bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2516: SL01, an oral gemcitabine prodrug as a potent anticancer drug
Authors: Li Wenbao , Yuan Hua , Qu Xianjun 
Published: May 2015

Abstract
SL01,dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)carbamoyl)pyrazine-2-carboxylate, is a gemcitabine prodrug synthesized by introducing the moiety of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl at the N4-position on the cytidine ring of gemcitabine. Our goal is to investigate the efficacy and the safety of this oral prodrug as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. The evaluation was accomplished by determining its inhibition of the growth of several tumors with gemcitabine administrated by injection as a control, and also by exploring its pharmacokinetics and its safety. In vivo, SL01 could effectively inhibit the growth of NCI-H460 human non-small cell lung cancer, MCF-7 human breast cancer, BxPC-3 human pancreatic cancer, ES-2 human bladder cancer, HepG2 human hepatocellular carcinoma cells and HCT-116 human colon adenocarcinoma cells in xenografts nude mice without loss their body weight significantly. After three weeks oral administration at the dosage of 30 umol/kg, the inhibition rates were 58.0%, 66.5%, 41.5%, 77.1%, 41.5% and 63.1%, respectively. Molecular analysis indicated that the high efficacy of SL01 was associated with its ability in inducing apoptosis, as evidenced by increase of TUNEL staining cells, activation of caspase-9, caspase-3 and cleaved poly ADP-ribose polymerase in tumor tissues. Pharmacokinetics studies indicated that SL01 exhibited a longer mean retention time and half-life than that of gemcitabine after oral administration in rat, further analysis showed that the bioavailability of SL01 was 22.1%, which indicating that the introduction of 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl moiety to gemcitabine could improve its bioavailability and reduce its first-pass metabolism. The metabolism analysis suggested that SL01 could transform into gemcitabine by hydrolyzing and then releasing into blood to keep the relatively long steady-state concentrations. Toxicity studies indicated that the LD50 was &gt;1.4 g/kg for its acute toxicity, and the tolerated dosage was 45 mg/kg for 4 weeks evaluation in rat. Based on these results, SL01 is proposed as a potent oral anticancer agent, which may supplant the use of gemcitabine in clinic. Acknowledgment: This project was supported by the Ministry of Science and Technology of China (2010ZX09401-302-2-07and 2011ZX09102-001-03).
Citation Format: Wenbao Li, Hua Yuan, Xianjun Qu. SL01, an oral gemcitabine prodrug as a potent anticancer drug. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2516. doi:10.1158/1538-7445.AM2014-2516
Abstract 2530: Optimization of 5,6-fused pyrimidine-based kinase inhibitors by computer-aided drug design for the treatment of AML
Authors: Hsu Yung Chang , Shiao Hui-Yi , Ke Yi-Yu , Hsu John T. A. , Lin Wen-Hsing , Chen Chun-Hwa , Hsieh Hsing-Pang 
Published: May 2015

Abstract
FMS-like receptor tyrosine kinase-3 (FLT3), a member of the class III tyrosine kinase receptor family, is expressed by immature hematopoietic cells, and highly associates with acute myeloid leukemia (AML). While acquired resistance to selective FLT3 inhibitors, the treatment became inefficient. Many literatures suggested that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML. Thus, utilizing dual FLT3-Aurora inhibitors may be the viable therapy for the treatment of AML.
Recently, our group reported a novel AURKA inhibitor by using high-throughput parallel synthesis and structure-based drug design (SBDD). Based on this, we wanted to modify the selective AURKA inhibitor to maintain its Aurora A inhibition as well as improve its FLT3 activity to develop dual FLT3-Aurora kinase inhibitors. Through rapid construction of the platform of FLT3 virtual screening, the lead was quickly and efficiently identified. Proceeding investigation of structure-activity relationship could lead to 6-phenyl pyrrolopyrimidine analogue, showing FLT3 inhibition with an IC50 of 101 nM as well as Aurora kinase A inhibition with an IC50 of 33 nM. To further increase the level of inhibition of FLT3, binding energy calculations and docking study of FLT3 model were introduced to select terminal groups of the side chain with high priority. The selected compounds were synthesized and evaluated the bioactivity. The dramatic antiproliferation of the dual FLT3-AURKA inhibitor against MOLM-13 and MV4-11 (FLT3-ITD (+) human AML cell lines) was observed, and its biologic mechanism of inhibition of FLT3 and Aurora kinase A was proved the by significant evidence of biomarker. For this finding, this novel inhibitor holds potential for further development of preclinical investigations as an anti-AML drug candidate.
Citation Format: Yung Chang Hsu, Hui-Yi Shiao, Yi-Yu Ke, John T. A. Hsu, Wen-Hsing Lin, Chun-Hwa Chen, Hsing-Pang Hsieh. Optimization of 5,6-fused pyrimidine-based kinase inhibitors by computer-aided drug design for the treatment of AML. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2530. doi:10.1158/1538-7445.AM2014-2530
Abstract 2554: DDX3X-specific effector T cells in small cell lung cancer patients reflect disease stage
Authors: Igarashi Natsue , Kagamu Hiroshi , Nozaki Koichiro , Shoji Satoshi , Okajima Masaaki , Miura Satoru , Watanabe Satoshi , Yoshizawa Hirohisa , Narita Ichiei 
Published: May 2015

Abstract
[Background] Small cell lung cancer (SCLC) possesses high tendency to disseminate. However, SCLC patients with paraneoplastic syndrome mediated by immunity against onconeural antigens remain in limited-stage disease (LD) without distant metastases. We previously demonstrated that effector-dominant CD4+ T cell balance was observed only in LD-SCLC but not in extended-stage disease (ED)-SCLC. CD4+ T cell balance in peripheral blood of SCLC patients reflected disease stage and recurrence.
Accumulating evidence suggests that most solid malignancies consist of heterogeneous tumor cells and that a relatively small subpopulation, which shares biological features with stem cells, is responsible for distant metastases and recurrence. We previously reported that DEAD/H (Asp-Glu-Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) is an immunogenic protein preferentially expressed in CD133+ murine melanoma cells exhibiting biological CSC features and that DDX3X-primed CD4+ T cells mediated potent antitumor therapeutic efficacy. We found that DDX3X is strongly expressed in small cell lung cancer (SCLC).
[Objectives] In the current study, we examine that DDX3X-specific effector T cells exist in SCLC patients.
[Patients and Methods] The present study comprised 20 consecutive SCLC patients, 5 long-term survivors, and 10 healthy volunteers from a single institution (Niigata University Medical and Dental Hospital). Specimens were collected after obtaining written informed consent approved by the Niigata University Ethical Committee.
[Results] Six of 12 LD-SCLC patients possessed DDX3X-responsive effector T cells. CD62Llow CD4+ effector T cells obtained from peripheral blood of 5 LD-SCLC secreted significantly more IFNγ upon DDX3X antigen stimulation in the presence of CD11c+ autologous dendritic cells. CD62Llow CD8+ effector T cells from one LD-SCLC patient responded to DDX3X. In contrast, effector T cells obtained from ED-SCLC patients or healthy volunteers never responded to DDX3X.
[Conclusion] DDX3X is likely one of major antigens that is expressed in SCLC and is recognized by T cell immune system. Antitumor immunotherapy to induce effector-dominant CD4+ T-cell immunity on DDX3X antigen may be a promising therapy to eliminate SCLC cells that mediate distant metastases.
Citation Format: Natsue Igarashi, Hiroshi Kagamu, Koichiro Nozaki, Satoshi Shoji, Masaaki Okajima, Satoru Miura, Satoshi Watanabe, Hirohisa Yoshizawa, Ichiei Narita. DDX3X-specific effector T cells in small cell lung cancer patients reflect disease stage. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2554. doi:10.1158/1538-7445.AM2014-2554
Abstract 2573: The immunocytokine NHS-IL12 as a potential cancer therapeutic
Authors: Fallon Jonathan K. , Tighe Robert , Lyon Amanda J. , Sabzevari Helen , Schlom Jeffrey , Greiner John W. 
Published: May 2015

Abstract
Targeted delivery of IL-12 might make this cytokine a safer, more effective cancer therapeutic. Here we evaluated whether fusing IL-12 to a tumor necrosis-targeting human IgG1 (NHS76) could improve its anti-tumor efficacy in vivo. In vivo imaging and immunohistochemistry staining were used to assess the ability of this novel immunocytokine (NHS-IL12) to target murine tumors. The anti-tumor efficacy of NHS-IL12 was examined at various doses and treatment schedules. Immune cell subset-depleting antibodies, flow cytometric methods, and in vitro cytotoxicity and ELISA assays were used to investigate the mechanisms of action of NHS-IL12. This immunocytokine was investigated in several models and in all cases NHS-IL12 outperformed recombinant IL-12 in anti-tumor activity. Depletion of immune cell subsets revealed that the anti-tumor activity depends primarily on CD8+ cells; mice that had complete tumor regression following NHS-IL12 treatment displayed durable anti-tumor memory responses. Combining NHS-IL12 treatment with a cancer vaccine, radiation, or chemotherapy resulted in greater anti-tumor effects than each individual therapy alone. These preclinical findings provide a rationale for the clinical testing of this immunocytokine, both as a single agent and in combination with vaccines, radiation, and chemotherapy. NHS-IL12 is currently being evaluated in a Phase 1 clinical trial (NCT01417546).
Citation Format: Jonathan K. Fallon, Robert Tighe, Amanda J. Lyon, Helen Sabzevari, Jeffrey Schlom, John W. Greiner. The immunocytokine NHS-IL12 as a potential cancer therapeutic. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2573. doi:10.1158/1538-7445.AM2014-2573
Abstract 2584: Complete regression and protective immune responses obtained in B16 melanomas after treatment with LTX-315 (Oncopore®)
Authors: Camilio Ketil André , Berge Gerd , Ravuri Chandra Sekhar , Rekdal Øystein , Sveinbjørnsson Baldur 
Published: May 2015

Abstract
Background: Malignant melanoma is the most aggressive and deadliest form of skin cancer, with a high mortality rate among late-stage melanoma patients. This calls for new and improved therapies within the field. Cationic antimicrobial peptides (CAPs) are naturally occurring molecules found in most species, in which they play a significant role in the first line of defense against pathogens, and several CAPs have shown promising anticancer activity. Structure-activity relationship studies on the CAP bovine lactoferricin has resulted in the design of a short chemically modified lytic anticancer peptide, LTX-315, which has potential as a new anticancer drug. Previous animal studies conducted with LTX-315 have demonstrated that intratumoral (i.t.) treatment of syngeneic murine A20 B-cell lymphomas and CT26WT colon carcinomas resulted in complete tumor regression. In the present study, we investigated the antitumor effects of LTX-315 against highly aggressive B16 melanomas in syngeneic mice. Methods: The cytotoxicity of LTX-315 was tested against a series of cell lines in vitro using the MTT assay. B16F1 melanoma cells (5 x 104) were intradermally inoculated into the abdomen of syngeneic C57BL/6N mice and established tumors treated i.t. with LTX-315. Tumor tissue and blood samples were taken for analysis to elaborate the mechanism of action of LTX-315 and for potential immune modulatory effects following i.t. treatment. Blood plasma was analyzed for IL 1β and IL 6 content and tumor tissue was analyzed for infiltrating immune cells and expression of pro-inflammatory cytokines using immunohistochemistry and real time qPCR, respectively. Results: LTX-315 rapidly kills B16 melanoma cells and induces the release of Danger-Associated Molecular Pattern molecules such as the High Mobility Group Box-1 protein in vitro. Intratumoral (i.t.) administration of LTX-315 resulted in tumor necrosis and the infiltration of immune cells into the tumor parenchyma followed by a complete regression of the tumor in the majority of the animals. Animals cured by LTX-315 treatment were protected against a re-challenge with live B16 tumor cells. Conclusions: Our results demonstrate that LTX-315 i.t. treatments with LTX-315 induces complete regression of solid B16F1 melanoma tumors, thus leading to local tumor control, followed by protective immune responses. Thus, LTX-315 has potential as a novel immunotherapeutic agent.
Citation Format: Ketil André Camilio, Gerd Berge, Chandra Sekhar Ravuri, Øystein Rekdal, Baldur Sveinbjørnsson. Complete regression and protective immune responses obtained in B16 melanomas after treatment with LTX-315 (Oncopore®). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2584. doi:10.1158/1538-7445.AM2014-2584
Abstract 2593: Multitargeted receptor tyrosine kinase inhibitors synergize with folate-hapten mediated immunotherapy in folate receptor positive cancers
Authors: Bandara Nimalka A. , Low Philip S. 
Published: May 2015

Abstract
The folate receptor (FR) which binds the vitamin folic acid with high affinity is overexpressed by a variety of human cancers including ovarian, endometrial, renal, and lung cancers. Consequently, the receptor has been exploited for the delivery of imaging agents and highly potent drugs exclusively to FR expressing tumors while avoiding uptake by the surrounding healthy tissue. This targeting mechanism can also be utilized for immunotherapy by vaccinating mice against a particular hapten in order to induce the production of anti-hapten antibodies and subsequently treating tumor bearing mice with a folate-hapten conjugate. The resulting reduction in tumor burden is achieved by antibody-dependent cellular cytotoxicity (ADCC). However, hapten mediated immunotherapy alone has been ineffective at controlling tumor progression over longer periods of time and requires supplementation with immunomodulatory cytokines for optimum therapeutic results. Several multitargeted receptor tyrosine kinase (RTK) inhibitors have recently shown promising synergy in a variety of different cancers when combined with other immunotherapies. Therefore, we examined the effect of combining the RTK inhibitors sunitinib and axitinib with folate-fluorescein therapy in tumor bearing mice that had previously been immunized against fluorescein. We report here that sunitinib synergizes with folate-fluorescein in both the L1210A lymphoma and the M109 lung cancer models resulting in slowed tumor progression, inhibition of tumor vasculature, and increased levels of circulating CD4+ and CD8+ T cells. The combination of axitinib with folate-fluorescein was only evaluated in mice bearing L1210A tumors and these mice have also demonstrated lower average tumor volumes than mice treated with either drug alone or not treated at all. These results suggest that RTK inhibitors play an important role in modulating the anti-tumor immunity of tumor bearing mice and could be a potent addition to ADCC mediated therapeutic approaches for cancers.
Citation Format: Nimalka A. Bandara, Philip S. Low. Multitargeted receptor tyrosine kinase inhibitors synergize with folate-hapten mediated immunotherapy in folate receptor positive cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2593. doi:10.1158/1538-7445.AM2014-2593
Abstract 2596: Suppression of lung cancer malignancy by peptides targeting MARCKS phosphorylation site domain: A comparative study
Authors: Chen Ching-Hsien , Statt Sarah , Thai Phillip , Lee Jasmine G. , Adler Kenneth B. , Yang Pan-Chyr , Wu Reen 
Published: May 2015

Abstract
We have recently reported elevated MARCKS phosphorylation (p-MARCKS) in lung cancer tissues but not in their adjacent normal non-cancer tissue sections. We have extended this study to a tumor tissue array from a cohort of 110 human patients with lung cancer. Immunohistochemistry results have shown a significant association of elevated p-MARCKS with advanced-stage, lymph node metastasis and malignant phenotypes of lung cancer, confirming the importance of p-MARCKS in lung cancer progression. To see if this newly discover biomarker can be a target for therapeutic treatment for the suppression of lung cancer malignancy, we have employed two peptides for this potential; one is the MANS peptide developed by our collaborator many years ago to target myristoylated N-terminal amino acid region for the control of airway mucus granule secretion, the other peptide is MPS that directly targets the MARCKS phosphorylation site domain. For MANS peptide, our recent publication has shown it is effective in blocking lung cancer cell migration and invasiveness in vitro as well as in vivo metastasis. A similar observation was seen for MPS peptide treatment. However, in contrast to MANS peptide, MPS treatment can directly block PIP3-dependent AKT signaling and repress lung tumor growth in vivo in addition to the suppression of metastasis, while MANS can only reduce cancer metastasis. These results support the initial notion on the involvement of p-MARCKS as a biomarker in lung cancer and the potential to target the phosphorylation site domain for controlling cancer progression. Our data have also suggested a direct targeting MARCKS phosphorylation site domain by MPS peptide is more effective in the suppression of lung cancer malignancy.
Citation Format: Ching-Hsien Chen, Sarah Statt, Phillip Thai, Jasmine G. Lee, Kenneth B. Adler, Pan-Chyr Yang, Reen Wu. Suppression of lung cancer malignancy by peptides targeting MARCKS phosphorylation site domain: A comparative study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2596. doi:10.1158/1538-7445.AM2014-2596
Abstract 2608: Dissecting Myc inhibition as a cancer therapy
Authors: Salisbury Nicholas J. H. , Wilson Catherine H. , Lu Dan , Littlewood Trevor D. , Evan Gerard I. 
Published: May 2015

Abstract
The MYC family of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors are critical for cell growth, proliferation and apoptosis. c-Myc is deregulated in most, if not all, cancers making it an attractive target for cancer therapy. Previously we have shown that Myc inhibition by a mutant c-Myc derivative, Omomyc, leads to tumor regression in several cancer models, notably in murine KRasG12D-driven lung adenocarcinomas. The mechanism by which Omomyc expression leads to tumor regression has not been fully elucidated, nor do we know the biochemical properties of a small molecule that could replicate Omomyc's activity. Therefore, we designed two novel Omomyc mutants (ΔMyc and MMO) that are hypothesised not to interact with the full Omomyc interactome but are still able to inhibit Myc transactivation. We subsequently created human lung adenocarcinoma cell lines (A549s) and transgenic mice which inducibly express Omomyc, ΔMyc and MMO. Unexpectedly Omomyc and ΔMyc inhibited proliferation in vitro but not MMO. In vivo, expression of the mutants has been detected and we are currently assessing their effect on KRasG12D-driven adenocarcinomas.
Citation Format: Nicholas J. H. Salisbury, Catherine H. Wilson, Dan Lu, Trevor D. Littlewood, Gerard I. Evan. Dissecting Myc inhibition as a cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2608. doi:10.1158/1538-7445.AM2014-2608
Abstract 2609: The role of focal adhesion kinase (FAK), PI3K/AKT and p53/mouse double minute 2 homologue (MDM2) complex in the pathobiology of Merlin-deficient tumors
Authors: Hanemann Clemens O. , Ammoun Sylwia , Schmid Marei C. , Zhou Lu 
Published: May 2015

Abstract
Deficiency of the tumor suppressor merlin leads to the development of schwannomas, meningiomas and ependymomas occurring spontaneously or as a part of a hereditary disease Neurofibromatosis type 2 (NF2). Another tumor suppressor/transcription factor p53 regulates proliferation, survival and differentiation. P53 deficiency/inactivation correlates with tumor development and can be negatively regulated by FAK, PI3K/AKT and MDM2 and possibly positively by merlin and JNK in different models. The function of p53 in merlin deficient tumors is not known. Using our in vitro model of primary human schwannoma cells we demonstrated that FAK is overexpressed/activated and localises to the nucleus in schwannoma cells leading to increased proliferation. AKT is strongly activated via PDGF- and IGF-I- receptors increasing survival. Here we investigated p53 regulation and its role in proliferation and survival of human primary schwannoma cells. p53 is downregulated and MDM2 upregulated in human schwannoma cells leading to increased proliferation and survival. p53 is regulated by merlin involving JNK FAK, AKT and MDM2. Thus merlin potentiates p53 activity and when using Nutlin-3 this increases p53 stability and total levels of p53 in schwannoma cells decreasing proliferation and survival. These findings are important to dissect mechanisms responsible for development of merlin-deficient tumors and identification of therapeutic targets.
Citation Format: Clemens O. Hanemann, Sylwia Ammoun, Marei C. Schmid, Lu Zhou. The role of focal adhesion kinase (FAK), PI3K/AKT and p53/mouse double minute 2 homologue (MDM2) complex in the pathobiology of Merlin-deficient tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2609. doi:10.1158/1538-7445.AM2014-2609