No abstract

Dynamic rearrangements of cell-cell adhesion underlie a diverse range of physiological processes, but their precise molecular mechanisms are still obscure. Thus, identification of novel players that are involved in cell-cell adhesion would be important. We isolated a human kelch-related protein, Kelch-like ECT2 interacting protein (KLEIP), which contains the broad-complex, tramtrack, bric-a-brac (BTB)/poxvirus, zinc finger (POZ) motif and six-tandem kelch repeats. KLEIP interacted with F-actin and was concentrated at cell-cell contact sites of Madin-Darby canine kidney cells, where it colocalized with F-actin. Interestingly, this localization took place transiently during the induction of cell-cell contact and was not seen at mature junctions. KLEIP recruitment and actin assembly were induced around E-cadherin-coated beads placed on cell surfaces. The actin depolymerizing agent cytochalasin B inhibited this KLEIP recruitment around E-cadherin-coated beads. Moreover, constitutively active Rac1 enhanced the recruitment of KLEIP as well as F-actin to the adhesion sites. These observations strongly suggest that KLEIP is localized on actin filaments at the contact sites. We also found that N-terminal half of KLEIP, which lacks the actin-binding site and contains the sufficient sequence for the localization at the cell-cell contact sites, inhibited constitutively active Rac1-induced actin assembly at the contact sites. We propose that KLEIP is involved in Rac1-induced actin organization during cell-cell contact in Madin-Darby canine kidney cells.

2976 Background: c-Met receptor tyrosine kinase (RTK) activity has been implicated in establishing the oncogenic phenotype across several human cancers with high levels of the activating c-Met ligand, hepatocyte growth factor (HGF). Malignant plasma cells secrete HGF-activator (HGFA), which converts HGF to its active form, and high HGF levels are correlated with a poor prognosis in multiple myeloma (MM). Syndecan 1 (CD138) on malignant plasma cells binds HGF and potentiates interleukin-6-induced growth and migration. HGF stimulation of myeloma cells also activates autophosphorylation of c-Met and other critical downstream signaling pathways promoting oncogenesis. Finally, pre-clinical studies have shown that suppression of c-Met signaling with a number of small molecules, including ARQ 197, induced myeloma cell apoptosis. Tevantinib-mediated cytotoxic response was observed at concentrations of less than 5 μM, which are achievable in the clinic. These findings supported the hypothesis that suppression of the HGF/c-Met signaling axis could be a rational strategy against relapsed multiple myeloma. Methods: In this phase II study, the efficacy and safety of ARQ 197, a non-competitive and highly selective inhibitor of the c-Met RTK, is being studied in patients with relapsed multiple myeloma. Primary objectives were to determine the overall response rate (ORR) to single-agent tivantinib in patients with relapsed multiple myeloma who had received one to four prior lines of therapy, and to define the toxicities in this population. ARQ 197 was administered at a starting oral dose of 360 mg twice daily with meals for each day of every 4-week treatment cycle. This dose was selected from prior phase I investigations in solid tumors, and at this dose level, steady-state plasma level sof ARQ-197 were 7 μM. Treatment could continue providing that patients did not experience undue toxicities, or disease progression. Tivantinib is provided through the Cancer Therapy Evaluation Program (CTEP), and this study is supported by CTEP, as well as the M. D. Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 10 patients have been enrolled and treated to date, all of whom were evaluable for toxicity, with 8 evaluable for response based on having completed two treatment cycles. Patients had received from 1–3 prior lines of therapy for their disease, and 7/10 (70%) had presented with International Staging System stage I disease at diagnosis. All patients on study had an ECOG performance status of 1 or better, and received a median of 3.5 cycles of tivantinib (range 1–7). The most common adverse events (AEs) of any grade seen in at least 30% of patients included diarrhea (30%), dizziness (30%), dry eyes (30%), shortness of breath (30%), memory change (30%), myalgias (40%), fatigue (60%), and neutropenia (60%). Serious AEs (SAEs) occurred in 2 patients, including one patient with grade 3 syncope, and another with grade 4 neutropenia and a grade 3 anal fissure. Stable disease (SD) has been seen as the best response in 5/7 (71%) evaluable patients, which was maintained for up to 7 cycles, while the remaining patients showed evidence of disease progression. Conclusion: Enrollment is continuing to this first study of any c-Met inhibitor in patients with relapsed multiple myeloma to better define the role of single-agent tivantinib in this setting. To date, tivantinib has been tolerated well, and some evidence of activity has been seen, with stable disease in 63% of patients, all of whom were progressing at the time of enrollment. Updated toxicity and efficacy data will be presented at the time of the Annual Meeting. Correlative studies are also underway with the goal of identifying potential predictive biomarkers. Disclosures: Off Label Use: Tivantinib is being evaluated for patients with relapsed myeloma, but is not yet approved in this setting.

No abstract

6607 Background: Outcomes of pts with AML remain suboptimal. The addition of cladribine to 3+7 has been shown to improve complete remission (CR) rates and 3-year survival. The aim of this study was to assess the efficacy and safety of idarubicin + cytarabine (IA, idarubicin 10 mg/m2 on days 1-3, cytarabine 1 g/m2 on days 1-5) combined with two other nucleoside analogs, clofarabine (C) or fludarabine (F), in pts with newly diagnosed and relapsed/refractory (RR) AML. Methods: Pts with newly diagnosed or RR non-M3 AML with normal organ function were eligible. Pts with RR disease were treated in the phase I portion defining the MTD of C. The starting dose of C was 15 mg/m2 with doses escalating to 25 mg/m2 on days 1-5 in subsequent cohorts. During phase II, patients were randomized in a Bayesian design to C at the MTD with IA or fludarabine (F) at 30 mg/m2 on days 1-5 with IA. Up to 6 consolidation cycles were planned according to an attenuated schedule using the same drugs. Dose adjustments were made for elderly pts or pts with poor PS. Results: 9 pts were enrolled in the phase I portion. The overall response rate (ORR) in this group was 44%. DLT were observed at C 20 mg/m2 and included hand/foot syndrome (HFS), elevated bilirubin, and prolonged myelosuppression. The MTD was 15 mg/m2 on days 1-5. 50 evaluable pts were enrolled (16 newly diagnosed, 34 RR) in the phase II. In the frontline cohort, median age was similar in both groups (C 56, F 55), as were the cytogenetic profiles. The CR rate was 100% in both groups (9 CIA, 7 FIA). Detailed efficacy information can be found in the Table. More than half of the RR cohort were receiving therapy as salvage 2 or higher, and most had short first CR durations. Notable toxicities included elevated liver function tests for both groups, and HFS in the C group. There were 4 deaths on study, though most pts were receiving therapy as second salvage and were over the age of 60. Conclusions: CIA and FIA are effective regimens for newly diagnosed or RR AML with manageable toxicity profiles. The ORR were 100% and 32% for newly diagnosed and RR AML pts, respectively, with low early mortality rates. The study is ongoing.