Poster Session – Cyclins and CDKs Thursday 8 November 2012 83 Table for abstract 269 Outcome measure Angiogenesis Inhibitor Total Anti-EGFR Small molecule Anti-EGFR Monoclonal antibody Breast Colon Lung OS Not stated 21 (35%) 21 (50%) 18 (35.3%) 22 (69%) 7 (39%) 3 (16%) Worse than standard 0 0 1 (2%) 0 1(6%) 0 Not significantly different than standard 33 (55%) 19 (45.2%) 17 (33.3%) 6 (17%) 8 (44%) 13 (68%) Better than standard 6 (8.4%) 2 (4.8%) 15 (29.4%) 7 (20%) 2 (11%) 3(16%) PFS Not stated 21 (35%) 21 (50%) 23(45%) 22 (63%) 7 (39%) 8 (42%) Worse than standard 0 0 1(2%) 0 1(6%) 0 Not significantly different than standard 17 (28%) 11(26%) 16(31%) 4 (11%) 7(39%) 7 (37%) Better than standard 22(37%) 10(24%) 11(22%) 9 (26%) 3(17%) 4 ORR Not stated 31 (51.7%) 22 (52.4%) 22 (43.1%) 23 (66%) 7(39%) 6 (21%) Worse than standard 0 0 0 0 0 0 Not significantly different than standard 14 (23.3%) 15 (35.7%) 11 (21.6%) 4 (11%) 4(22%) 11 (58%) Better than standard 15 (25%) 5 (11.9%) 18 (35.3%) 8(23%) 7(39%) 2(11%) Total toxicities Not stated 36 (38.7%) 17 (40.5%) 19 (37.3%) 18(51%) 5(29%) 5(26%) Worse than standard 42 (45.2%) 14 (33.3%) 28 (54.9%) 10(29%) 12(67%) 10(53%) Not significantly different than standard 14 (15.1%) 10 (23.8%) 4 (7.8%) 7(20%) 1(6%) 3(16%) Better than standard 1 (1.1%) 1 (2.4%) 0 0 0 1(5%) marginal benefit and worse toxicity. Monoclonal antibodies, and inhibition of breast cancer, appears to be more efficacious. We will be presenting meta-analysis HRs for OS, PFS, and ORR. Subgroup analysis for tumor type, adjuvant versus metastatic treatment, and monoclonal versus small molecule inhibitors will be included. This data raises the question of how best to approach combination therapy. 270 POSTER The Impact of a Tissue Acquisition Program On Research in Molecular Targeted Therapy of Melanoma M.C. Kelley 1 , A. Richmond 2 , S. Chase 1 , A. Gecewich 3 , H. Crandall 3 , M.A. Hooks 1 , I. Puzanov 3 , J.A. Sosman 3 . 1 Vanderbilt-Ingram Cancer Center, Surgical Oncology, Nashville TN, USA; 2 Vanderbilt-Ingram Cancer Center, Cancer Biology, Nashville TN, USA; 3 Vanderbilt-Ingram Cancer Center, Hematology-Oncology, Nashville TN, USA Background: Progress in targeted therapy research has been limited by the availability of high quality tissue samples with clinical information. The purpose of this study is to assess the relationship between developing an integrated tissue acquisition program and targeted therapy research in melanoma. Methods: In June, 2003, an IRB-approved tissue repository was developed to prospectively collect and store snap frozen and fixed tissue samples from patients with melanoma after informed consent. Specimens are collected in the clinic and operating room following a standard protocol. Demographics, clinical, pathological, treatment, and outcome data are recorded on a prospective database. In June of 2008, a tissue acquisition clinic was developed. Most patients undergo punch, excisional, or core biopsy in clinic under local anesthesia. We examined repository accrual, samples obtained and biopsies completed and compared these data to the number of extramural grants funded, targeted therapy clinical trials opened, and peer reviewed publications utilizing these resources. Results: As of June 25 th , 2012, 1,421 patients participated in the repository; 6,195 samples (5994 frozen, 201 blocks) were obtained from 444 patients. 473 samples from 165 patients were studied by 9 investigators according to protocol. 142 biopsies have been performed in the tissue acquisition clinic. The progress of targeted therapy research in melanoma among is listed in table 1, below. Table 1 1999–2003 2003–2008 2008–2012 Grants (total funding) 3 ($825,000) 3 ($1,960,000) 6 ($3,470,000) Clinical trials (total accrual) 2 (63) 3(102) 10(217) Publications 13 14 27 Conclusions: Implementation of a tissue acquisition program has been associated with a substantial increase in melanoma targeted therapy research at our institution. A comprehensive tissue acquisition program is a critical component of an integrated basic, translational, and clinical research program in personalized medicine and targeted therapy of solid tumors. Cyclins and CDKs 271 POSTER In Vitro Studies of Novel Ruthenium(II) and Osmium(II) Indoloquinoline Complexes S. G¨ oschl 1 , L.K. Filak 1 , A. Egger 1 , M.A. Jakupec 1 , B.K. Keppler 1 , V.B. Arion 1 . 1 University of Vienna, Inorganic Chemistry, Wien, Austria Indoloquinolines have been developed as analogues of paullones (in- dolobenzazepines), known as cdk inhibitors, from which they differ by a six- membered pyridine (instead of a seven-membered azepine) ring, yielding a planar molecule. As solubility is a limiting factor for the biocompatibility of indoloquinolines, structural modifications and metal complexation were accomplished enabling tests for biological activity in vitro and in vivo. The novel ruthenium(II) and osmium(II) complexes with modified indoloquinoline ligands reported herein are the first ones which are coordinated via position 2 of the indoloquinoline backbone. To determine the cytotoxicity of the complexes the colorimetric MTT assay was used in three different cancer cell lines, A549 (non small lung cancer), CH1 (ovarian carcinoma) and SW480 (colon carcinoma). To find out whether the presence of a lactam moiety, which is known to be necessary for cdk inhibition in case of metal- free paullones, alters the impact on the cell cycle, complexes containing and lacking this moiety were tested in a FACS based assay. Cellular accumulation studies of ruthenium complexes in SW480 cells, measured by ICP-MS, were performed to check for correlations between uptake of the substances and their cytotoxicity. These novel compounds, mostly yielding IC 50 values in the micromolar range, are up to forty times more active in CH1 than in A549. The ruthenium complexes are found to be at least 2-4 times more potent than their osmium analogues, except for the complexes with a lactam moiety, which show the reverse pattern. The effects of osmium complexes on the cell cycle are negligible, whereas those of their ruthenium analogues are more pronounced. For the ruthenium complexes an increase of up to 20% of G2/M phase fraction was observed. The studies on cellular accumulation revealed a partial correlation between cell cycle arrest and uptake of the compounds. Overall, these results lead to the conclusion that the metal center plays an important role in the activity of the complexes. A comparison to previous results with indoloquinoline complexes with a different coordination pattern [1], allows a deeper insight into structure-activity relationships of this class of compounds. Figure: Ruthenium(II) and osmium(II) complexes with indoloquinoline- based ligands.