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PDF file - 51KB, Body weights of MDA-MB-231 bearing mice treated with E-3810, 5FU, DDP and their combinations.

PDF file - 63KB, Circulating factors in plasma of mice bearing MDA-MB-231 tumors untreated or treated with E-3810 (E), brivanib (B), sunitinib (S), paclitaxel (PTX) and their combinations as described in Material amd Methods.

PDf file - 30KB, Survival curves of MDA-MB-231 bearing mice treated with E-3810, PTX and their combination.

PDF file - 41KB, Dose response curve of PTX in MDA-MB-231 cells alone or in combination with E-3810, sunitinb and brivanib.

PDF file - 101KB

Supplementary Table 1 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Figures 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Table 2 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Supplementary Methods, Figure Legends 1-4 from E-3810 Is a Potent Dual Inhibitor of VEGFR and FGFR that Exerts Antitumor Activity in Multiple Preclinical Models

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and rapidly lethal tumor, poorly responsive to conventional treatments. In this regards, the identification of molecular alterations underlying DMPM onset and progression might be exploited to develop novel therapeutic strategies. Here, we focused on miR-550a-3p, which we found downregulated in 45 DMPM clinical samples compared to normal tissues and whose expression levels were associated with patient outcome. Through a gain-of-function approach using miRNA mimics in 3 DMPM cell lines, we demonstrated the tumor-suppressive role of miR-550a-3p. Specifically, miRNA ectopic expression impaired cell proliferation and invasiveness, enhanced the apoptotic response, and reduced the growth of DMPM xenografts in mice. Antiproliferative and proapoptotic effects were also observed in prostate and ovarian cancer cell lines following miR-550a-3p ectopic expression. miR-550a-3p effects were mediated, at least in part, by the direct inhibition of HSP90AA1 and the consequent downregulation of its target proteins, the levels of which were rescued upon disruption of miRNA-HSP90AA1 mRNA pairing, partially abrogating miR-550a-3p-induced cellular effects. Our results show that miR-550a-3p reconstitution affects several tumor traits, thus suggesting this approach as a potential novel therapeutic strategy for DMPM.

Summary Background: The DNA repair protein O 6 -alkylguanine-DNA alkyl transferase (AT) mediates resistance to chloroethylnitrosoureas. Agents depleting AT such as DTIC and its new analogue temozolomide (TMZ) can reverse resistance to chloroethylnitrosoureas. We report the results of a dose finding study of TMZ in association with fotemustine. Patients and methods: Twenty-four patients with metastatic melanoma or recurrent glioma were treated with escalating dose of oral or intravenous TMZ ranging from 300 to 700 mg/m 2 , divided over two days. Fotemustine 100 mg/m 2 was given intravenously on day 2, 4 hours after TMZ. AT depletion was measured in peripheral blood mononuclear cells (PBMCs) and in selected cases in melanoma metastases and was compared to TMZ pharmacokinetics. Results: The maximum tolerated dose (MTD) of TMZ was 400 mg/m 2 (200 mg/m 2 /d) when associated with fotemustine the 2nd day with myelosuppression as dose limiting toxicity. The decrease of AT level in PBMCs was progressive and reached 34% of pretreatment values on day 2. There was however wide interindividual variability. AT reduction was neither dose nor route dependent and did not appear to be related to TMZ systemic exposure (AUC). In the same patients, AT depletion in tumour did not correlate with the decrease of AT observed in PBMCs. Conclusions: PBMCs may not be used as a surrogate of tumour for AT depletion. Further study should concentrate on the pharmacokinetic pharmacodynamic relationship in tumour to provide the basis for individually tailored therapy.