bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5330: Methioninase-loaded erythrocytes: a promising drug for L-methionine restriction therapy in cancer
Authors: Gay Fabien , Bes Julie , Bourgeaux Vanessa , Godfrin Yann 
Published: August 2015

Abstract
Several studies reported a complete dependence of different tumor cells on L-methionine (Met), an essential amino acid, for maintaining their high proliferation rate while normal cells keep their ability to grow on Met-deprived medium (Cavuoto and Fenech, 2012).
Met restriction appearing as an important strategy for cancer treatment, different therapeutic approaches using either Met restricted regimens or Met-catabolizing enzymes were investigated.
Phase I and II clinical trials associating dietary Met restriction with chemotherapy were conducted with cancer patients (Thivat et al., 2009; Durando et al, 2010). A 40% reduction of plasmatic methionine was achieved with a 1-day Met-free diet per month. Interesting long-duration of disease stabilization was observed in some patients. However this diet is extremely difficult to maintain.
In order to obtain longer Met depletion in plasma, enzyme therapy using Methionine gamma-lyase (MGL), a pyridoxal-dependent enzyme that specifically degrades Met into alpha-ketobutyrate, ammonia and thiols, was explored. MGL enzyme isolated from Pseudomonas putida was selected as preferred candidate for the development of therapy. However, preclinical studies conducted in primates showed a very short half-life of the active form of MGL enzyme (2h) due to a rapid in vivo dissociation of the pyridoxal (PLP) cofactor (Yang et al., 2004).
To overcome this problem of PLP-dissociation, we encapsulated the active MGL into erythrocytes, natural pool of PLP in the body and evaluated PK-PD parameters of product over a 5-day period in a mouse model. Once entrapped into erythrocytes, the MGL enzyme maintained more than 30% of its specific activity after 5 days in circulation. A 60-70% Met depletion was achieved 15 min post-injection and then depletion was stabilized at 40% over the 5 day-period of the study. In comparison, administration of the free MGL at similar doses led to a rapid loss of the active form in several hours. Met was totally deprived 15 min post-injection but plasmatic Met level returned to baseline by 24h. Increasing two-fold the concentration of free methioninase did not improved the in vivo Met depletion.
In conclusion, we report that methioninase-loaded-erythrocytes can lower Met concentration in mouse plasma for at least 5 days and may be an innovative strategy to kill tumors by met-starvation.
Citation Format: Fabien Gay, Julie Bes, Vanessa Bourgeaux, Yann Godfrin. Methioninase-loaded erythrocytes: a promising drug for L-methionine restriction therapy in 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 5330. doi:10.1158/1538-7445.AM2015-5330
Abstract 5336: Improved antitumor effect of combining WNT/beta-catenin inhibition with sorafenib in hepatocellular carcinoma
Authors: Lin Hsiao-Hui , Feng Wen-Chi , Lu Li-Chun , Shao Yu-Yun , Cheng Ann-Lii , Hsu Chih-Hung 
Published: August 2015

Abstract
[Background] Sorafenib is currently the only approved systemic agent for advanced hepatocellular carcinoma (HCC); however, its efficacy is limited. Aberrant activation of WNT/β-catenin signaling pathway has been shown to mediate resistance to various types of anti-cancer therapy. We hypothesized that inhibition of WNT/β-catenin signaling pathway would improve the anti-tumor effect of sorafenib in HCC.
[Materials and Methods] Human HCC cell lines, including Huh7, HepG2, PLC5, and Hep3B, were included. Inhibition of WNT/β-catenin pathway was achieved by ICG-001, a small molecule disrupting the interaction of cAMP-responsive element binding (CREB)-binding protein (CBP) and β-catenin and inhibiting the β-catenin-mediated transcription activities, or by RNA interference (RNAi)- downregulation of β-catenin. The efficacy of sorafenib combined with WNT/β-catenin pathway inhibition in HCC cells was determined by MTT for cell viability, and by flow cytometry and Western blotting for apoptosis. The in vivo efficacy was evaluated in a subcutaneous xenograft mode of Huh7 cells.
[Results] In multiple HCC cell lines, ICG-001 enhanced the anti-proliferative effect of sorafenib dose-dependently; the combination of ICG-001 and sorafenib showed a synergistic antitumor effect. Downregulation of β-catenin by RNAi increased sorafenib sensitivity, whereas overexpression of β-catenin decreased sorafenib sensitivity in Huh7 cells. Furthermore, the sorafenib-sensitization effect by short hairpin RNA (shRNA)-mediated β-catenin downregulation in Huh7 cells was offset by β-catenin overexpression. Mechanistically, sorafenib in combination of ICG-001 or shRNA- mediated β-catenin downregulation augmented the induction of apoptosis, and resulted in a more prominent downregulation of Mcl-1 in HCC cells. Finally, ICG-001 in combination of sorafenib showed a more significantly growth-retarding effect in Huh7 xenograft than either drug alone.
[Conclusion] Our data indicate that inhibition of WNT/β- catenin signaling pathway improves the antitumor effect of sorafenib against HCC in vitro and in vivo.(This study was supported by grants NRPB-100CAP1020-2 and NSC-101-2314-B-002-141, 100CAP1020-2).
Citation Format: Hsiao-Hui Lin, Wen-Chi Feng, Li-Chun Lu, Yu-Yun Shao, Ann-Lii Cheng, Chih-Hung Hsu. Improved antitumor effect of combining WNT/beta-catenin inhibition with sorafenib in hepatocellular 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 5336. doi:10.1158/1538-7445.AM2015-5336
Abstract 5345: Enhanced inhibition of PC-3 xenograft prostate tumor growth by combination of green tea and quercetin with docetaxel
Authors: Wang Piwen , Henning Susanne , Heber David , Vadgama Jaydutt 
Published: August 2015

Abstract
Chemotherapy with docetaxel (Doc) is a standard treatment for metastatic and castration-resistant prostate cancer. However, the development of chemoresistance and its side effects limit the clinical success of Doc. Previously we demonstrated that the combined use of natural products green tea (GT) and quercertin (Q) with Doc synergistically enhanced the anti-proliferative effect in androgen-independent prostate cancer PC-3 cells. The objective of the present study was to confirm the combined effect of GT, Q and Doc in xenograft prostate cancer mouse models and determine underlying mechanisms. Male severe combined immunodeficiency (SCID) mice (n = 10 per group) were inoculated with 5×105 PC-3 cells subcutaneously. When tumors reached a size of about 100mm3 the intervention started. Mice were administered with GT+Q, Doc 5mg/kg (LD), GT+Q+LD Doc, Doc 10mg/kg (HD) or control. The concentration of GT polyphenols in brewed tea administered as drinking water was 0.07% and Q was supplemented in diet at 0.4%. Doc was given through tail vein once a week for 4 weeks. There was a nonsignificant inhibition of tumor growth by GT+Q or LD Doc alone compared to control. However the combination treatment with GT+Q+LD Doc significantly inhibited the tumor growth by 62% compared to LD Doc alone after 7 weeks intervention. The combined effect was comparable to that by HD Doc treatment. Western blot analysis demonstrated a significantly increased ratio of Bax to Bcl-2 protein expression by GT+Q+LD Doc treatment compared to GT+Q or LD Doc. ELISA analysis of blood samples demonstrated that the combination treatment significantly decreased the blood concentrations of several growth factors, including VEGF, EGF, TGF-β, FGF-β, and TNF-α compared to GT+Q or LD Doc alone. A liver toxicity evaluation revealed that the blood alanine aminotransferase (ALT) level was significantly elevated with HD Doc treatment compared to control, while not changed by other groups. Further mechanistic investigations using protein array and tissue microarray assays are ongoing. This study provides a promising regimen by combining GT and Q with Doc to enhance chemotherapeutic effect in advanced prostate cancer in a less toxic manner. The results warrant future clinical trials to confirm the combined effect of the mixture in humans.
Citation Format: Piwen Wang, Susanne Henning, David Heber, Jaydutt Vadgama. Enhanced inhibition of PC-3 xenograft prostate tumor growth by combination of green tea and quercetin with docetaxel. [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 5345. doi:10.1158/1538-7445.AM2015-5345
Abstract 5357: Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin for cancer therapy
Authors: Ali-Rahmani Fatima G. , Fitzgerald David , Martin Scott , Patel Paresma , Thomas Craig , Pastan Ira 
Published: August 2015

Abstract
Discoidin domain receptor 1 (DDR1) is an emerging anti-cancer target that belongs to the family of tyrosine kinases that are activated by collagen, the most abundant component of extracellular matrix (ECM). Collagen mediated induction of DDR1 facilitates cell adhesion, migration, proliferation and matrix remodeling. The collagen/DDR1 axis is also thought to modulate tumor-stromal interaction and potentially can affect tumor response to therapy. Mesothelin is a cell-surface tumor-associated antigen over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a clinically optimized recombinant immunotoxin (RIT) being developed in collaboration with Roche that should enter clinical trials late this year. It consists of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A in which immunogenic B cell epitopes are silenced. Activation of tyrosine kinase mediated signaling in tumor cells has been shown to modulate the activity of RITs. Therefore, we hypothesized that DDR1 regulates RIT activity and its inhibition might enhance the activity of RG7787. Knockdown of DDR1 by siRNA or its inhibition with a novel and specific inhibitor, ‘7rh’, synergistically enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed the knockdown of DDR1 increased mesothelin expression, internalization of RG7787, and enhanced inhibition of protein synthesis. Furthermore, stimulation of DDR1 activity by collagen treatment protected cancer cells from killing by RG7787. However, this collagen mediated resistance of cancer cells to RIT therapy can be overcome by addition of 7rh. Combination of 7rh with RG7787 synergistically inhibited growth of A431/H9 tumors in nude mice. In conclusion, we report that collagen protects cells from killing by RITs through DDR1 and that lowering DDR1 protein or inhibiting DDR1 kinase activity enhances the cytotoxic activity of RITs. Our data suggest that the combination of ‘7rh’ and RG7787 represents a novel therapeutic strategy to target mesothelin-expressing cancers. These data also provide insight into how tumor stroma might be protecting cancer cells from therapy.
Citation Format: Fatima G. Ali-Rahmani, David Fitzgerald, Scott Martin, Paresma Patel, Craig Thomas, Ira Pastan. Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin for cancer therapy. [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 5357. doi:10.1158/1538-7445.AM2015-5357
Abstract 5379: A potent EZH2 inhibitor exhibits long residence time and anti-tumor activity
Authors: Ott Heidi , van Aller Glenn , Ward Jessica , Le BaoChau , Rominger Cynthia , Foley James , Korenchuk Susan , McHugh Charles , Butticello Michael , Blackledge Charles , Brackley James , Burgess Joelle , Duquenne Celine , Johnson Neil , Kasparec Jiri , LaFrance Louis , Li Mei , McNulty Kenneth , Newlander Kenneth , Romeril Stuart , Schmidt Stanley , Schulz Mark , Su Dai-Shi , Suarez Dominic , Tian Xinrong , Carpenter Christopher , Luengo Juan , Kruger Ryan , Knight Steven , McCabe Michael T. 
Published: August 2015

Abstract
The EZH2 histone methyltransferase is frequently mutated in diffuse large B-cell lymphoma leading to increased trimethylation of histone H3 lysine 27 (H3K27me3). Drug discovery efforts have previously identified a pyridone-based chemical series of EZH2 inhibitors that potently and selectively inhibit EZH2 catalytic activity. These compounds are capable of globally decreasing H3K27me3 levels, de-repressing EZH2 target genes, and inducing growth inhibition of many lymphoma cell lines both in cell culture and in vivo. Through medicinal chemistry optimization, we have developed EZH2 inhibitors with significantly improved potency in both biochemical and cellular assays. These compounds exhibit a prolonged enzyme residence time that can be further extended in vitro through the addition of an H3K27me3 peptide. Herein, we report the biochemical and cellular activity of these new EZH2 inhibitors.
Citation Format: Heidi Ott, Glenn van Aller, Jessica Ward, BaoChau Le, Cynthia Rominger, James Foley, Susan Korenchuk, Charles McHugh, Michael Butticello, Charles Blackledge, James Brackley, Joelle Burgess, Celine Duquenne, Neil Johnson, Jiri Kasparec, Louis LaFrance, Mei Li, Kenneth McNulty, Kenneth Newlander, Stuart Romeril, Stanley Schmidt, Mark Schulz, Dai-Shi Su, Dominic Suarez, Xinrong Tian, Christopher Carpenter, Juan Luengo, Ryan Kruger, Steven Knight, Michael T. McCabe. A potent EZH2 inhibitor exhibits long residence time and anti-tumor activity. [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 5379. doi:10.1158/1538-7445.AM2015-5379
Abstract 5389: Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation
Authors: Hong Soon-Sun , Kim Soo Jung , Jung Kyung Hee , Yan Hong Hua , Fang Zhenghuan , Lim Joo Han , Ryu Jeong Seon 
Published: August 2015

Abstract
Chronic myeloid leukemia (CML) is characterized by a constitutive activation of Bcr-Abl tyrosine kinase. Bcr-Abl/T315I is the predominant mutation that causes resistance to Imatinib. In the present study, we synthesized a novel Bcr-Abl inhibitor, HS-543, and investigated its effect on cell survival or apoptosis in CML cells bearing Bcr-Abl/T315I (BaF3/T315I) or wild-type Bcr-Abl (BaF3/WT). HS-543 showed anti-proliferative effects in the BaF3/WT cells as well as the BaF3/T315I cells with resistance to Imatinib and strongly inhibited the Bcr-Abl signaling pathways in a dose dependent manner. Furthermore, it significantly increased the sub G1 phase associated with early apoptosis, with increased levels of cleaved PARP and caspase-3, as well as the TUNEL-positive apoptotic cells. In addition, we found that HS-543 induced apoptosis with the loss of mitochondrial membrane potential by decreasing the expression of Mcl-1 and survivin, together with increasing the expression of Bax. In BaF3/T315I xenograft models, HS-543 significantly delayed tumor growth, unlike Imatinib. Our results demonstrate that HS-543 exhibits the induction of apoptosis and anti-proliferative effect by blocking the Bcr-Abl signaling pathways in the T315I-mutated Bcr-Abl cells with resistance to Imatinib. We suggest that HS-543 may be a novel promising agent to target Bcr-Abl and overcome Imatinib resistance in CML patients.
Citation Format: Soon-Sun Hong, Soo Jung Kim, Kyung Hee Jung, Hong Hua Yan, Zhenghuan Fang, Joo Han Lim, Jeong Seon Ryu. Novel kinase inhibitor for imatinib-resistant chronic myeloid leukemia with T315I mutation. [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 5389. doi:10.1158/1538-7445.AM2015-5389
Abstract 5407: T-type Ca2+ channel inhibitors sensitize ovarian cancer to carboplatin through downregulation of survivin gene expression
Authors: Dziegielewska Barbara , Casarez Eli V. , Yang Wesley Z. , Dziegielewski Jaroslaw , Slack-Davis Jill K. 
Published: August 2015

Abstract
Recent studies by our group and others have shown that T-type Ca2+ channels play a reinforcing role in cancer cell proliferation, cell cycle progression and apoptosis evasion. We have demonstrated drug cooperativity between T-type Ca2+ channel inhibitor, mibefradil and carboplatin in vivo in ovarian cancer xenografts. To investigate the molecular mechanism by which T-type Ca2+ channels affect tumor growth, we used a panel of ovarian cancer cell lines together with mibefradil or small interfering RNA (siRNA) to silence the T-channels gene expression. Inhibition of T-type Ca2+ channels with mibefradil or by silencing expression resulted in growth suppression in ovarian cancer with simultaneous increase in apoptosis and decrease in expression of the anti-apoptotic gene survivin (BIRC5). Combining carboplatin with mibefradil resulted in increased apoptosis. Analysis of intracellular signaling revealed T-type Ca2+ channel inhibitors induced changes in the levels of FOXO proteins, which regulate BIRC5 gene expression. Mibefradil treatment caused greater nuclear retention of FoxO1 and FoxO3a, two transcription factors that repress BIRC5 expression, while protein expression of the transcription factor that activates BIRC5 expression, FoxM1, decreased. Chromatin immunoprecipitation of FOXO proteins from mibefradil treated ovarian cancer cells demonstrated binding of FoxM1 and FoxO1 within the BIRC5 (survivin) promoter. Together, the data show that T-type Ca2+ channels support ovarian cancer cell cycle, proliferation and regulate pro-survival pathways through the FOXO-survivin signaling axis, which has been reported to be deregulated in ovarian cancer. Moreover, our results provide the rationale for future use of T-type antagonists as sensitizing agents in combination with standard chemotherapeutics.
Citation Format: Barbara Dziegielewska, Eli V. Casarez, Wesley Z. Yang, Jaroslaw Dziegielewski, Jill K. Slack-Davis. T-type Ca2+ channel inhibitors sensitize ovarian cancer to carboplatin through downregulation of survivin gene expression. [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 5407. doi:10.1158/1538-7445.AM2015-5407
Abstract 5423: Identification of immunotargets in Hedgehog medulloblastoma for immunotherapy
Authors: Tan Grace S. , Curran Tom 
Published: August 2015

Abstract
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Although approximately 75% of patients survive with current therapies, the associated complications drastically affect their quality of life, including severe neurological impairment and secondary cancers.
Approximately 30% of MB cases exhibit activated hedgehog signaling pathway (HH-MB). Recent clinical trials using small molecular HH inhibitors exhibit promising results. Unfortunately, there are also indications of high rates of resistance and relapses, affirming the pressing need to develop complimentary therapies.
Although immunotherapy has previously been proposed to treat MB, unique antigens are rare and monoclonal antibody therapies may not ensure tumor cytotoxicity, without additional adjuvants and associated severe side effects. However, recent successful developments of various cancer immunotherapies, especially the chimeric antigen receptor modified T-cell therapy, have rekindled interest in MB immunotherapies.
To address the heterogeneity of MB and to develop a precision immunotherapy, we propose to identify uniquely or differentially overexpressed cell surface proteins in HH-MB, using human MB microarray and RNA-Seq data. Our preliminary studies have identified 39 potential candidates that are differentially expressed in HH-MB. We are currently confirming the presence and cellular localization of these candidate proteins using human MB tissue microarrays.
This work is supported by NIH (T32 HL07915 [GST]) and Stand Up To Cancer - St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research.
Citation Format: Grace S. Tan, Tom Curran. Identification of immunotargets in Hedgehog medulloblastoma for immunotherapy. [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 5423. doi:10.1158/1538-7445.AM2015-5423
Abstract 5439: Development of a robust reporter-based T-cell activation assay for bispecific therapeutic antibodies in immunotherapy
Authors: Stecha Pete , Grailer Jamison , Cheng Zhi-jie Jey , Hartnett Jim , Fan Frank , Cong Mei 
Published: August 2015

Abstract
Bispecific T-cell Engager (BiTE), which simultaneously targets CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, has emerged as a promising immunotherapy approach to treat cancer. Current methods for bispecific antibody potency determination measure T-cell proliferation or cytokine release using primary peripheral blood mononuclear cells. They can be complex and highly variable. Here we report the development of a reporter-based T cell activation assay using two Jurkat cell lines stably expressing luciferase reporter driven by IL-2 promoter or NFAT-response element. Both Jurkat reporter cell lines showed robust reporter signal upon stimulation of crossed-linked CD3 antibody. These cell lines were developed in Thaw-and-Use format and showed similar assay performance as that from the cells fresh-from-culture. When tested with bispecific therapeutic antibody catumaxomab, we showed specific reporter response by co-culturing Jurkat reporter cells with cancer target cells endogenously expressing EpCAM, such as MDB-MA-231 and SK-BR-3 cells. No signal was observed without target cells or with EpCAM negative Raji cells. The assay can measure the relative potency for catumaxomab with good precision. It also can detect changes in biological activity for catumaxomab in stressed stability study, and therefore has appropriate stability-indicating property. In summary, the reporter-based T cell activation assay provides a simple and robust approach to quantitatively measure antibody potency for bispecific antibody. It can potentially serve as a potency bioassay for bispecific therapeutic antibodies during drug development and manufacture.
Citation Format: Pete Stecha, Jamison Grailer, Zhi-jie Jey Cheng, Jim Hartnett, Frank Fan, Mei Cong. Development of a robust reporter-based T-cell activation assay for bispecific therapeutic antibodies in immunotherapy. [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 5439. doi:10.1158/1538-7445.AM2015-5439