Association of high TUBB3 with resistance to adjuvant docetaxel-based chemotherapy in gastric cancer: translational study of ITACA-S.

BACKGROUND: No predictive markers for chemotherapy activity have been validated in gastric cancer (GC). The potential value of class III ß-tubulin (TUBB3) as biomarker for prognosis and resistance to taxane-based therapy was reported. METHODS: We analyzed GC samples of patients enrolled in the Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S), a randomized adjuvant study comparing 5-fluorouracil/leucovorin (5-FU/LV) and docetaxel-based sequential chemotherapy. TUBB3 was quantitated by selected reaction monitoring mass spectrometry and patients were stratified using a threshold of 750 attomoles per microgram (amol/µg). Cox proportional modeling and Kaplan-Meier survival analysis were used to assess the impact of TUBB3 expression on overall survival (OS) and disease-free survival. RESULTS: Patients with TUBB3 protein levels >750 and <750 amol/µg were 21.9% and 78.1%, respectively, and were well-balanced between treatment arms. TUBB3 protein levels were not prognostic. Whereas no survival differences according to the 2 arms were observed in the subgroup with low TUBB3 expression (5-year OS 47% vs 40%; p = 0.44), patients with high TUBB3 had a clinically meaningful poorer OS when receiving docetaxel-based versus 5-FU/LV chemotherapy (5-year OS 31% vs 54%; p = 0.09), with a statistically significant interaction between TUBB3 and treatment (p = 0.049). CONCLUSIONS: The quantification of TUBB3 might be considered as a negative predictive biomarker of benefit from taxane-based therapy in GC. Studies are needed to evaluate its role in the neoadjuvant setting.

ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.

ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC(50) values ranging from 0.025 to 0.7 µmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer.

Identification and characterization of a very low density lipoprotein receptor-binding peptide from tissue factor pathway inhibitor that has antitumor and antiangiogenic activity.

Tissue factor pathway inhibitor (TFPI) is the major physiologic inhibitor of the extrinsic coagulation pathway. We have previously shown that TFPI is also a potent inhibitor of endothelial proliferation in vitro and of primary and metastatic tumor growth in vivo. Surprisingly, the antitumor activity of TFPI was demonstrated to be independent of its anticoagulant activity, suggesting a possible nonhemostatic mechanism of action for TFPI in these models. This antitumor mechanism may involve the very low density lipoprotein (VLDL) receptor because the in vitro antiproliferative activity of TFPI is mediated through interaction with the VLDL receptor. In the current study, we identify a 23-amino acid fragment of TFPI (TFPIc23) localized to the C-terminus, which mediates binding to the VLDL receptor. The TFPIc23 peptide inhibits endothelial cell proliferation through an apoptotic mechanism and blocks vessel outgrowth in the in vitro assays, and this activity is mediated through interaction with the VLDL receptor. In vivo, this peptide potently inhibits angiogenesis in Matrigel and chick chorioallantoic membrane models and also inhibits metastatic tumor growth. Our data demonstrate that this VLDL receptor-binding fragment of the TFPI molecule has apoptotic, antiangiogenic, and antitumor activity and suggests a possible mechanism whereby TFPI can regulate angiogenesis and tumor growth independently of its anticoagulant activity.

Tissue factor/factor VIIa inhibitors block angiogenesis and tumor growth through a nonhemostatic mechanism.

An association between cancer and thrombosis has been recognized for more than a century. However, the manner by which tumor growth is regulated by coagulation in vivo remains unclear. To assess the role of coagulation on tumor growth, in vivo, we tested coagulation inhibitors specific for either tissue factor (TF)/factor VIIa (fVIIa) complexes or factor Xa (fXa) for antitumor activity. Here, we show that two inhibitors of TF/fVIIa, TF pathway inhibitor (TFPI) and the nematode anticoagulant protein rNAPc2, inhibit both primary and metastatic tumor growth in mice. In addition, we show that rNAPc2 is also a potent inhibitor of angiogenesis. In contrast, rNAP5, a second nematode anticoagulant protein that specifically inhibits fXa, does not exhibit antitumor activity. Because the hemostatic activity of TF/fVIIa is mediated through activation of fXa, these data suggest that proteolytic activity of TF/fVIIa promotes tumor growth and angiogenesis through a novel proangiogenic mechanism and independently of hemostasis.