bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 246: Phase 1 study: Ipilimumab (anti CTLA-4) in combination with Lenalidomide in patients with advanced cancers
Authors: Sakamuri Divya , Betancourt Cuellar Sonia L. , Glitza Isabella C. , Fu Siqing , Wheler Jennifer J. , Falchook Gerald S. , Tsimberidou Apostolia M. , Hong David S. , Subbiah Vivek , Fanale Michelle A. , Cabanillas Maria E. , Meric-Bernstam Funda , Janku Filip 
Published: August 2015

Abstract
Background: Ipilimumab, a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody potentiates an antitumor T-cell response. Lenalidomide, a derivative of thalidomide possesses immunomodulatory, antiangiogenic, and antineoplastic properties and thereby inhibits the growth of blood vessels and exhibits an anti-inflammatory effect. The potential synergistic effect of stimulating one's own immune system to attack cancer in combination with depriving further tumor growth provides rationale for combining Ipilimumab and Lenalidomide.
Methods: We designed a phase I study (3+3 design) to determine the safety of Ipilimumab (1.5-3mg/kg IV q 28 days x 4) and Lenalidomide (10-25mg PO daily x 21 q 28 days) until disease progression or unacceptable toxicity in advanced cancers. Endpoints included maximum tolerated (MTD), dose limiting toxicities (DLT), safety, and response per immune response criteria (iRC).
Results: To date, 21 patients (men, n = 8; women, n = 13), median age 56 (19-75) years, median of 3 (0-6) prior therapies (including 3 patients with prior ipilimumab) were enrolled in 3 of 5 dose levels ranging from 1.5-3mg of Ipilimumab and Lenalidomide 10-15 mg. The MTD has not been reached yet. DLT included grade (G) 3 macular rash in 2 patients (dose levels 2 and 3) and G3 pancreatitis (dose level 2). Other G3/4 drug related toxicities included G4 hypopituitarism (n = 1) and G3 pulmonary embolism (n = 1). Of 21 treated patients, 11 (52%) patients had stable disease. The median change in size of target lesions per iRC was 13% (-44% to +86%) with 5 (24%) of patients with at least -10% shrinkage (Hodgkin lymphoma, n = 2; melanoma, n = 1; follicular thyroid carcinoma, n = 1; teratoma, n = 1) lasting for 0.9 to 12.3+ months. The median time-to-treatment failure was 2.1 months (95% CI 1.4-2.8).
Conclusion: Ipilimumab and Lenalidomide have manageable side effect profile and demonstrate possible activity in patients with refractory Hodgkin lymphoma, melanoma, follicular thyroid cancer and teratoma.
Citation Format: Divya Sakamuri, Sonia L. Betancourt Cuellar, Isabella C. Glitza, Siqing Fu, Jennifer J. Wheler, Gerald S. Falchook, Apostolia M. Tsimberidou, David S. Hong, Vivek Subbiah, Michelle A. Fanale, Maria E. Cabanillas, Funda Meric-Bernstam, Filip Janku. Phase 1 study: Ipilimumab (anti CTLA-4) in combination with Lenalidomide in patients with advanced cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 246. doi:10.1158/1538-7445.AM2015-246
Abstract 2486: Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar
Authors: Zhu Zhongyu , Boopathy Ramakrishnan , Li Jinyu , Prabakaran Ponraj , Colantonio Simona , Feng Yang , Wang Yanping , Dyba Marzena A. , Dimitrov Dimiter S. 
Published: August 2015

Abstract
Conjugation of small molecule drugs to specific sites on the antibody molecule has been increasingly used for the generation of relatively homogenous preparations of antibody-drug conjugates (ADCs) with physicochemical properties similar or identical to those of the naked antibody. We previously developed a method for conjugation of small molecules to glycoproteins through existing glycans by using an engineered glycotransferase and a chemically reactive sugar as a handle to conjugate a small molecule. Here, for the first time, we report the use of this method with some modifications to generate an ADC from a monoclonal antibody, m860, which we identified from a human naïve phage display Fab library by panning against the extracellular domain of human HER2. M860 bound to cell surface-associated HER2 with affinity comparable to that of trastuzumab (Herceptin®), but to a different epitope. The ADC m860 was generated by enzymatically adding a reactive keto-galactose to galactose-free m860 using an engineered glycotransferase and conjugating the reactive m860 to aminooxy auristatin F with a non-cleavable linker. It exhibited exceptional serum stability and potent and specific cell-killing activity against HER2 positive cancer cells, including trastuzumab-resistant breast cancer cells. This unique ADC may have utility as a potential therapeutic for HER2 positive cancers alone or in combination with other drugs. Our results also validate the keto-galactose/engineered glycotransferase method for generation of functional ADCs, which could potentially also be used for preparation of ADCs targeting other disease markers.
This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by federal funds from the National Cancer Institute, NIH, under contract N01-CO-12400, HHSN261200800001E as well as by the SU2C-St.Baldrick's Foundation.
Citation Format: Zhongyu Zhu, Ramakrishnan Boopathy, Jinyu Li, Ponraj Prabakaran, Simona Colantonio, Yang Feng, Yanping Wang, Marzena A. Dyba, Dimiter S. Dimitrov. Site-specific antibody-drug conjugation through an engineered glycotransferase and a chemically reactive sugar. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2486. doi:10.1158/1538-7445.AM2015-2486
Abstract 2495: STING agonists formulated into cancer vaccines (STINGVAX) can cure established tumor resistant to immune checkpoint blockade by activating NK cells
Authors: Kim Young , Pardoll Drew , Fu Juan , Dubensky Tom 
Published: August 2015

Abstract
Stimulator of Interferon Genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides, activating TBK-1/IRF-3, NF-κB, and STAT6 signaling pathways to induce robust type I interferons and proinflammatory cytokines. Cyclic dinucleotide ligands were formulated with GM-CSF-producing cellular cancer vaccines - termed STINGVAX - that demonstrated potent in vivo anti-tumor efficacy in multiple therapeutic models of established cancer. We found that rationally designed synthetic CDN derivative molecules, including one with an Rp,Rp dithio diastereomer and non-canonical c[A(2′,5′)pA(3′,5′)p] phosphate bridge structure conferred significantly enhanced therapeutic anti-tumor efficacy in multiple aggressive therapeutic models of established cancer in mice. Anti-tumor activity was STING-dependent and correlated with increased activation of dendritic cells and tumor antigen-specific CD8+ T cells. Tumors from STINGVAX treated mice demonstrated dramatic PD-L1 upregulation, which was associated with tumor infiltrating CD8+IFNγ+ T-cells. When combined with PD-1 blockade, STINGVAX induced regression of palpable, poorly immunogenic tumors that did not respond to PD-1 blockade alone. We found that the STINGVAX's anti-tumor efficacy is NK cell dependent, and demonstrated that CDN are potent activators of IFNg in NK cells.
Citation Format: Young Kim, Drew Pardoll, Juan Fu, Tom Dubensky. STING agonists formulated into cancer vaccines (STINGVAX) can cure established tumor resistant to immune checkpoint blockade by activating NK cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2495. doi:10.1158/1538-7445.AM2015-2495
Abstract 2514: Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma
Authors: Shen Li , Orillion Ashley , Adelaiye Remi , Ciamporcero Eric , Ramakrishnan Swathi , Pili Roberto 
Published: August 2015

Abstract
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and represents 80% of the cases. Treatment options for patients with advanced disease are limited. Targeted molecular therapies have shown survival benefit but most patients develop therapy resistance overtime. Preclinical and clinical studies indicate that immunotherapies are effective and may play a role in the treatment of advanced RCC. However, the response rate is ∼ 20%, with a limited number of patients achieving durable remission. A major barrier to vaccine therapy is the presence of immunosuppressive cell populations including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). In the current study, we designed a tumor cell and Tregs dual-targeting vaccine by inducing Foxp3 expression in tumor cells, and tested this vaccine along with an unmodified vaccine in an orthotopic murine model of RCC, RENCA. We observed that both RENCA cell vaccine and RENCA Foxp3 cell vaccine prevented tumor growth in 6 out 10 animals. Interestingly, in an intervention setting, the RENCA Foxp3 tumor cell vaccine was superior to the RENCA tumor cell vaccine with a significant anti-tumor activity (45% inhibition of tumor weights) (p&lt;0.01). Moreover, RENCA Foxp3 tumor cell vaccine reduced the number of tumor infiltrating Tregs (42% reduction, p&lt;0.05) and Treg Foxp3 expression both in peripheral blood and tumor infiltrates. In summary, our results suggest that a strategy targeting Tregs along with vaccine therapy or a dual targeting vaccine strategy may be beneficial in established RCC. We also observed that suppressive myeloid cell (SMCs) populations dominate the established tumor microenvironment and we are currently testing the combination of the dual-targeting vaccine with a SMC-targeting agent.
Citation Format: Li Shen, Ashley Orillion, Remi Adelaiye, Eric Ciamporcero, Swathi Ramakrishnan, Roberto Pili. Activity of a novel Foxp3-tumor cell vaccine in a murine model of renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2514. doi:10.1158/1538-7445.AM2015-2514
Abstract 2546: HDAC and Hsp90 inhibition as therapeutic strategy for translocation renal cell carcinoma
Authors: Ku Sheng-Yu , Ramakrishnan Swathi , Ciamporcero Eric , Xu Bo , Azabdaftari Gissou , Cheney Richard , Pili Roberto 
Published: August 2015

Abstract
Background: Xp11.2 translocation renal cell carcinoma (tRCC) is an aggressive subtype of kidney cancer, which mainly occurs in young patients. The prevalence of this disease is about 30% in pediatric RCC, but ∼1% in adult RCC cases. Patients with tRCC are refractory to standard therapies for clear cell RCC. Therefore, there is no efficient treatment for this type of kidney cancer. The tRCC harbors gene fusions involving the TFE3 transcription factor on chromosome X with several partner genes, leading to TFE3 elevation in the cell nucleus, but its function remains unclear. We have successfully established a cell line and patient-derived xenograft from a tRCC patient to develop rational therapeutic strategies and understand the tumor biology.
Methods: We have utilized a feeder layer containing a ROCK inhibitor to favorably generate a cell line, 277T, from a young tRCC patient. Also, we have implanted tumor samples from the patient subcutaneously into SCID mice to establish a patient-derived xenograft model, RP-R-07, and continuously maintain tumor growth in vivo. Cells were treated with different drugs, and then assessed by MTT assay and trypan blue staining for growth inhibition and cell death investigations. TFE3 expression in cells and tumors were detected by immunofluorescence and immunohistochemistry. The combined drug effects were determined by CalcuSyn analysis.
Results: Our preliminary results demonstrated that TFE3 is predominately expressing in the nucleus of 277T cells and RP-R-07 tumor model compared to other subtypes of RCC by immunofluorescence and immunohistochemistry, respectively. Further, we treated 277T cells with several cytotoxic drugs showing that the cells didn't respond to docetaxel, doxorubicin, rapamycin, or a PI3K-mTOR inhibitor, but were sensitive to the Hsp90 inhibitor AUY922, and the HDAC inhibitor LBH589. Moreover, combining both AUY922 and LBH589 induced greater cell death compared to each single treatment (73% vs 41% for LBH589; 73% vs 19% for AUY922). In addition, an in vivo experiment indicated that LBH589 did inhibit tumor growth.
Conclusions: Overall our results indicate that tRCC is sensitive to HSP90 and HDAC inhibitors both in vitro and in vivo. The combination of LBH589 and AUY922 represents a promising strategy for treating tRCC
Citation Format: Sheng-Yu Ku, Swathi Ramakrishnan, Eric Ciamporcero, Bo Xu, Gissou Azabdaftari, Richard Cheney, Roberto Pili. HDAC and Hsp90 inhibition as therapeutic strategy for translocation renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2015-2546
Abstract 2566: Combination of taxanes with mesothelin-targeted immunotoxin RG7787 induces synergistic killing of pancreatic cancer
Authors: Alewine Christine Campo , Kolyvas Emily , Boslett Klaus , Pastan Ira 
Published: August 2015

Abstract
Pancreatic cancer has a poor prognosis with a 5 year median overall survival of just 6%. Most pancreatic adenocarcinomas express the cells surface antigen mesothelin (MSLN). RG7787 is a cytolytic fusion protein that uses an anti-mesothelin (MSLN) antibody Fab to target a modified, deimmunized Pseudomonas exotoxin A cytotoxic payload to cells that express MSLN. The immunotoxin is internalized by cells, releasing the toxin to the cytosol, where it enzymatically modifies elongation factor-2 causing a global halt in protein synthesis. We have previously observed that combination of paclitaxel with RG7787 significantly enhances anti-tumor effect in a KLM1 xenograft model of pancreatic cancer. Here, we report that co-treatment with nab-paclitaxel induces durable complete regressions in this model as well as explore the mechanisms underlying the favorable interaction of RG7787 with taxanes. We demonstrate that the enhanced killing with the combination can also be observed in vitro. Co-treatment lowers the dose of RG7787 required to achieve complete cell killing to the physiologic range. This favorable interaction requires the toxin portion of the molecule and cannot be replicated by treating with the anti-MSLN Fab alone. The timing of treatment with the two drugs is not critical, as similar cytotoxic effects are observed when taxane is given 24 hrs before, 24 hrs after or simultaneously with RG7787. Addition of taxane does not increase immunotoxin-mediated protein synthesis inhibition, nor can combination of taxane with the protein synthesis inhibitor cycloheximide reproduce the enhanced killing seen with the taxane/ RG7787 combination. Further studies exploring the critical factors in this interaction are ongoing.
Citation Format: Christine Campo Alewine, Emily Kolyvas, Klaus Boslett, Ira Pastan. Combination of taxanes with mesothelin-targeted immunotoxin RG7787 induces synergistic killing of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2566. doi:10.1158/1538-7445.AM2015-2566
Abstract 26: Suppression of E-cadherin mediates gallotannin-induced apoptosis in Hep G2 hepatocelluar carcinoma cells
Authors: Kwon Hee Young , Jung Ji Hoon , Lee Hyun Joo , Jeong Myoung Seok , Jung Deok-Beom , Kim Bonglee , Lee Hyemin , Kim Sung-Hoon 
Published: August 2015

Abstract
Though gallotannin was known to have anti-oxidant and antitumor activity, the underlying antitumor mechanism of gallotannin still remains unclear. Thus, in the present study, antitumor mechanism of gallotannin was elucidated in hepatocellular carcinoma cells. Gallotannin significantly exerted cytotoxicity against Hep G2 and Chang hepatocellular carcinoma cells with the accumulation of the sub-G1 population and increase of terminal deoxynucleotidyltransferasedUTP nick end labeling (TUNEL) positive cells as an apoptotic feature. Also, gallotannin attenuated the expression of pro-caspase9, pro-caspase3, Bcl2 and integrin β1 and cleaved poly(ADP)-ribose polymerase (PARP) in Hep G2 and Chang cancer cells. Furthermore, gallotannin suppressed cell repair motility by wound healing assay and also inhibited cell adhesion in Hep G2 cells. Of note, gallotannin attenuated the expression of epithelial cadherin (E-cadherin) to form cell-cell adhesion from the early stage, and also beta-catenin at late phase in Hep G2 cells. Consistently, Immunofluorescence assay showed that E-cadherin or β-catenin expression was suppressed in a time dependent manner by gallotannin. Furthermore, silencing of E-cadherin by siRNA transfection method enhanced PAPR cleavage, caspase 3 activation and sub G1 population and attenuated the cell adhesion induced by gallotannin in Hep G2 cells. Overall, our findings demonstrate that the disruption of cell adhesion junction by suppression of E-cadherin mediates gallotannin enhanced apoptosis in Hep G2 liver cancer cells.
Citation Format: Hee Young Kwon, Ji Hoon Jung, Hyun Joo Lee, Myoung Seok Jeong, Deok-Beom Jung, Bonglee Kim, Hyemin Lee, Sung-Hoon Kim. Suppression of E-cadherin mediates gallotannin-induced apoptosis in Hep G2 hepatocelluar carcinoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 26. doi:10.1158/1538-7445.AM2015-26
Abstract 2609: Disruption of CAS scaffolds: A novel mechanism for microtubule targeting agents
Authors: Dybdal-Hargreaves Nicholas F. , Rohena Cristina C. , Risinger April L. , Mooberry Susan L. 
Published: August 2015

Abstract
Microtubule targeting agents (MTAs) are an important class of anticancer drugs. While their anticancer mechanisms were considered exclusively as antimitotic for decades, evidence now suggests that the ability of MTAs to inhibit functions of interphase microtubules likely plays an essential role in their clinical anticancer actions. Interphase microtubules are responsible for intracellular trafficking of many constituents including proteins involved in signal transduction. Efficient signal transduction requires precise coordination of signaling partners through their appropriate localization. Scaffold proteins regulate signal transduction pathways by assembling signaling components into complexes both temporally and spatially. Assembly of scaffold complexes can be dependent on a functional microtubule network. Several scaffold proteins have been identified with importance in breast cancer, including BCAR1, a member of the crk associated substrate (CAS) family of scaffolds. BCAR1 expression in breast cancer is associated with resistance to anti-estrogens. We hypothesized that the ability of diverse MTAs to interrupt the function of these signaling scaffolds could contribute to their activities in breast cancer cells. The effects of eribulin, vinorelbine, paclitaxel, docetaxel, and ixabepilone on the localization and associated signaling of BCAR1 was evaluated. The MTAs disrupted the localization of BCAR1 and differential effects were noted among the MTAs. There were also distinct effects of the agents on BCAR1 associated signaling. To determine whether BCAR1 expression was related to sensitivity of breast cancer cell lines to specific MTAs we separated the breast cancer cell lines based on their ability to initiate cytotoxic or only antiproliferative effects and evaluated them for BCAR1 expression. Two cell lines with the highest BCAR1 expression were resistant to the cytotoxic effects of each MTA of this panel. Thus, high levels of BCAR1 in breast cancer cells can overcome the ability of diverse MTAs to disrupt scaffold function and lead to resistance. Our results suggest that the ability of MTAs to interrupt BCAR1 scaffolds represents a new mechanism of action for these drugs. However, MTA disruption of the BCAR1 CAS scaffold complexes can be overcome by high BCAR1 expression. Funding for the work was provided by Eisai Inc.
Citation Format: Nicholas F. Dybdal-Hargreaves, Cristina C. Rohena, April L. Risinger, Susan L. Mooberry. Disruption of CAS scaffolds: A novel mechanism for microtubule targeting agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2609. doi:10.1158/1538-7445.AM2015-2609
Abstract 2614: Targeting heat shock protein 90 with Ganetespib for the treatment of lymphoma
Authors: Tu Zhigang , Liu Hanqing , Zhao Jingjing , Zhang Peishan , Liang Zhiquan , Ruan Lingling , Lu Yongjin , Shang Dongsheng , Sun Ying , Xu Lili , Chen Keping , Danzeng Quji 
Published: August 2015

Abstract
Effective treatments for lymphoma remain a serious unmet medical need: the incidence of lymphoma continues to rise, and lymphoma tumors can relapse in patients who initially respond to treatment. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating many many cancers, including blood cancers. In our study, we show that ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor, dramatically reduced growth of a couple of different kinds of lymphoma, such as mantle cell lymphoma and Burkitt's lymphoma in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all studied cell lines, such as Ramos, Jeko-1, Granta-519, Raji, etc. Ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with doxorubicin. Results of H&E staining, TUNEL assays, and immunohistochemistry staining of Ki-67 revealed significant differences in ganetespib-treated tumors. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. In summary, our data suggest that ganetespib can be potentially used for the molecularly targeted therapy of lymphoma patients.
Citation Format: Zhigang Tu, Hanqing Liu, Jingjing Zhao, Peishan Zhang, Zhiquan Liang, Lingling Ruan, Yongjin Lu, Dongsheng Shang, Ying Sun, Lili Xu, Keping Chen, Quji Danzeng. Targeting heat shock protein 90 with Ganetespib for the treatment of lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2614. doi:10.1158/1538-7445.AM2015-2614