bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4689: Anti-proliferative effect and tumor targeting properties of SurVaxM-derived monoclonal antibodies
Authors: Ciesielski Michael J. , Figel Sheila , Wiltsie Laura , Galbo Phillip , Frank Cheryl , Fenstermaker Robert A. 
Published: July 2017

Abstract
Background: Survivin is an inhibitor of apoptosis protein (IAP) which is upregulated in many cancers. SurVaxM (active anti-survivin immunotherapy) is currently being evaluated in a multi-center phase II clinical trial. Circulating anti-survivin antibodies were recently detected in recurrent glioblastoma patients who received SurVaxM immunizations in a previous phase I study. Though primarily functioning as an intracellular molecule, survivin has also been identified in patient serum, and, recently, in tumor-derived exosomes.
Methods: Patients in the completed SurVaxM phase I clinical trial produced both antibody and CD8+ T cell responses against survivin. In order to gauge whether antibodies to the vaccine provided any therapeutic benefit, or might serve as potential biomarkers for SurVaxM responsiveness, we tested these antibodies in pre-clinical tumor models. Murine hybridomas derived from the SurVaxM peptide were established and purified yielding several high-affinity IgG antibodies. These antibodies were characterized for target recognition and therapeutic potential.
Results: Two of the clones with the highest affinities, 2C2 (IgG2a) and H30 (IgG1), recognized both SurVaxM peptide and the wild type survivin counterpart (ELISA assay), as well as endogenous, full-length survivin (western blotting). Survivin was detected on cells with these antibodies using both immunofluorescence and flow cytometry. Following s.c. implantation of glioblastoma (GL261) and melanoma (B16) tumors in immuno-competent C57BL/6 mice, administration of 2C2 and H30 antibodies (i.p. injection) reduced tumor growth in both models compared to an irrelevant IgG. An orthotopic intracranial glioma study showed similar anti-tumor effects when treated with SurVaxM-derived antibodies. Tumor growth was also inhibited in immuno-compromised (nude) animals treated with 2C2 or H30 antibodies, although to a lesser extent.
Conclusions: Antibodies generated in response to the SurVaxM vaccination are highly cross-reactive to survivin and provide therapeutic benefit in immuno-competent mouse tumor models. These antibodies retain some efficacy in immuno-compromised models, indicative of a direct T-cell independent effect. An anti-tumor response through anti-survivin targeted antibodies is unexpected as surface-accessible survivin expression has not yet been well described in the literature. Data presented here highlight possible avenues for investigation of mechanism(s) of action.
Citation Format: Michael J. Ciesielski, Sheila Figel, Laura Wiltsie, Phillip Galbo, Cheryl Frank, Robert A. Fenstermaker. Anti-proliferative effect and tumor targeting properties of SurVaxM-derived monoclonal antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4689. doi:10.1158/1538-7445.AM2017-4689
Abstract 469: Microrna signature as a potential biomarker for predicting survival in colon cancer
Authors: Jacob Havjin , Stanisavljevic Luka , Storli Kristian Eeg , Dahl Olav , Myklebust Mette Pernille 
Published: July 2017

Abstract
Background: Colon cancer is one of the most common cancers with increasing incidence and high mortality worldwide. Prognosis and choice of treatment is largely based on the tumor stage at presentation. Thus, finding novel biomarkers for predicting survival is highly desirable. Lately, several studies have been looking at microRNAs (miRNAs) in several cancers, including colon cancer. MicroRNAs are conserved, non-coding RNA molecules that play an important role in the regulation of post-transcriptional gene expression.
Material and Methods: In the present study, we have profiled miRNA in one hundred and seventy two TNM stage I-IV colon cancer patients and 10 corresponding normal colon tissue samples. Total RNA was extracted from freshly frozen tissues, and the expression of miRNA profile were assessed using Pick and Mix focus panels from Exiqon containing 84 miRNAs that have been linked to cancer.
Results: The results were visualized in a heatmap (Qlucore omics Software) and more than 20 miRNAs were found to be differentially expressed in tumors compared to the normal colon. Further, twelve miRNAs were found to discriminate between relapse and no-relapse patients in TNM- stage II and III, and four of these miRNAs (miR-23a, miR-25, miR-30d and miR-31) were found to be statistically significant in binary logistic regression with relapse as outcome variable. In univariate analysis, low expression of the four-miRNA signature was associated with better 3-year disease-free survival (DFS), 88 % versus 63% in low versus high signature, respectively (P=0.001). Moreover, the signature was a predictor of poor relapse-free survival in multivariate analyses (P=0.001; HR 31; 95% CI: 3.8-248.9). Another regression analyses method (LASSO) identified a 16-miRNA signature, and the four miRNAs found earlier were among them. The 16-miRNA signature was associated with better survival (P&lt;0.001).
Conclusion: The present study has identified a four-miRNA signature predicting relapse in colon cancer stage II and III patients.
Citation Format: Havjin Jacob, Luka Stanisavljevic, Kristian Eeg Storli, Olav Dahl, Mette Pernille Myklebust. Microrna signature as a potential biomarker for predicting survival in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 469. doi:10.1158/1538-7445.AM2017-469
Abstract 4693: Fc effector bioassays enable faster and quantitative measurement of ADCC and ADCP mechanisms of action
Authors: Cheng Zhi-Jie Jey , Moravec Rich , Paguio Aileen , Garvin Denise , Krishnan Gopal B. , Fan Frank , Cong Mei 
Published: July 2017

Abstract
Antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cell-mediated phagocytosis (ADCP) are recognized as important mechanisms of action (MOA) of therapeutic antibodies. Primary peripheral blood mononuclear cells (PBMCs) are routinely used in traditional bioassays to measure potency, stability of antibody drugs in ADCC and ADCP. However these methods are labor intensive and highly variable. Here we report the development of a luciferase-based reporter assay that measures activation of effector cells via cross-linking of Fc receptors with target cell-bound antibodies. We will discuss functional cell-based Fc effector reporter bioassays developed to measure Human FcgRIIIa (V158 and F158 variants), Human FcgRIIa (H131 and R131 variants), Human FcgRI as well as Mouse FcgRIV and FcgRIII. Compared to primary cell-based assays these reporter bioassays are less variable, easier to use and provide more consistent analysis of the important MOAs that are critical to for drug development programs. In qualification studies, performed in accordance with ICH guidelines for antibody screening and characterization, we tested the bioassays for specificity, accuracy, precision and linearity.
Citation Format: Zhi-Jie Jey Cheng, Rich Moravec, Aileen Paguio, Denise Garvin, Gopal B. Krishnan, Frank Fan, Mei Cong. Fc effector bioassays enable faster and quantitative measurement of ADCC and ADCP mechanisms of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4693. doi:10.1158/1538-7445.AM2017-4693
Abstract 4701: Blocking FSTL1 ameliorates immunity against osteosarcoma
Authors: Kudo-Saito Chie , Ogiwara Yamato , Aoki Kazunori 
Published: July 2017

Abstract
Purposes: Osteosarcoma is a rare malignant tumor of bone in children and young adults, and it is very hard to successfully control the systemic metastases and life-threatening health problems more than a decade after the completion of the care due to the intensiveness of the conventional treatments including surgical resection of the primary tumor and chemotherapy. Therefore, non/low-toxic but advanced treatments have been expected for a long while. We recently found that a BMP family FSTL1 is highly and functionally expressed in murine and human osteosarcoma cell lines, and systemically expands pluripotent mesenchymal stem/stromal cells (MSCs), which play a central role in amplification of tumor heterogeneity that is consequence of reciprocal evolution together with the tumor microenvironment, including induction of immune suppression and dysfunction, desmoplasia, and angiogenesis. FSTL1 and its induced MSCs also directly confer higher invasive and metastatic properties on tumor cells leading to further cancer progression. In this study, we evaluated antitumor efficacy induced by anti-FSTL1 mAb on murine osteosarcoma models, and also compared the therapeutic efficacy with those induced by immune checkpoint inhibitory mAbs (ICIs).
Results: We used two syngeneic tumor models that were subcutaneously implanted with murine osteosarcoma NHOS cells in BALB/c mice, or LM3 cells in C3H mice. These mice were intraperitoneally injected with anti-FSTL1 mAbs (10mg/kg) twice on day 5 and day 8 after tumor implantation, and were sacrificed for immunological analysis of tumor-infiltrating cells, spleen cells and bone marrow cells on day 15. In both osteosarcoma models, CD45- MSCs as well as other immunosuppressive CD4+Foxp3+ Tregs and CD11b+Gr1+ MDSCs systemically increased, indicating impairment of antitumor immunity in the mice. Treatment with the anti-FSTL1 mAb significantly induced potent tumor-specific CTLs through reduction of MSCs, resulting in tumor-free in some of the treated mice. Although the antitumor efficacy was similar to those induced by ICIs, the mode of action was totally distinct because MSCs and the MSC-inducible exhausted CD8+PD1+Tim3+ T cells were reduced only in the anti-FSTL1-treated mice, but not in the ICI-treated mice.
Conclusions: These results suggest that blocking FSTL1 properly reprograms immunity toward elimination of osteosarcoma by reducing the tumor-supportive MSCs. Anti-FSTL1 mAb may be a promising drug for treating osteosarcoma more moderately but effectively in clinical settings.
Citation Format: Chie Kudo-Saito, Yamato Ogiwara, Kazunori Aoki. Blocking FSTL1 ameliorates immunity against osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4701. doi:10.1158/1538-7445.AM2017-4701
Abstract 4709: Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition
Authors: Kaneko Kensuke , Osada Takuya , Haystead Timothy A. , Morse Michael A. , Lyerly Herbert K. 
Published: July 2017

Abstract
Background: Immunotherapy has become an emerging anti-cancer therapy, as immune checkpoint blockade with PD-1 or PD-L1 inhibition have been active against multiple cancer types. Nonetheless, there remain many non-responders, suggesting that combinations may improve activity, particularly combinations which can target tumors and have low toxicity. Methods & Results: We have developed a novel Hsp90 targeted photodynamic therapy (Hsp90-PDT), which causes local anti-tumor responses. Hsp90-PDT can be combined with immune checkpoint blockade to generate potent anti-tumor effects. We synthesized well characterized PDT agent, verteporfin (VP) tethered to a HSP90 small molecule inhibitor, to create a Hsp90-PDT agent (Hsp90i-VP). We first compared the uptake of VP and Hsp90i-VP into the breast cancer cell lines (E0771-OVA) in vitro. Hsp90i-VP showed stronger incorporation than VP when the compounds were added 3μM or less in concentration. We next performed in vitro and vivo PDT with Hsp90i-VP and laser exposure (690 nm wavelength). Killing efficiency of VP and Hsp90i-VP was analyzed by MTT assay, which showed increased killing in a dose dependent manner for both photosensitizers (0-30µM) and laser (0-120J/cm2). Next, we treated E0771-OVA tumor-bearing C57BL/6 mice with Hsp90i-VP (25nmol/mouse) administration alone, laser irradiation (240J/cm2) alone, or the combination of Hsp90i-VP and laser. Suppression of the tumor growth was confirmed only in Hsp90i-VP and laser group. In addition, induction of tumor-specific immune response by PDT was confirmed by ELISA, where the elevation of anti-OVA antibody was seen only in PDT group. Furthermore, combination treatment of Hsp90-PDT and anti-PD-L1 mAbs was able to enhance cytotoxic T-cell response and suppress tumor growth significantly even with relatively PDT-resistant cell line. Conclusions: Hsp90-PDT showed a significant ability to induce antigen-specific immune response in both in vitro and in vivo. These results suggest that Hsp90-PDT can play an important role in anti-cancer immune therapy. Our future plan is to investigate the effect of local photodynamic therapy combined with various types of checkpoint inhibitor in breast cancer models.
Citation Format: Kensuke Kaneko, Takuya Osada, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly. Induction of enhanced tumor-specific immunity by Hsp90 targeted photodynamic therapy (Hsp90-PDT) combined with immune checkpoint inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4709. doi:10.1158/1538-7445.AM2017-4709
Abstract 472: Role of miRNAome deregulation in the pathogenesis of non-alcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma
Authors: Ortega Juliana F. , DeConti Aline , Dreval Kostiantyn , Moreno Fernando S. , Beland Frederick A. , Pogribny Igor P. 
Published: July 2017

Abstract
Recent epidemiological studies have attributed the growing incidence of liver cancer, including hepatocellular carcinoma (HCC), in the United States to NASH, an advanced form of non-alcoholic fatty liver disease. Elucidating the molecular pathways that lead to the development of NASH-derived HCC is critical not only for identifying early diagnostic biomarkers of the disease, but also for treatment and prevention. We have investigated the role of microRNAs (miRNAs) in the development of NASH-derived HCC by using a Stelic Animal Model (STAM) of liver carcinogenesis. Using Liver miFinder PCR arrays, we examined the miRNA profiles in the livers of STAM mice and identified 25 and 35 miRNAs that were differentially expressed at a NASH-fibrotic stage (12 weeks) and in full-fledged HCC (20 weeks), respectively. Among these differentially expressed miRNAs, 18 miRNAs were in common. Multi-algorithm target prediction analysis of the common differentially expressed miRNAs revealed the involvement of these miRNAs in the deregulation of major molecular processes associated with the development of HCC, including epithelial-mesenchymal transition, HCC stem cell activation, and the induction of the β-catenin/Wnt and Hippo signaling pathways. These findings were confirmed by a marked up-regulation of Yes-associated protein 1 (YAP1), the main effector of the Hippo-pathway, the activation of epithelial-mesenchymal transition, and an increased-expression of hepatic progenitor cell markers. In addition to the common differentially expressed miRNAs, 10 miRNAs, including 5 members of the polycistronic oncomir miR-17-92 cluster, were found to be over-expressed in only HCC. These results indicate the fundamental role of miRNAs in the development of NASH-associated HCC. This is evidenced by the early occurrence of miRNA alterations at the preneoplastic stage of liver carcinogenesis, the persistence of these changes in HCC, and the accumulation of additional miRNA alterations in HCC, and by the existence of a mechanistic link between miRNA alterations and deregulation key cancer-related pathways.
Citation Format: Juliana F. Ortega, Aline DeConti, Kostiantyn Dreval, Fernando S. Moreno, Frederick A. Beland, Igor P. Pogribny. Role of miRNAome deregulation in the pathogenesis of non-alcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 472. doi:10.1158/1538-7445.AM2017-472
Abstract 4733: Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer
Authors: Li Hui , Jia Lei , Yan Fan , Zhou Pengbo 
Published: July 2017

Abstract
Background: The Cullin-RING ubiquitin ligases 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human cancer patients.
Methods: 352 lung cancer and 62 benign lung specimens of Asian origin were constructed into tissue microarrays (TMAs) of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B and their substrates was detected by immunohistochemistry (IHC), and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability.
Results: Both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A&lt;0.001, PCUL4B&lt;0.001), and significantly associated with tumor size (PCUL4A&lt;0.001, PCUL4B=0.002), lymphatic invasion (PCUL4A=0.004, PCUL4B&lt;0.001), metastasis (PCUL4A=0.019, PCUL4B=0.006), and advanced TNM stage (PCUL4A&lt;0.001, PCUL4B&lt;0.001), which parallels gene amplification and abnormal activation of the canonical Wnt signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (P=0.01), and inversely correlated with XPC and p21, both of which are substrates of CUL4A (PCUL4A=0.019, PCUL4B=0.006). Higher levels of CUL4A or CUL4B are significantly associated with patients’ OS (PCUL4A&lt;0.001, PCUL4B&lt;0.001) and PFS (PCUL4A&lt;0.001, PCUL4B=0.001).
Conclusion: Our findings revealed that CUL4A and CUL4B are differentially associated with etiological factors for pulmonary malignancies and are independent prognostic markers for survival of distinct lung cancer subtypes.
Citation Format: Hui Li, Lei Jia, Fan Yan, Pengbo Zhou. Dysregulation of CUL4A and CUL4B ubiquitin ligases in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4733. doi:10.1158/1538-7445.AM2017-4733
Abstract 4735: Expression of Notch1 and Numb in small cell lung cancer
Authors: Kikuchi Hajime , Sakakibara-Konishi Jun , Furuta Megumi , Yokouchi Hiroshi , Nishihara Hiroshi , Yamazaki Shigeo , Hidetaka Uramoto , Tanala Fumihiro , Harada Masao , Akie Kenji , Sugaya Fumiko , Fujita Yuka , Takamura Kei , Kojima Tetsuya , Harada Toshiyuki , Higuchi Mitsunori , Honjo Osamu , Minami Yoshinori , Watanabe Naomi , Oizumi Satoshi , Suzuki Hiroyuki , Ishida Takashi , Dosaka-Akita Hiotoshi , Isobe Hiroshi , Munakata Mitsuru , Nishimura Masaharu 
Published: July 2017

Abstract
Background: Notch signaling plays an important role in tumorigenesis. Numb represses intracellular Notch signaling. Previous studies have demonstrated that Notch signaling suppresses the proliferation of small cell lung cancer (SCLC) cell lines. However, in SCLC, the association between Notch1 and Numb expression and clinicopathological factors or prognosis has remained unclear. In this study, we evaluated the expression of Notch1 and Numb in SCLC.
Methods: We immunohistochemically assessed 125 SCLCs that were surgically resected at 16 institutions participating in either the Hokkaido Lung Cancer Clinical Study Group Trial (HOT) or the Fukushima Investigative Group for Healing Thoracic Malignancy (FIGHT) between 2003 and 2013. Correlations between Notch1 or Numb expression and various clinicopathological features were evaluated.
Results: Notch1 expression was associated with ECOG performance status. Numb expression was associated with age, sex, and pathological histology (SCLC or Combined SCLC). Analysis of cellular biological expression did not demonstrate a significant correlation between the expression of Notch1 and of Numb. Multivariate Cox regression analysis showed that high Notch1 expression was an independent favorable prognostic factor for SCLC (hazard ratio = 0.503, P = 0.023).
Conclusions: We demonstrate that Notch1 expression, but not Numb, is associated with prognosis in SCLC and may provide a novel prognostic marker of SCLC.
Citation Format: Hajime Kikuchi, Jun Sakakibara-Konishi, Megumi Furuta, Hiroshi Yokouchi, Hiroshi Nishihara, Shigeo Yamazaki, Uramoto Hidetaka, Fumihiro Tanala, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Toshiyuki Harada, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Satoshi Oizumi, Hiroyuki Suzuki, Takashi Ishida, Hiotoshi Dosaka-Akita, Hiroshi Isobe, Mitsuru Munakata, Masaharu Nishimura. Expression of Notch1 and Numb in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4735. doi:10.1158/1538-7445.AM2017-4735