3066 Background: D is a small molecule that inhibits Aurora Kinases, proteins regulating mitosis and overexpressed in many tumors. Investigation of the combination is based on additive effect of the drugs in preclinical models, their different mechanism of action and non-overlapping toxicity profiles. Methods: Objectives: to define first cycle (C) dose limiting toxicities (DLTs) and thereby the recommended phase 2 dose (RP2D), safety, PK profiles and antitumor activity. Cohorts of 3-6 pts were sequentially allotted to dose levels (DL) 1, 2, 3 of D (190, 250, 330 mg/m2, respectively, on days [d] 1 and 8) and fixed dose of B (15 mg/kg, on d1) given IV every 3 weeks. DLTs were defined as grade 4 neutropenia (G4 ANC) for >7d, febrile neutropenia (FN), neutropenic infection, G4 thrombocytopenia (PLT), G3 PLT for >7d or with bleeding, any G3/4 non-hematologic toxicities, failure to administer 80% of D in C1, >2 week-delay in starting C2. Results: 20 pts (10 males), median age 54 [22-70] were treated. Primary tumor types: 11 colorectal ca, 2 pancreatic ca and 7 others. All pts had metastatic disease. Median ECOG PS: 1 [0-1]. Four pts were treated at DL1, 10 at DL2 and 6 at DL3. DLTs consisted of G3 diarrhea and G3 nausea in 1 pt each at DL3. DL2 was then expanded to 6 pts; one of them experienced G3 fatigue as DLT. This DL was again expanded to 10 pts for completing PK evaluations at RP2D and 1 pt experienced a DLT (failure to administer due to G2 bilirubin). Treatment emergent G3/4 hematological toxicities were ANC and PLT (63 and 5% of pts, respectively). The most frequent treatment-related events were usually of G1/2 severity and included fatigue, nausea, diarrhea, anorexia, mucosal inflammation and vomiting. PK parameters were dose and time independent and characterized by low inter-pt variability. B did not change the PK profile of D. Conclusions: The RP2D of 250 mg/m2 of D and 15 mg/kg of B is safe and allows a dose increase of D to 330 mg/m2 from C2 if no toxicities are experienced in C1 since reported toxicities at DL3 (essentially non-hematological) were easily manageable. One PR at DL3 in a rectal ca. pt progressing under previous B and 5 clinically relevant SD (> 6 months) have been reported (2 at DL3, 3 at DL2). Further investigations in phase II trials should be warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Accelera, Nerviano Medical Sciences Chemotherapy Foundation Nerviano Medical Sciences

Tripartite Motif Containing 11 (TRIM11), a member of TRIM proteins is overexpressed in gliomas and lung cancer. However, the role of TRIM11 in hepatocellular carcinoma (HCC) is unknown.Herein, we aimed to investigate the expression and clinical significance role of TRIM11 in HCC.In this study, our data showed significant higher TRIM11 in HCC tissues (n = 117) than in the matched non-tumor liver (NTL) tissues (P < 0.01). In consistent with above data, we also found TRIM11 protein expression was significantly increased compared with the matched NTL (P < 0.01) by immunohistochemistry analysis. Additionally, our results showed that TRIM11 protein expression in HCC tissues was significantly associated with pathological grade (P < 0.01), tumor postoperative metastasis (P = 0.031), recurrence (P = 0.022), and serum a-fetoprotein (AFP) (P < 0.01). Moreover, patients’ survival was negatively correlated with TRIM11 protein expression. Furthermore, we found that TRIM11 protein was an independent prognostic factor for disease-free (P < 0.01) and overall survival (P < 0.01) in HCC patients.Our data showed that TRIM11 expression was significantly elevated in HCC tissues. The overexpression of TRIM11 is closely associated with HCC progression and poor survival of the patients, indicating TRIM11 is a potential therapeutic target for HCC patients.

Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination.Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of > 1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of > 100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (> 18 weeks) stable disease.Further studies of the combination of brostallicin and cisplatin are warranted.

Ensuring that cytokinesis occurs at the right time and in the right place is essential to maintain euploidy and cell-cycle progression. Cytokinesis is triggered by the RhoA GEF Ect2, which localizes to the spindle midzone during anaphase and activates RhoA at the overlying cell cortex to stimulate contractile ring formation. Using a chemical inhibitor of the Polo kinase Plk1, Petronczki et al. (2007) showed that Plk1 is essential for cytokinesis, because it specifically promotes Ect2 localization and interaction with its midzone receptor HsCyk-4.I liked this paper for three reasons. As a biologist, I was impressed because the paper explains an important part of biology: how a cell-cycle kinase determines when and where cytokinesis occurs. As a geneticist, I appreciate a “tight allele.” The paper is a beautiful example of the power of chemical genetics to specifically and rapidly inhibit Polo at a specific cell-cycle stage. Finally, as a yeast cell-cycle researcher, it is always nice to see the dramatic conservation between yeast and mammals. In budding yeast, even though the bud neck and not the spindle midzone determines the site of cytokinesis, Polo kinase phosphorylates Rho GEFs to initiate contractile ring formation and cytokinesis.This PaperPick refers to “Polo-like Kinase 1 Triggers the Initiation of Cytokinesis in Human Cells by Promoting Recruitment of the RhoGEF Ect2 to the Central Spindle,” by M. Petronczki, M. Glotzer, N. Kraut, and J.-M. Peters, published in May 2007.

Two new compounds, 10-O-β-d-glucopyranosyl aloenin (4) and 8-C-β-d-glucopyranosyl-7-O-methyl-(R)-aloesol (6), were isolated from a commercial sample of Kenya aloe together with the known products aloenin (2), aloenin 2′-p-coumaroyl ester (3), aloenin aglycone (1), orcinol and acetylorcinol. All structures were determined or confirmed by spectral analyses.

It is suggested that the spectra of the Be-8 ground-state (gs) nuclei produced in the interaction of C-12 with Co-59 at incident energies varying from 8.3 to 33.3 MeV/amu can he explained by introducing a dissipative friction interaction mechanism preceding projectile break-up.

It is suggested that the spectra of the 8 Be ground-state (gs) nuclei produced in the interaction of 12 C with 59 Co at incident energies varying from 8.3 to 33.3MeV/amu can be explained by introducing a dissipative friction interaction mechanism preceding projectile break-up.

It is suggested that the spectra of the 8Be ground-state (gs) nuclei produced in the interaction of 12C with 59Co at incident energies varying from 8.3 to 33.3MeV/amu can be explained by introducing a dissipative friction interaction mechanism preceding projectile break-up.