Şahin, İlyas

TPS587 Background: Biliary tract cancer (BTC) is characterized by generally poor prognoses with limited treatment options. Systemic chemotherapy usually begins with gemcitabine, platinum agents, and a checkpoint inhibitor followed by 5-FU and oxaliplatin, irinotecan or a taxane. Presently, there is no consensus second-line therapy for patients with BTC. The DLL/Notch signaling pathway has been described to be a major driver of cholangiocarcinogenesis and VEGF-A overexpression has been reported in BTC tumors, correlating with stage, metastasis, and prognosis of the disease. CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Methods: COMPANION-002 (CTX-009 -002) is an open-label, randomized, controlled study in patients in second line advanced or metastatic BTC. To be eligible, patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease. 150 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include stage (locally advanced vs. metastatic), anatomic subsite of primary tumor (intrahepatic cholangiocarcinoma vs. other, i.e. extrahepatic cholangiocarcinoma, gallbladder, or ampullary), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The patients randomized to paclitaxel arm can crossover after disease progression if selection criteria continue to be met. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. Clinical trial information: 251040.

Abstract Background. Endothelial progenitor cells (EPCs) are circulating precursors with the capacity to differentiate into endothelial lineage cells through a process known as “vasculogenesis” thus contributing to vessel formation. We studied the role of endothelial progenitor cells in multiple myeloma (MM) pathogenesis. Methods. EPC levels were evaluated in peripheral blood (PB) of patients with smoldering MM (SMM), and active myeloma (MM) and in PB of healthy controls, by using flow-cytometry (CD34+VEGFR2+ cells), and by performing endothelial colony forming assays. EPC levels were studied in PB from transgenic Vk*MYC mice harboring either early MM (smoldering-like stage); or late (active MM-like stage); as well as in mice injected intravenously with either murine MM 5TGM1-turboRFP+ cells or human MM1S-GFP+/luc+ cells. Healthy syngeneic mice were used as controls. GFP-bone marrow (BM) transplantation and sub-cutaneous femur implantation were performed in recipient mice to study EPC BM mobilization (GFP+CD34+VEGFR2 cells) and EPC BM recruitment to the implanted femurs during 5TGM1 MM model progression. Transgenic ID1+/-ID3-/- mice (with a defect in EPC mobilization and differentiation ability) were injected with transplantable Vk*MYC cells and followed for survival. Wild type littermates were used as controls. Similar experiments were performed using transgenic ID1+/-ID3-/- mice transplanted with BM of wild type littermates. Therapeutic activity of DC101 anti-murine VEGFR2 Ab was evaluated in the MM1S human orthotopic xenograft model, using both early and late treatment approaches. Results. EPC levels were significantly increased in PB of MM patients, including SMM, compared to healthy controls (P<0.05). PB mononuclear cells (PBMCs) from SMM and aMM patients showed an increase ability to form both EC-CFUs (P<0.01) and ECFCs compared to those from healthy controls (P<0.05). EPC levels were significantly increased in PB of transgenic Vk*MYC mice at both early and advanced stage of MM development compared to healthy syngenic mice. In orthotopic MM models we found that levels of circulating EPCs increase early after i.v. injection of either human MM1S-GFP+/luc+ cells (1.5 and 2 times higher after 1 week and 2 weeks, respectively) or murine 5TGM1-turboRFP+ MM cells (2.5 and 3 times higher after 2 and 3 weeks, respectively) compared to naïve mice. By coupling GFP-BM transplantation and subcutaneous femur implantation, we generated a new model that allows the study of BM derived-cell trafficking from one site to another of the BM. The levels of BM-derived GFP+ EPC increased early after i.v. injection of 5TGM1-turboRFP+ cells (2 times increase after 2 weeks, P<0.01); also, the percentage of both total GFP+ cells (7.92% versus 2.635%, P<0.05) and GFP+ EPCs (0.22% versus 0.068%, P<0.05) increased in the BM of implanted femurs of tumor cell injected mice compared to controls. Survival of ID1+/-ID3-/- mice was significantly increased compared to that of wild type littermates after injection of MM Vk*MYC cells (62 versus 27 days median survival time, P=0.0005); this survival advantage was lost after wild type BM was transplanted in ID1+/-ID3-/- mice (34 versus 35 days median survival time). In human MM1S orthotopic xenograft model, treatment with anti-murine VEGFR2 DC101 Ab was able to inhibit MM progression when treatment was started early during smoldering like stages, but not when it was started after significant tumor burden (50.5, 41.5 and 40 days median survival time in DC101 early, late and untargeted IgG treated mice respectively) Conclusion. These results show that EPC mediated vasculogenesis is an important pathogenic process that occurs during the early/smoldering MM stage. Knockout mouse experiments confirm that EPCs are essential for MM tumor progression. These results indicate that anti-angiogenic agents could be effective as an early therapeutic intervention in SMM patients. Disclosures Ghobrial: Millennium/Takeda: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract Citron Rho-interacting serine/threonine kinase (CIT) is a serine/threonine kinase that acts as a key component of the midbody and is essential for cytokinesis. CIT has been reported to be highly expressed in some tumor tissues and to play a role in cancer proliferation; however, the significance of CIT has not been investigated in multiple myeloma (MM). Here, we identified, by protein microarray and immunohistochemistry, that CIT is 1 of the upregulated proteins in the plasma cells of MM patients compared with healthy controls. Analysis of a gene expression profile data set showed that MM patients with high CIT gene expression had significantly worse overall survival compared with MM patients with low CIT gene expression. CIT silencing in MM cell lines induced cytokinesis failure and resulted in decreased MM cell proliferation in vitro and in vivo. TP53 expression was found to be an independent predictor of CIT dependency, with low-TP53 cell lines exhibiting a strong dependency on CIT. This study provides the rationale for CIT being a potential therapeutic target in MM in future trials.