bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4231: Combination of epigenetic, differentiation and DNA damaging agents induce tumor cell death and stem cell depletion in breast cancer
Authors: Merino Vanessa F. , Nguyen Nguyen , Sadik Helen , Cho Soonweng , Cope Leslie , Zhou Xian C. , Zhang Zhe , Chen Qian , Pan Duojia , Huso David L. , Ali Syed , Adams Christina , Győrffy Balázs , Sukumar Saraswati 
Published: August 2015

Abstract
The histone deacetylase inhibitor, entinostat, is a new-generation epigenetic drug, which has recently demonstrated notable clinical efficacy when used in combination with standard therapy. Retinoids induce differentiation in various types of stem cells. However, its delivery to patients is challenging because of its rapid metabolism. Also, epigenetic changes in the retinoic acid receptors often render cancer cells retinoid-resistant. We have shown that a combination of entinostat, all-trans retinoic acid (ATRA) and doxorubicin causes significant regression of xenografts of triple negative breast cancer (TNBC) cells and investigated the mechanism underlying the effectiveness of this combination therapy. Combinations of entinostat, retinoic acid and doxorubicin were optimal in causing tumor regression in triple negative breast cancer xenografts. Gene expression analysis of treated TNBC cells identified genes most effectively reprogrammed by entinostat and doxorubicin (ED) combination therapy. These genes are involved in cell cycle arrest, inflammation and differentiation, which are related to better survival outcome in patients. Entinostat sensitizes the cells to doxorubicin-induced growth arrest, resulting in increased apoptosis and necrosis. Adding ATRA to ED regulated interferon genes and members of the cancer/testis antigens (CTA) and tripartite motif (TRIM) family of proteins and induces inflammation in nude mice. Entinostat/ATRA/dox therapy was most effective to target breast cancer stem cells (BCSC) in limiting dilution assays of growth in mammary fat pads. The epithelium-specific ETS transcription factor-1 (ESE-1 or ELF3), known to regulate cellular proliferation and differentiation mediates the epigenetic differentiation effect. Patient-derived distant metastases responded to entinostat/ATRA/dox therapy in culture. Thus, the combination therapy may have significant effects in decreasing both local and metastatic growth in breast cancer, especially in decreasing recurrence by targeting breast cancer stem cells.
Citation Format: Vanessa F. Merino, Nguyen Nguyen, Helen Sadik, Soonweng Cho, Leslie Cope, Xian C. Zhou, Zhe Zhang, Qian Chen, Duojia Pan, David L. Huso, Syed Ali, Christina Adams, Balázs Győrffy, Saraswati Sukumar. Combination of epigenetic, differentiation and DNA damaging agents induce tumor cell death and stem cell depletion in breast 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 4231. doi:10.1158/1538-7445.AM2015-4231
Abstract 4233: Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models
Authors: Fischer Marcus M. , Yen Wan-Ching , Zheng Chun , Henner Randall , Cattaruzza Fiore , Tang Tracy , Yeung Pete , Biswas Tanuka , Lewicki John , Gurney Austin , Kapoun Ann M. , Hoey Timothy 
Published: August 2015

Abstract
Ovarian cancer is the deadliest gynecologic malignancy and the fifth leading cause of death from cancer in women in the U.S. The Wnt/beta-catenin pathway, which signals through the Frizzled (FZD) receptor family and several co-receptors, has long been implicated in cancer. We have developed ipafricept (FZD8-Fc, OMP-54F28), a recombinant fusion protein consisting of the ligand-binding domain of FZD8 and a human IgG1 Fc fragment. This fusion protein blocks Wnt signaling induced by multiple Wnt family members by binding and sequestering WNT.
Using minimally passaged ovarian patient-derived xenograft tumors (PDX), we demonstrate that ipafricept is efficacious in combination with chemotherapy in four of eight ovarian cancer PDX tumors examined. Utilizing an in vivo serial transplantation assay, we quantified a reduction of the tumor initiating cell frequency by ipafricept in combination with paclitaxel. Additionally, we have discovered that pre-treatment with ipafricept several days prior to paclitaxel therapy enhances the activity of both agents when compared to delivering the drugs simultaneously.
The anti-tumor effect observed is directly associated with a modulation of Wnt pathway gene sets. In responsive tumors, we discovered that a large number of WNT target genes were significantly down-regulated by ipafricept (e.g, AXIN2, LRP5/6, and FZD8). Conversely, in non-responsive tumors, these genes were either unchanged or up-regulated by the combination therapy. Histologic analysis revealed that total beta-catenin protein levels were reduced by ipafricept alone and in combination with paclitaxel in responsive tumors but were unchanged in non-responsive tumors. We are using these tumors to develop biomarkers that can be used clinically.
Our data demonstrates the potential therapeutic benefit of targeting Wnt signaling in ovarian cancer. A Phase 1b clinical trial is currently examining ipafricept in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.
Citation Format: Marcus M. Fischer, Wan-Ching Yen, Chun Zheng, Randall Henner, Fiore Cattaruzza, Tracy Tang, Pete Yeung, Tanuka Biswas, John Lewicki, Austin Gurney, Ann M. Kapoun, Timothy Hoey. Wnt pathway antagonist ipafricept (FZD8-Fc, OMP-54F28) inhibits tumor growth and reduces tumor-initiating cell frequency in ovarian patient-derived xenograft models. [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 4233. doi:10.1158/1538-7445.AM2015-4233
Abstract 4272: Potent in situ cancer immunotherapy with synthetic human STING-activating cyclic dinucleotides
Authors: Glickman Laura Hix , Kanne David B. , Gauthier Kelsey E. , Katibah George E. , Leong Justin J. , Metchette Ken , Dubensky Thomas W. , McWhirter Sarah M. 
Published: August 2015

Abstract
Spontaneous tumor-initiated T cell priming is dependent on IFN-β production by tumor-resident dendritic cells. Based on recent observations indicating that IFN-β expression was dependent upon activation of the host STING (Stimulator of Interferon Genes) pathway, we hypothesized that direct engagement of STING through intratumoral administration of specific agonists would result in effective anti-tumor therapy. To this end, we generated novel synthetic cyclic dinucleotide (CDN) derivatives with superior STING-activating and anti-tumor properties. The most potent molecule contains a 2′-5′ and 3′-5′ phosphate bridge that increases its affinity for STING at least 10-fold. Additionally, sulfur atoms at the non-bridging oxygens of the internucleotide phosphate bridge enable both superior STING binding affinity, as well as resistance to host cell phosphodiesterases. Importantly, the lead molecule activates PBMCs from a panel of human donors representing all known STING alleles, including homozygotes for the most refractory allele. Intratumoral injection of the lead CDN molecule induced profound regression of established B16 melanoma tumors, generated substantial systemic immune responses capable of rejecting distant metastases and provided long-lived immunologic memory. Cures in entire cohorts of mice bearing well-established 4T1 mammary and CT26 colon carcinoma models correlated with induction of cytokine-mediated innate and adaptive antigen-specific T cell immunity, both systemically and in the tumor microenvironment. Immune activation and anti-tumor efficacy was lost in mice encoding non-functional STING. In vivo activation of STING with the lead CDN administered by multiple routes demonstrated a high safety and tolerability margin in preclinical toxicology studies. In addition, pharmacokinetic analysis indicates that the lead CDN compound was rapidly cleared from systemic circulation, consistent with pulsatile STING activation and transient systemic cytokine and hematological changes. These results demonstrate that CDNs have high translation potential for treatment strategies to induce activation of the tumor microenvironment, leading to effective tumor-initiated T cell priming and anti-tumor immunity.
Citation Format: Laura Hix Glickman, David B. Kanne, Kelsey E. Gauthier, George E. Katibah, Justin J. Leong, Ken Metchette, Thomas W. Dubensky, Sarah M. McWhirter. Potent in situ cancer immunotherapy with synthetic human STING-activating cyclic dinucleotides. [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 4272. doi:10.1158/1538-7445.AM2015-4272
Abstract 4274: Anticancer mechanisms of a small amphipathic molecule, LTX-401, against B16 melanoma cancer cells
Authors: Eike Liv-Marie , Mauseth Brynjar , Camilio Ketil , Rekdal Oystein , Sveinbjornsson Baldur 
Published: August 2015

Abstract
In the present study we investigated the mechanism behind the killing of B16F1 murine melanoma cells by the small amphipathic β(2,2)-amino acid derivative, LTX-401 (Mw&lt;500Da). In vitro, LTX-401 induced lytic cell death and the release of Danger-Associated-Molecular-Pattern Molecules(DAMPs) such as ATP and HMGB-1. In addition, the cells released pro-Cathepsin-B and cytochrome-c following LTX-401 treatment. Flow cytometry and confocal microscopy studies revealed reduced signal from the lysomal dye Lysotracker-DND-26, indicating loss of lysomal integrity. Furthermore, flow cytometry analysis showed that the mitochondrial membrane potential was unaffected in the LTX-401 treated cells. Transmission electron microscopy of LTX-401 treated cells showed little or no ultra structural changes in the mitochondria. The in vivo antitumor effect of LTX-401 against intradermally established B16F1 melanoma was assessed in syngeneic mice. Intratumoral administration of the molecule caused rapid tumor necrosis and complete tumor regression in the majority of the animals treated. In conclusion, these findings demonstrate that LTX-401 has the ability to cause immunogenic cell death in cancer cells and induce complete tumor regression in solid tumors and thus might have a potential as an immunotherapeutic agent.
Citation Format: Liv-Marie Eike, Brynjar Mauseth, Ketil Camilio, Oystein Rekdal, Baldur Sveinbjornsson. Anticancer mechanisms of a small amphipathic molecule, LTX-401, against B16 melanoma cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4274. doi:10.1158/1538-7445.AM2015-4274
Abstract 4277: Oral administration of a traditional herbal remedy, JC001, suppresses pancreatic tumorigenesis in mice via regulating immune cell functions
Authors: Jan Ming-Shiou , Hsu Fong-Rong , Lin You-Chain , Chuang Shu-Han , Lin Jia-Wei , Chuang Meng-Hsein , Hsu Li-Jin 
Published: August 2015

Abstract
The traditional Chinese herbal medicine JC001 is widely used as an effective liver-protecting remedy in Taiwan and China for decades. We have first examined the antitumor effects of JC001 using both mouse xenograft and oncogene-induced tumor models. Our results indicated that the numbers of M1-type macrophages, mitogen-stimulated T cell proliferation and natural killer cell activity were increased in wild-type mice with oral administration of JC001. Interestingly, continuous administration of JC001 for a month markedly reduced the numbers and the sizes of tumor nodules in a mouse pancreatic xenograft model. In contrast to this observation in immune-competent mice, our data revealed that the average tumor size in JC001-administrated nude mice was comparable with that of the control tumor-bearing nude mice without JC001 treatment, suggesting that JC001-induced antitumor activity is mediated by T cells. Adoptive transfer of the splenocytes isolated from immune-competent mice with JC001 treatment into tumor-bearing nude mice reduced tumor growth in these T cell-deficient mice. Moreover, increased cytotoxic activity of natural killer (NK) cells was also observed in mice treated with JC001. In an oncogene-induced tumor model, orally administered JC001 significantly suppressed caerulein-triggered development of pancreatic neoplasias and cancer cell metastasis in KrasG12D/w Pdx-Cre transgenic mice. Together, our results clearly suggest that JC001 exerts immunomodulatory activity mainly through regulating T and NK cell responses to suppress pancreatic cancer development and metastasis.
Citation Format: Ming-Shiou Jan, Fong-Rong Hsu, You-Chain Lin, Shu-Han Chuang, Jia-Wei Lin, Meng-Hsein Chuang, Li-Jin Hsu. Oral administration of a traditional herbal remedy, JC001, suppresses pancreatic tumorigenesis in mice via regulating immune cell functions. [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 4277. doi:10.1158/1538-7445.AM2015-4277
Abstract 4289: Targeting of phosphatidylserine by monoclonal antibodies enhances the activity of immune checkpoint inhibitors in breast tumors
Authors: Gong Jian , Yin Shen , Nguyen Van , Hutchins Jeff , Freimark Bruce D. 
Published: August 2015

Abstract
Phosphatidylserine (PS) is a phospholipid normally residing in the inner leaflet of the plasma membrane that becomes exposed on tumor vascular endothelial cells (ECs) and tumor cells. PS exposure becomes enhanced in response to chemotherapy, irradiation, and oxidative stresses in the tumor microenvironment. PS exposure in tumors promotes an immunosuppressive microenvironment which includes the recruitment of myeloid derived suppressor cells (MDSCs), immature dendritic cells and M2-like macrophages, as well as, the production of anti-inflammatory cytokines. Binding of PS targeting antibodies on tumor endothelial cells, tumor cells and their secreted microparticles triggers an Fc-FcR mediated pro-inflammatory cellular and cytokine response that reverses the immunosuppressive PS meditated checkpoint, thereby enhancing anti-tumor immunity. A chimeric PS-targeting antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in multiple late-stage clinical trials. Using breast tumors in immune competent mice, we demonstrate PS targeting antibodies enhance the anti-tumor activity of combination therapies including anti-PD-1 antibodies. Tumor growth inhibition correlates with statistically significant increases in the infiltration of CD8+ T cells and a reduction of myeloid-derived suppressor cells (MDSCs). The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.
Citation Format: Jian Gong, Shen Yin, Van Nguyen, Jeff Hutchins, Bruce D. Freimark. Targeting of phosphatidylserine by monoclonal antibodies enhances the activity of immune checkpoint inhibitors in breast tumors. [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 4289. doi:10.1158/1538-7445.AM2015-4289
Abstract 4303: Programmed death ligand 1 (PD-L1) expression in paired melanoma tumor samples
Authors: Steiniche Torben , Vestergaard Danielsen Allan , Wang Zhen (Adelle) , Switten Nielsen Patricia , Bastholt Lars , Schmidt Henrik , Svane Inge Marie , Dolled-Filhart Marisa , Emancipator Kenneth , Wu Dianna Y. , Busch-Sorensen Michael , Zhou Wei 
Published: August 2015

Abstract
Background: There is limited information on changes in PD-L1 expression levels over time in melanoma.
Methods: PD-L1 expression was measured in melanoma tumor samples collected at different time points from the same patient using a prototype immunohistochemistry (IHC) assay with the 22C3 antibody. PD-L1 positivity was defined as staining in ≥1% of cells. The concordance of PD-L1 expression in paired samples was analyzed by treating the IHC proportion score as a continuous variable or classifying staining as positive or negative.
Results: 48 patients were included. Median age was 65 years (range, 23-85), 73% were male, and 60% had stage I-IIIA disease. All first samples and 85% of second samples were surgical samples. The median interval between sample collection dates was 25.3 months (range, 3.1-203.5). There was no statistically significant correlation of the PD-L1 IHC proportional score between paired samples (Pearson correlation coefficient, 0.13). 40% of patients had an increased proportion score at the second time point, and 10% had a decreased score. The prevalence of PD-L1 positivity was 31% in first samples and 46% in second samples. The concordance rate was 65% (95% CI, 49%-78%) when PD-L1 expression was categorized as positive or negative (Table). The concordance rate was similar in paired samples collected within and beyond 2 years.
Concordance of PD-L1 Expression in Paired Melanoma Samples (N = 48)Later Time PointPD-L1 ExpressionPositive, n (%)Negative, n (%)Earlier Time PointPositive10 (20.8)5 (10.4)Negative12 (25.0)21 (43.7)
Conclusion: Our preliminary analysis did not suggest a significant correlation of PD-L1 expression in paired melanoma samples collected at different time points. Similar results were observed when samples were categorized as PD-L1 positive or PD-L1 negative. The 35% discordance rate between initial and subsequent tumor samples should be considered if PD-L1 expression is used for selection of enrollment in clinical trials.
Citation Format: Torben Steiniche, Allan Vestergaard Danielsen, Zhen (Adelle) Wang, Patricia Switten Nielsen, Lars Bastholt, Henrik Schmidt, Inge Marie Svane, Marisa Dolled-Filhart, Kenneth Emancipator, Dianna Y. Wu, Michael Busch-Sorensen, Wei Zhou. Programmed death ligand 1 (PD-L1) expression in paired melanoma tumor samples. [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 4303. doi:10.1158/1538-7445.AM2015-4303
Abstract 4323: ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC
Authors: Bu Rong , Prabhakaran Sarita , Beg Shaham , Jehan Zeenath , Siraj Abdul K. , Ahmed Maqbool , Hussain Azhar , Alsobhi Saif A. , Al-Dayel Fouad , Uddin Shahab , Al-Kuraya Khawla S. 
Published: August 2015

Abstract
Aberrant activation of anaplastic lymphoma kinase (ALK) gene caused by mutation, rearrangement or overexpression plays a fundamental role in tumorigenesis in several tumors and represents an important therapeutic target. Currently, only limited data is available on thyroid cancer with respect to the genetic alteration of ALK. Therefore we investigate the ALK overexpression and amplification, and its correlation with various clinicopathological features and molecular biomarkers in a large cohort of 1040 Middle Eastern PTC. In our study, ALK protein expression was determined by immunohistochemistry. ALK gene amplification and rearrangement were analyzed by in situ hybridization (FISH). We also correlated the data with clinicopathological characteristics and other molecular markers. Our data showed that ALK is overexpressed in 136 of the 997 (13.6%) PTC samples. ALK amplification and rearrangement were not observed by FISH. ALK overexpression was significantly associated with surgical margin, but had no effect on the survival of PTC patients. Interestingly, ALK overexpression was found to be significantly correlated with the higher expression of pAKT and PIK3CA in PTC samples, suggesting that ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC. In addition, ALK overexpression is also correlated with overexpression of anti-apopototic marker XIAP and BCL-XL and cell cycle regulatory marker SKP2. Altogether, our results suggest that ALK overexpression presents in a small subset of samples and is not associated with survival in PTC. However ALK overexpression is significantly correlated with PI3K/AKT signaling pathway and might provide a potential therapeutic target for PTC patients with ALK overexpression.
Citation Format: Rong Bu, Sarita Prabhakaran, Shaham Beg, Zeenath Jehan, Abdul K. Siraj, Maqbool Ahmed, Azhar Hussain, Saif A. Alsobhi, Fouad Al-Dayel, Shahab Uddin, Khawla S. Al-Kuraya. ALK overexpression is associated with activation of PI3K/AKT signaling pathway in PTC. [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 4323. doi:10.1158/1538-7445.AM2015-4323
Abstract 4325: The role of FGFR fusion genes as novel oncogenic targets
Authors: Martinez Cardona Gabriela , Bell Katherine , Gaffney Dana , Portale Joseph , Platero Suso , Lorenzi Matthew , Karkera Jayaprakash 
Published: August 2015

Abstract
Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Gene fusions can lead to the production of oncogenic fusion proteins or to enhanced expression of oncogenes. Advances in next-generation sequencing technologies have made possible to identify more efficiently novel fusion proteins in cancer. Recently, several FGFR fusion genes with intact kinase domains have been identified in bladder, lung, breast, thyroid, oral, and prostate cancers, as well as other tumor types. To date, several FGFR3 partner genes have been identified. In this study, we focused on the FGFR3-BAIAP2L1 and FGFR3-TACC3 gene fusions and investigated their tumorigenic activity, mechanism of activation, and sensitivity to the FGFR inhibitor JNJ-42756493. To determine the role and significance of FGFR fusion genes in cancer, FGFR fusion expression constructs were designed and individually transfected into normal rat kidney epithelial cells. FGFR fusion overexpressing cells not only showed increased cell proliferation, but also exhibited anchorage-independent cell growth. Cells harboring the FGFR fusions showed increased sensitivity to the FGFR inhibitor JNJ-42756493 in vitro, whereas the wild-type FGFR3 did not in the absence of FGF ligands. In addition, Western blotting analyses indicated that the overexpression of the FGFR fusions resulted in highly activated proteins that induce signaling via the MAPK pathway. These findings underline the oncogenic potential of the FGFR fusion genes and highlight their unique potential as predictive biomarkers in the selection of patients for FGFR-targeted therapy.
Citation Format: Gabriela Martinez Cardona, Katherine Bell, Dana Gaffney, Joseph Portale, Suso Platero, Matthew Lorenzi, Jayaprakash Karkera. The role of FGFR fusion genes as novel oncogenic targets. [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 4325. doi:10.1158/1538-7445.AM2015-4325