell lines expressing RET-PTC1 (TPC1), or the activating mutations BRAF(V600E) (8505C) and RAS(G13R) (C643). The effect of SPP86 on RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK pathway signaling and cell proliferation in MCF7 breast cancer cells was also investigated. RESULTS: SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells. In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228. In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen. Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree. CONCLUSION: SPP86 selectively inhibits RET downstream signaling in RET/PTC1 but not BRAF(V600E) or RAS(G13R) expressing cells, indicating that downstream kinases were not affected. SPP86 also inhibited RET signaling in MCF7 breast cancer cells. Additionally, RET- FAK crosstalk may play a key role in facilitating PTC1/RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1471-2407-14-853) contains supplementary material, which is available to authorized users

The efficacy of rhBMP-2 versus autograft for posterolateral lumbar spine fusion in elderly patients

Few studies have specifically examined the outcomes following rhBMP-2 usage in patients 65 years and older. The purpose of this retrospective study is to evaluate the efficacy of rhBMP-2 with allograft versus autograft for posterolateral lumbar fusion in patients 65 years and older. One hundred twenty-seven patients were divided into three groups based on fusion material and age. Subjects in group A (n = 34) consisted of patients 65 years and older who received rhBMP-2 and allograft. Group B (n = 52) was composed of patients under 65 years of age with rhBMP-2 and allograft. Subjects in group C (n = 41) were 65 years and older with autograft use. A comparison was made of fusion rate, fusion time (noticed, solid), clinical outcome, VAS, perioperative complications and revision rate between each group. The fusion rate and fusion time were similar in groups A and C; however, these were lower than that observed in group B. Clinical outcomes were similar amongst the groups. There were no significant differences in VAS and perioperative complication rate between groups A and C. In patients 65 years and older, rhBMP-2 with allograft may lead to acceptable fusion rates and fusion times, good clinical outcomes and reduced perioperative complications. The combination of rhBMP-2 with allograft yields equivalent outcomes as autograft in elderly patients undergoing instrumented posterolateral lumbar fusion. Additionally, when compared to patients under 65 years of age undergoing posterolateral lumbar fusion, the use of rhBMP-2 was not sufficient to overcome all aspects of the age-related weakened osteoinductive capacity encountered in elderly patients