EP-004

In the mesothelioma section, two presentations were given. First, Dr. Donington delivered an overview of the most common targeted pathways and agents studied in malignant pleural mesothelioma (MPM). As described, the current front-line standard of care for unresectable MPM patients remains platinum pemetrexed, and numerous targeted agents have been investigated in combination with front-line chemotherapy and in the salvage setting. Although mesothelioma has the highest secreted levels of VEGF of any solid tumor, adding bevacizumab to cisplatin-gemcitabine did not improve PFS or OS in the ITT population from a large phase II randomized trial. 1 Nevertheless, targeting the VEGF pathway may still be relevant in MPM, because patients with serum VEGF levels below the median who received bevacizumab had a superior OS (p 0.028). In the salvage setting, several phase I and II studies that targeted angiogenesis (VEGFR, PDGFR), EGFR, TRAILR1,2, Bcl-2, tRNA, immunotherapy, and mesothelin were discussed. In general, only modest results from these studies (negative results from the monotherapy EGFR tyrosine kinase inhibitor and imatinib mesylate studies) were reported. In terms of promising new agents under investigation, a large international phase III trial of vorinostat versus placebo in second- and third-line therapy was discussed. 2 This trial has completed its accrual of 660 patients and will have the results presented later this year. If positive, this will potentially alter the treatment landscape in the salvage setting for MPM. In the second presentation, a phase I neoadjuvant dasatinib trial being conducted at MDACC was presented. This study is the first neoadjuvant targeted therapy study to be conducted in MPM and consists of tissue harvesting from multiple areas of the tumor at two time points, before and after 4 weeks of neoadjuvant dasatinib therapy. The preliminary results suggest that Src kinase Tyr419 IHC overexpression may be a valid biomarker at baseline that predicts for a response to dasatinib therapy and is a consistent pharmacodynamic marker. 3 A phase I trial in the unresectable MPM patients using cisplatin-pemetrexed-imatinib mesylate was presented which seemed to stabilize the cancer more than achieve a response. Nevertheless, this trial provided the rationale for SWOG 0905, a phase I/II trial in chemonaive MPM patients evaluating cisplatin-pemtrexed cediranib (VEGFR, PDGFR inhibitor). S0905 is open for enrollment and has completed the phase I portion and has established the phase II cediranib dose as 20 mg po daily. Small Cell Lung Cancer Although standard therapy for extensive stage SCLC remains chemotherapy, several new therapeutic approaches for SCLC are currently under investigation. VEGFR pathway inhibitors SCLC is known to overexpress ligands for the VEGF and PDGF receptors and frequently harbor c-KIT amplifications. Cediranib, an inhibitor of all three receptor tyrosine kinases, is being investigated in combination with etoposide and cisplatin (EP) chemotherapy. In phase I testing, cediranib demonstrated promising activity in combination with EP, with a median progression-free survival of 8.9 months and a objective response rate of 70%, results that compare favorably with historical controls. A phase II/III trial is currently in development. In phase II, promising activity has also been observed for bevacizumab in combinations with EP 4 or irinotecan/carboplatin. 5 BCL-2 inhibitors BCL-2 is frequently overexpressed in SCLC and is associated with resistance to chemotherapy-induced apoptosis. The BCL-2 inhibitor ABT-263 was tested in patients with SCLC and other solid tumors. Among 29 patients with SCLC or pulmonary carcinoid, one patient had a durable partial response, whereas eight had prolonged stable disease. Progastrin-releasing peptide was identified as a surrogate for Bcl-2 amplification. ABT-263 is currently undergoing further testing in combination with EP.

In the human, prostanoids are known to be important mediators of uterine relaxation and contraction during pregnancy and parturition. We have previously shown that stretch of uterine smooth muscle cells increased prostaglandin H synthase 2 (PGHS-2) mRNA expression, PGHS-2 peptide synthesis and activity, however, the net effect on uterine contractility of this increase in prostaglandin synthesis would be determined by the expression of the different prostanoid receptors. Therefore, the aims of this study were to establish the expression of prostanoid receptor mRNA in uterine myocytes obtained from women in different reproductive states and to test the hypothesis that stretch of uterine myocytes alters prostanoid receptor mRNA expression to promote uterine contractility. Myocytes were isolated from women undergoing hysterectomy (NP) and pregnant women undergoing LSCS either before (NL) or after the onset of labour (L) and were subjected to 11% stretch for 1 h (n = 6 in all cases). Copy numbers of the individual receptors varied widely with reproductive state but followed the pattern: FP > IP = DP = EP-4 > TP = EP-3 = EP-2 > EP-1. FP mRNA expression was significantly lower in the NL group compared to the NP group and EP-3, EP-4 and TP mRNA expression was significantly lower in both NL and L groups compared to NP group levels. The level of mRNA expression of EP-1, EP-2, DP and IP did not differ between NP, NL and L groups. Stretch of cells derived from the NP group resulted in a significant decrease in EP-4 mRNA expression alone and of the NL group a significant decrease in EP-2 mRNA expression alone. Stretch had no effect on cells derived from the L group. These data show that pregnancy is associated with a significant reduction in 3 of 4 pro-contraction associated prostanoid receptor mRNA expression and 1 of 4 pro-relaxant. Stretch elicited no consistent change in prostanoid receptor mRNA expression.