bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT157: PANOVA-3: A phase III study of TTFields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC)
Authors: Weinberg Uri , Farber Ori , Giladi Moshe , Bomzon Zeev , Lavy-Shahaf Gitit , Kirson Eilon D. 
Published: August 2018

Abstract
Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of patients with glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of pancreatic cancer. The Phase 2 PANOVA study was the first trial testing TTFields in pancreatic cancer patients, and demonstrated the safety of TTFields when combined with nab-paclitaxel and gemcitabine in both metastatic and LAPC. The Phase 3 PANOVA-3 trial (NCT03377491) is designed to test the efficacy of adding TTFields to nab-paclitaxel and gemcitabine combination in LAPC.
Trial Design: Patients (N=556) with unresectable, LAPC (per NCCN guidelines) will be enrolled in this prospective, randomized trial. Patients should have an ECOG score of 0-2 and no prior progression or treatment. Patients will be stratified based on their performance status and geographical region, and will be randomized 1:1 to TTFields plus nab-paclitaxel and gemcitabine or to nab-paclitaxel and gemcitabine alone. Chemotherapy will be administered at standard dose of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2 once weekly). TTFields (150kHz) will be deilvered at least 18 hours/day until local disease progression per RECIST Criteria V1.1. Follow up will be performed q8w, including a CT scan of the chest and abdomen. Following local disease progression, patients will be followed monthly for survival. Overall survival will be the primary endpoint and progression-free survival, objective response rate, rate of resectability, quality of life and toxicity will all be secondary endpoints. Sample size was calculated using a log-rank test comparing time to event in patients treated with TTFields plus chemotherapy with control patients on chemotherapy alone. PANOVA-3 is designed to detect a hazard ratio 0.75 in overall survival. Type I error is set to 0.05 (two-sided) and power to 80%.
Citation Format: Uri Weinberg, Ori Farber, Moshe Giladi, Zeev Bomzon, Gitit Lavy-Shahaf, Eilon D. Kirson. PANOVA-3: A phase III study of TTFields with nab-paclitaxel and gemcitabine for front-line treatment of locally-advanced pancreatic adenocarcinoma (LAPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT157.
Abstract LB-011: Novel nano-formulation of paclitaxel for pancreatic cancer therapy
Authors: Hafeez Bilal B. , Massey Andrew E. , Kashyap Vivek K. , Sikander Mohammad , Shetty Advit , Chaib Mehdi , Mandil Hassan , Yallapu Mohan , Jaggi Meena , Chauhan Subhash C. 
Published: August 2018

Abstract
Pancreatic cancer (PanCa) is one of the leading causes of cancer-related mortality in the United States due to very limited therapeutic options. Thus, there is an urgent need to develop novel therapeutic strategies for the management of this disease. Paclitaxel (PTX), a natural product derived from the Pacific Yew tree, is an agent typically used in combination therapy for PanCa. Currently, PTX nanoparticles (Abraxane®) along with gemcitabine are in use for the treatment of advanced PanCa. Herein, we have generated and characterized a novel nano-formulation of PTX comprised of PLGA core, stabilized with polyvinyl alcohol (PVA) and coated with poly-L-lysine (PLL). Dynamic light scattering (DLS) characterization indicated that the average particle size of this formulation was approximately 160 nm, and exhibited Zeta potentials of ~ -6.02 mV in 10% serum, along with an outstanding PL loading efficiency. We also evaluated the uptake mechanism of PPNPs in PanCa cells using different endocytosis inhibitors (Genistein, amiloride, nocodazole, chlorpromazine, and methyl beta cyclodextrin). Our results demonstrated that PPNPs were taken up mainly by lipid raft mediated endocytosis pathway in an energy-dependent manner. Next, we evaluated its therapeutic efficacy and underlying molecular mechanisms in human PanCa cells (HPAF-II, Panc1, and MiaPaCa-2) by performing various in vitro experiments. We first performed MTS and colony formation assays to determine the effects of free PTX and PPNPs on growth of PanCa cells. In this experiment, cells were treated with various concentrations of free PTX or abraxane, or PPNPs (2.5-160 nM) for 48 hrs. As a result, the PPNPs formulation showed more therapeutic effect over free abraxane as determined by decrease in cell proliferation and enhanced apoptosis induction in PanCa cells. PPNPs also showed a significant (P&lt;0.01) inhibition in colony formation compared to free PTX. Moreover, PPNPs showed a superior inhibition of the invasive and migratory potential of HPAF-II and Panc1 as determined by commercially available kits (Invitrogen). PPNPs more effectively inhibited expression of GLI-1 and SHH as determined by qPCR and Western blot analysis. In conclusion, our findings suggest that PPNPs formulation has more anti-cancer potential than free PTX/Abraxane against PanCa and could be a novel therapeutic modality for the treatment of PanCa.
Citation Format: Bilal B. Hafeez, Andrew E. Massey, Vivek K. Kashyap, Mohammad Sikander, Advit Shetty, Mehdi Chaib, Hassan Mandil, Mohan Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel nano-formulation of paclitaxel for pancreatic cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-011.
Abstract LB-042: Successful tumor formation following xenotransplantation of primary human ovarian cancer cells into severe combined immunodeficient (SCID) pigs
Authors: Boettcher Adeline N. , Kiupel Matti , Adur Malavika , Cocco Emiliano , Santin Alessandro , Charley Sara , Risinger John , Tuggle Christopher , Shapiro Erik 
Published: August 2018

Abstract
Ovarian cancer (OvCa) is the most lethal gynecologic malignancy, with 2/3 of patients having late-stage disease (stages II-IV) at diagnosis. Preclinical animal models for cancer research have primarily been restricted to rodents, but many preclinical cancer drug trials that succeed in mice fail in humans, potentially due to vast differences in physiology and size. Therefore, we sought to determine if pigs, which are more similar to humans in terms of anatomy and physiology, would be a viable preclinical animal model for OvCa. Our group has pioneered the development of severe combined immunodeficiency (SCID) pigs for biomedical research, a key technological advancement for xenotransplantation of human ovarian cancer cells to form tumors. In this study, we injected human OSPC-ARK-1 cells, a chemotherapy-resistant primary ovarian serous papillary carcinoma cell line, into the neck muscle and ear tissue of four SCID and two non-SCID pigs. Tumors developed in the ears of three SCID pigs, while two SCID pigs developed tumors in neck tissue, all of which were confirmed at pathology as true neoplasms. Non-SCID animals did not develop tumors in any location. Confirmation that OSPC-ARK1 cells can form tumors in SCID pigs substantiates further development of orthotopic models of OvCa in pigs for researching improved OvCa therapeutic and diagnostic methods.
Citation Format: Adeline N. Boettcher, Matti Kiupel, Malavika Adur, Emiliano Cocco, Alessandro Santin, Sara Charley, John Risinger, Christopher Tuggle, Erik Shapiro. Successful tumor formation following xenotransplantation of primary human ovarian cancer cells into severe combined immunodeficient (SCID) pigs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-042.
Abstract LB-047: Novel anti-psychotic drug for pancreatic cancer treatment
Authors: Ramachandran Sharavan , Srivastava Sanjay K. 
Published: August 2018

Abstract
Pancreatic cancer is one of the most deadly malignancy with a five-year survival rate of 7%. Despite advances in cancer treatment, this disease is still incurable and the treatment outcomes are limited. Few studies have shown that neuroleptic drugs exert better anti-proliferative effects in pancreatic cancer cells when compared to conventional chemotherapeutic agents gemcitabine and oxaliplatin. In the current study, we evaluated the anti-cancer effects of pimavanserin, an anti-psychotic drug used for the treatment of Parkinson's disease psychosis. Pimavanserin significantly suppressed the proliferation of AsPC1, BxPC3, PANC1, MIAPaCa2 and PO2 pancreatic cancer cells with the IC50 between 3 - 9µM at 24, 48 and 72 hours. Pimavanserin treatment induced 2-5 fold apoptosis in pancreatic cancer cells. Notably, no significant cell death was observed in normal human pancreatic ductal epithelial (HPDE-6) cells by pimavanserin treatment. Furthermore, pimavanserin treatment inhibits the expression of key oncogenic proteins and cancer stem cell markers such as pAkt(S473), pSTAT3(Y705), β-catenin, GLI-1, GLI-2, c-Myc, Oct-4, SOX-2, NANOG and CD44. We further evaluated the efficacy of pimavanserin in two different in vivo tumor models. Oral administration of 10mg/kg pimavanserin suppressed 50% of sub-cutaneously implanted BxPC3 tumors in athymic nude mice. In another setting, 10mg/kg pimavanserin by oral gavage inhibited the growth of orthotopically implanted PANC1 pancreatic tumors by 75%. Moreover, chronic administration of pimavanserin did not show any general signs of toxicity and no apparent changes were observed in the behavioral activity of mice. Further mechanistic studies are in progress. Since pimavanserin is already available in the clinic with established safety profile, our results will accelerate its clinical development for treatment of patients with pancreatic cancer. Our study is the first to demonstrate the anti-cancer effects of pimavanserin.
Citation Format: Sharavan Ramachandran, Sanjay K. Srivastava. Novel anti-psychotic drug for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-047.
Abstract LB-056: Novel molecular mechanism underlying cancer drug resistance: Involvement of p58IPKchaperone pathway
Authors: Athar Mohammad , Srivastava Ritesh 
Published: August 2018

Abstract
Rhabdomyosarcoma (RMS) is an aggressive and highly malignant form of pediatric cancer that develops from skeletal muscle cells. A third of these cancers become drug resistant, metastatic and fatal. Current therapeutic approaches have not resulted in significant improvement in outcome for patients with recurrent and/or metastatic disease. Here, employing two RMS-derived cell lines (RH30, a drug sensitive and RD, a drug resistant), we demonstrate a novel underlying molecular mechanism of drug resistance in these tumor subtypes. We show that in response to chemotherapeutics drugs [actinomysin D, torisol, etoposide and arsenic trioxide (ATO)], endoplasmic reticulum (ER) stress associated unfolded protein response (UPR) signaling pathway could be induced in RH30 cell only, while drug resistance RD cells largely lack this ability. The mechanism underlying UPR induction involves activation of multifunctional molecular chaperone P58IPK that besides regulating protein homeostasis is an inhibitor of the interferon-induced double-stranded RNA-activated protein kinase (PKR). We observed that the expression of p58IPK is high in drug resistance RD cells as compared to drug sensitive RH30 cells. To confirm its role in drug resistance, we ablated or overexpressed p58IPK respectively in drug resistant RD and drug sensitive RH30 cells. The p58IPK depleted RD cells became sensitive to chemotherapeutic agents while overexpressing p58IPK RH30 cells manifested drug resistance. To further demonstrate the known functional consequences of manipulation in the expression of p58IPK we found that P58IPK over-expression in RH30 cells inhibited eIF2α phosphorylation and diminished apoptosis by downregulating ATF4/CHOP/Cleaved caspase-3, while silencing of p58IPK in RD cells enhanced eIF2α phosphorylation and increased ATF4/CHOP/Cleaved caspase-3-dependent apoptosis in response to chemotherapeutic drug treatment. The underlying mechanism by which P58IPK alters drug sensitivity in RMS cells involves its chaperone function by its binding to drug transporters ABCB-1 and ABCC-1. At baseline, in RD cells with high p58IPK manifest significantly higher dye efflux as compared to RH30 with low p58IPK. This baseline drug exclusion profile correlated with the ATPase activity of these ABC transporters. However, ablation or overexpression of p58IPK respectively, in RH30/RD cells reversed their drug resistance phenotype. Thus, we have identified a novel drug resistance mechanism in RMS. These results may have translational implications in overcoming drug-resistance in deadly neoplasm. These studies are in progress in our laboratory.
Citation Format: Mohammad Athar, Ritesh Srivastava. Novel molecular mechanism underlying cancer drug resistance: Involvement of p58IPKchaperone pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-056.
Abstract LB-066: A high-throughput screen of an annotated small molecule library identifies substrates of P-glycoprotein
Authors: Lee Tobie D. , Lee Olivia W. , Brimacombe Kyle R. , Shen Min , Chen Lu , Guha Rajarshi , Tebase Bethelihem , Robey Robert W. , Ambudkar Suresh V. , Gottesman Michael M. , Hall Matthew D. 
Published: August 2018

Abstract
A major difficulty in treating cancer is the development of cellular resistance to chemotherapeutics, a phenomenon known as multidrug resistance (MDR). MDR is primarily conferred by an upregulation of ATP-binding cassette (ABC) transporters, most notably P-glycoprotein (P-gp, MDR1, ABCB1), which are responsible for the active transport of drugs out of the cells thereby minimizing drug-target interactions. While numerous strategies to overcome transporter-mediated MDR have been explored, none have proved successful. An alternative approach is to exploit resistance by identifying drugs that target MDR cells over the nonresistant parental cells from which they were selected. As such, the development of MDR1-selective agents represents a novel and relatively unexplored strategy for resolving multidrug resistance. To identify such agents, we developed a series of robust, high-throughput assays to examine differential toxicity between drug-naïve cancer cell lines and their drug-selected, multidrug-resistant sublines. We performed high-throughput screens against several libraries of annotated compounds including the NCATS Pharmaceutical Collection (NPC), a comprehensive collection of all clinically approved drugs - to identify P-gp substrates, and classes of small molecules that exhibit selective toxicity against MDR tumor lines. Further mechanistic evaluation of these compounds has provided valuable insight into targets or pathways that appear to have been rendered more sensitive to inhibition in the course of multidrug resistance development.
Citation Format: Tobie D. Lee, Olivia W. Lee, Kyle R. Brimacombe, Min Shen, Lu Chen, Rajarshi Guha, Bethelihem Tebase, Robert W. Robey, Suresh V. Ambudkar, Michael M. Gottesman, Matthew D. Hall. A high-throughput screen of an annotated small molecule library identifies substrates of P-glycoprotein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-066.
Abstract LB-189: Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer
Authors: Newman Jenna H. , NeMoyer Rachel E. , Augeri David , Malhotra Jyoti , Langenfeld Elaine , Chesson Charles B. , Lee Micheal J. , Tarabichi Saeed , Jhawar Sachin R. , Bommareddy Praveen K. , Marshall Sh'rae , Sadimin Evita T. , Kerrigan John E. , Goedken Michael , Minerowicz Christine , Jabbour Salma K. , Li Shengguo , Dobias Natalie , Carayannopolous Mary O. , Zloza Andrew , Langenfeld John 
Published: August 2018

Abstract
Purpose: Studies have shown that bone morphogenetic protein (BMP) signaling is aberrantly expressed in lung and other carcinoma leading to pro-oncogenic effects on tumor growth. The BMP receptor inhibitor DMH2 induces death of lung cancer cells through the downregulation of anti-apoptotic proteins XIAP, TAK1, and Id1-Id3. Since DMH2 does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics better BMP inhibitors are needed.
Experimental Design: Here, we identified a site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We examined the effects of JL5 to downregulate BMP signaling and induce cell death of lung cancer cells in vitro and in vivo. We also queried the The Cancer Genome Atlas (TCGA) to assess if genetic alterations in lung cancer would affect drug targetability of the BMP receptors.
Results: We show that JL5 has improved pharmacokinetic profile compared to DMH2. JL5 suppresses BMP signaling in lung cancer cells in vitro and in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. The TCBA database analysis suggests that genetic alterations in the BMP signaling cascade will not limit targeting with small molecule inhibitors.
Conclusion: Our studies show that the BMP signaling pathway is targetable and BMP receptor inhibitors should be developed as a therapeutic to treat lung and other cancer patients.
Citation Format: Jenna H. Newman, Rachel E. NeMoyer, David Augeri, Jyoti Malhotra, Elaine Langenfeld, Charles B. Chesson, Micheal J. Lee, Saeed Tarabichi, Sachin R. Jhawar, Praveen K. Bommareddy, Sh'rae Marshall, Evita T. Sadimin, John E. Kerrigan, Michael Goedken, Christine Minerowicz, Salma K. Jabbour, Shengguo Li, Natalie Dobias, Mary O. Carayannopolous, Andrew Zloza, John Langenfeld. Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-189.
Abstract LB-197: Transposon mutagenesis and CRISPR/Cas9 screening reveal pathways driving peripheral nerve sheath tumor development and maintenance
Authors: Reyes German L. Velez , Koes Nicholas , Kaufmann Gabriel , Ryu Esther , Largaespada David A. 
Published: August 2018

Abstract
Malignant Peripheral Nerve Sheath tumors(MPNSTs) are highly aggressive soft tissue sarcomas derived Schwann cell tumors. Half of these tumors occur sporadically, while the rest occur in the context of Neurofibromatosis Type 1 Syndrome (NF1) developing from pre-existing plexiform neurofibromas. NF1 is characterized by loss-of-function mutations in the gene encoding neurofibromin, a negative regulator of the oncogenic Ras pathway. To better understand genetic factors that give rise to MPNSTs, we performed a Sleeping Beauty (SB) transposon screen in mice. The results implicated Wnt/β-catenin, PI3K-AKT-mTOR, growth factor receptor signaling, and other pathways. It is our goal to understand the role of these pathways in human Schwann cell transformation, tumorigenesis, and tumor maintenance. We next sought to validate SB screen gene hits in a human cellular model using CRISPR/Cas9 technology as a tool to induce loss-of-function mutations in tumor suppressor gene (TSG) and oncogene candidates. A total 103 genes were independently targeted with multiple guideRNAs in immortalized human Schwann and MPNST cell lines and effects on transformation assessed. Transformation was assessed by anchorage-independent colony formation in soft agar, transwell migration, and tumor formation in NRG mice. In these assays, more than 30 genes scored as TSG candidates. Our results revealed a role for the Wnt/β-catenin, Hippo/Yap, PI3K-AKT-mTOR, Rho, and growth factor receptor signaling pathways in human neurofibroma and MPNST development and maintenance. These are generating hypothesis driven pre-clinical treatment studies we're pursuing now.
Citation Format: German L. Velez Reyes, Nicholas Koes, Gabriel Kaufmann, Esther Ryu, David A. Largaespada. Transposon mutagenesis and CRISPR/Cas9 screening reveal pathways driving peripheral nerve sheath tumor development and maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-197.
Abstract LB-205: hnRNPM-IRES-mediated translation promotes colon cancer tumorigenesis
Authors: Chen Tsung-Ming , Lai Ming-Chih , Li Yi-Han , Tsai Shaw-Jenq , Sun H. Sunny 
Published: August 2018

Abstract
Internal Ribosome Entry Site (IRES)-mediated translation is known to play a vital role for cell survival under stress conditions, yet the crucial players involved in this translational reprogramming remain largely unidentified. This study aims to elucidate the missing piece of pathway underlying the hypoxia-induced, IRES-mediated translational activation in the cancer genome. By using the proteomic profiling approach, we discovered hnRNPM as a new IRES interacting factor to activate translation in colon cancer cells. Mechanistic studies revealed that hypoxia increases hnRNPM binding onto mRNA and promotes translation of a set of critical genes relating to cell survival and metabolism. Transcriptomics and translatomics analyses discovered a unique set of hnRNPM-target mRNAs with increased ribosome occupancy under hypoxia to provoke tumorigenesis. Clinical specimen and mouse carcinogenesis model showed that hnRNPM overexpression accompanies colorectal cancer development and positively correlated with hypoxia biomarker. Collectively, these data highlight the novel role of hnRNPM-IRES-mediated translation in transforming hypoxia-induced proteome toward malignancy and demonstrate significant implications for targeting hnRNPM in future anticancer therapy.
Citation Format: Tsung-Ming Chen, Ming-Chih Lai, Yi-Han Li, Shaw-Jenq Tsai, H. Sunny Sun. hnRNPM-IRES-mediated translation promotes colon cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-205.