tbuckley/cabot-search huggingface dataset:
Abstract 3156: Multiple acquired resistance mechanisms against third generation <i>EGFR</i>-TKI osimeritinib in non-smal cell lung cancer cells
Authors: Kei Namba, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka
Journal: Cancer Research (2017)

Abstract Background Osimertinib (AZD9291; Tagrisso) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) known to be effective against the EGFR-T790M variant, which is accounts for half of the acquired resistance mechanisms to the first generation EGFR-TKIs. However, resistance to osimertinib is likely to progress and the study of potential osimertinib-resistance mechanisms in advanced is necessary. In this study, we investigated the molecular and cellular profiles of the acquired resistance cells to osimertinib in EGFR-mutant non-small cell lung cancers. Materials and Methods Five EGFR-mutant cell lines were exposed to osimertinib by stepwise escalation or high-concentration exposure methods, and resistant sublines to osimertinib were established. The molecular profiles and cellular phenotypes of these resistant sublines were characterized. Results EGFR-C797S mutation which was reported to be a major mechanism of resistance to osimertinib in clinical samples was not detected in established resistance cells by using direct sequencing. Several osimertinib-resistance cell lines displayed MET amplification, and some of these cells were sensitive to the combination of osimertinib plus MET inhibitor crizotinib. However, one cell line that displayed MET amplification was not sensitive to this combination therapy. On the other hand, several osimertinib-resistance cell lines displayed epithelial-to-mesenchymal transition (EMT) features. The HCC827-derived subline established by the high-concentration exposure method exhibited not only EMT features but also cancer stem cell (CSC)-like properties, including aldehyde dehydrogenase isoform 1 (ALDH1A1) and ATP binding cassette subfamily B member 1 (ABCB1) overexpression. Conclusion We established osimertinib-resistant cells and found that MET amplification, EMT, and CSC -like features were observed. These findings may provide clues to overcome acquired resistance to EGFR-TKIs. In some cell lines, however, the mechanisms of acquired resistance to osimertinib were not revealed yet. Citation Format: Kei Namba, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka. Multiple acquired resistance mechanisms against third generation EGFR-TKI osimeritinib in non-smal cell lung cancer cells [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 3156. doi:10.1158/1538-7445.AM2017-3156
The natural history of imatinib-naive GIST: A retrospective analysis of 929 cases with long-term follow-up
Authors: A. P. Dei Tos, S. Rossi, L. Messerini, I. Bearzi, G. Mazzoleni, C. Capella, G. Arrigoni, A. Sonzogni, P. Amore, P. G. Casali
Journal: Journal of Clinical Oncology (2009)

10555 Background: GIST represent a rare form of malignancy and one of best paradigms of molecularly targeted therapy. While the natural history of GIST following treatment with tyrosine kinase inhibitors is relatively well known, most information on imatinib naïve GIST are drawn form either small series or larger studies with possible referral bias. Methods: 1,021 GIST diagnosed between 1980 and 2000 were retrieved from the archives of 35 Departments of Pathology throughout Italy. Pathologic and clinical data were collected. All cases were centrally reviewed and stratified according to NIH 2002 and NCCN 2008 risk classifications. The prognostic meaning of a large set of morphologic and clinical parameters were evaluated by uni- and multi-variate analysis. Informed consent was obtained from all living patients. Results: 92 cases were excluded as non-GIST. Mean and median age were 63 and 65 years. Females were 52%. Disease status at diagnosis was localized in 767 and metastatic in 111 cases. 516 cases were gastric, 229 ileal/jejunal, 26 duodenal, 22 colonic, 28 rectal, and 25 peritoneal/retroperitoneal. NIH 2002 risk classification was available in 917 cases: 121 (13%) very low, 247 (27%) low, 201 (22%) moderate and 348 (38%) high risk. NCCN 2008 risk classification was available in 892 patients. Metastatic sites included liver (5%), peritoneum (10%), lymph-node (1%), skin and soft tissue (0.5%), and lungs (0.2%). Median follow-up was 75 months (range 1–323). Median survival was 88 months. 62% patients died (ED in 46%). Mitotic activity, tumor size and anatomic site correlated with overall survival at multivariate analysis. Striking differences were observed for groups with &lt; 5 mitoses/50HPF, 5 and 10, 10 and 30, and &gt;30. Non gastric GIST exhibit a significant poorer outcome. R2 surgery represents a negative prognostic factor. Conclusions: Mitotic rate has a deep prognostic impact if split in more than two intervals. Setting only two categories may be a limitation of existing prognostic classifications, although the mitotic count is affected by reproducibility issues. Survival curves according to the two main prognostic classifications will be shown. [Table: see text]
Abstract 2327: Apoptosis of melanoma induced by non-thermal atmospheric pressure bio-compatible plasma activated media
Authors: Ihn Han, Ying Li, Eun Ha Choi
Journal: Cancer Research (2017)

Abstract Melanoma is the most dangerous type of skin cancer, which mostly related with the exposure of ultraviolet (UV), and especially happened to those who have low skin pigment levels. Epidemiological studies showed Europeans and North Americans have a high incidence of melanoma, while it is less common in Asia and Africa. Therefore, the new and more effective methods to treat melanoma are still necessarily needed. Non-thermal atmospheric pressure bio-compatible plasma (NBP) is defined as a partially ionized gas with electrically charged particle, which has been reported have cytotoxicity on various cancer cells induce DNA damage and apoptosis other than normal cells. Reactive oxygen and/or nitrogen species (RONS) were proved to play the most important role during this process, by inducing oxidative stress and depolarization of mitochondria membrane potential with the consequence of various cancer cells apoptosis. The plasma activated media (PAM), which the media treated directly by NBP with different time, containing mostly long-live secondary species such as hydrogen peroxide (H2O2) which have been confirmed anti-microorganism and cytotoxic activity. Researches already investigated that PAM also effective in cancer therapy via inducing apoptosis. However, the underlying molecular mechanisms of apoptosis are remaining elusive. The purpose of this study was to evaluate the potential of PAM as an effective tool to induce apoptosis in melanoma cells. Our results showed that PAM has a killing effect to melanoma cells in a time-dependent manner, for 3minutes treatment could induce almost 40% cells entry death, after treated by 5 minutes more than 60%, and 10 minutes treatment reduced the cell viability to approximately 30%. Annexin-V/PI staining demonstrated that PAM kills these cells via apoptosis pathway. We also found that with a manner of treatment time PAM significantly increased the concentration of intracellular NO and H2O2, reflecting an influx of extracellular RONS may result in melanoma cells apoptosis. Besides, western blot assay showed that P53 and caspase 3 increased after PAM treatment. Taken together, PAM is effective to induce the apoptosis in melanoma cells in vitro, further in vivo experiments will be performed to investigate the functional effects in the animals. Citation Format: Ihn Han, Ying Li, Eun Ha Choi. Apoptosis of melanoma induced by non-thermal atmospheric pressure bio-compatible plasma activated media [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 2327. doi:10.1158/1538-7445.AM2017-2327
Abstract 1702: Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo
Authors: Beatrice Wang, Tasnim Kothambalwala, Paul Hinton, Dean Ng, Avneesh Saini, Ramesh Baliga, Bruce Keyt
Journal: Cancer Research (2017)

Abstract Death receptor 5 (DR5) is a member of the TNF receptor superfamily that induces apoptosis upon receptor trimerization. It is expressed on many tumor types and has therefore been an important target for developing antibody based treatments of epithelial, solid tumors. However several agonistic Anti-DR5 IgG antibodies that have demonstrated efficacy in preclinical models have been unsuccessful in clinical trials, likely due to insufficient receptor crosslinking by bivalent IgGs. We have developed a multimeric anti-DR5 IgM antibody which has strong avidity for the receptor. The IgM binds Colo205 cells and triggers apoptosis, and is 1000-fold more potent than the respective IgG and 100-fold more potent than crosslinked IgG in vitro. Anti-DR5 IgM displays strong in vitro potency across a panel of tumor cell lines, including ones that are IgG-resistant. Anti-DR5 IgM causes tumor regression and delays tumor growth in various in vivo xenograft models including Colo205, HCT15 and MDA-MB231. These results support the development of an human anti-DR5 IgM therapeutic with the potential to treat solid tumors. Citation Format: Beatrice Wang, Tasnim Kothambalwala, Paul Hinton, Dean Ng, Avneesh Saini, Ramesh Baliga, Bruce Keyt. Multimeric anti-DR5 IgM antibody displays potent cytotoxicity in vitro and promotes tumor regression in vivo [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 1702. doi:10.1158/1538-7445.AM2017-1702
Abstract LB-002: Optimizing immunogenicity prediction of neoepitopes
Authors: Zeynep Kosaloglu-Yalcin, Manasa Lanka, John Sidney, Kerrie Vaughan, Jason Greenbaum, Alessandro Sette, Bjoern Peters
Journal: Cancer Research (2017)

Abstract Epitopes that arise from a somatic mutation, so called neoepitopes, are now known to play a key role in cancer immunology and immunotherapy. Recent advances in high-throughput sequencing have made it possible to identify all mutations and thereby all potential neoepitope candidates in an individual cancer. It has however become evident that the vast majority of these neoepitope candidates do not induce a T cell response when tested in vivo or in vitro, i.e. they are not immunogenic. Especially in patients with a high mutational load, usually hundreds of potential neoepitopes are detected, highlighting the need to further narrow down this candidate list. Several studies have used different combinations of immunoinformatic tools such as MHC binding predictions to prioritize the initial set of neoepitopes candidates. The tools to use and thresholds to apply for this prioritization has so far been largely based on experience with epitope identification in other settings such as infectious disease and allergy. To establish the appropriate tools and thresholds in the cancer setting, we here curated a set of immunogenic neoepitopes from the published literature and performed detailed analyses to detect what features discriminate immunogenic neoepitopes from a background set of mutated peptides. We experimentally measured the HLA binding affinity of all curated immunogenic neoepitopes. In doing so, we aimed to identify the optimal affinity threshold to effectively identify immunogenic neoepitopes. As a next step, we sought to assess the added value of different immunoinformatics tools, including various HLA binding prediction algorithms, processing prediction, stability prediction, and immunogenicity prediction, to most effectively detect immunogenic neoepitopes. The obtained results are now going to be used to facilitate the development of more accurate prediction algorithms. Citation Format: Zeynep Kosaloglu-Yalcin, Manasa Lanka, John Sidney, Kerrie Vaughan, Jason Greenbaum, Alessandro Sette, Bjoern Peters. Optimizing immunogenicity prediction of neoepitopes [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 LB-002. doi:10.1158/1538-7445.AM2017-LB-002
Abstract 1192: Regorafenib (Stivarga®) reverses BCRP-mediated multidrug resistance <i>in vitro</i> and <i>in vivo</i>
Authors: Yun-Kai Zhang, Yi-Jun Wang, Guan-Nan Zhang, Wen-Ji Zhang, Meng-Ning Wei, Zhi Shi, Zhe-Sheng Chen
Journal: Cancer Research (2017)

Abstract Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in various kinds of cancers, such as breast, colon, lung and ovarian cancers. Regorafenib, an oral multi-kinase inhibitor, was found to have inhibitory effects on BCRP-mediated MDR both in vitro and in vivo. Regorafenib significantly sensitized BCRP-overexpressing cancerous cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Our mechanism studies revealed that regorafenib inhibited the ATP-driven efflux function of BCRP. Our induced-fit docking and molecular dynamics simulations suggested the existence of strong and stable interactions between regorafenib and BCRP protein. Animal study revealed that the combination of regorafenib and topotecan resulted in great inhibitory effects on the growth of S1-M1-80 xenograft tumors. Regorafenib significantly increased the intratumoral concentration of topotecan but had no significant effects on topotecan plasma concentration. In conclusion, our study indicated that regorafenib could be useful in combating multidrug resistance in cancer treatments. Citation Format: Yun-Kai Zhang, Yi-Jun Wang, Guan-Nan Zhang, Wen-Ji Zhang, Meng-Ning Wei, Zhi Shi, Zhe-Sheng Chen. Regorafenib (Stivarga®) reverses BCRP-mediated multidrug resistance in vitro and in vivo [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 1192. doi:10.1158/1538-7445.AM2017-1192
<i>In Vivo</i> Cancer Cells Elimination Guided by Aptamer-Functionalized Gold-Coated Magnetic Nanoparticles and Controlled with Low Frequency Alternating Magnetic Field
Authors: Irina V. Belyanina, Tatiana N. Zamay, Galina S. Zamay, Sergey S. Zamay, Olga S. Kolovskaya, Tatiana I. Ivanchenko, Valery V. Denisenko, Andrey K. Kirichenko, Yury E. Glazyrin, Irina V. Garanzha, Valentina V. Grigorieva, Alexandr V. Shabanov, Dmitry V. Veprintsev, Alexey E. Sokolov, Vladimir M. Sadovskii, Ana Gargaun, Maxim V. Berezovski, Anna S. Kichkailo
Journal: Theranostics (2017)

Biomedical applications of magnetic nanoparticles under the influence of a magnetic field have been proved useful beyond expectations in cancer therapy.Magnetic nanoparticles are effective heat mediators, drug nanocarriers, and contrast agents; various strategies have been suggested to selectively target tumor cancer cells.Our study presents magnetodynamic nanotherapy using DNA aptamer-functionalized 50 nm gold-coated magnetic nanoparticles exposed to a low frequency alternating magnetic field for selective elimination of tumor cells in vivo.The cell specific DNA aptamer AS-14 binds to the fibronectin protein in Ehrlich carcinoma hence helps deliver the gold-coated magnetic nanoparticles to the mouse tumor.Applying an alternating magnetic field of 50 Hz at the tumor site causes the nanoparticles to oscillate and pull the fibronectin proteins and integrins to the surface of the cell membrane.This results in apoptosis followed by necrosis of tumor cells without heating the tumor, adjacent healthy cells and tissues.The aptamer-guided nanoparticles and the low frequency alternating magnetic field demonstrates a unique non-invasive nanoscalpel technology for precise cancer surgery at the single cell level.
Abstract 26: Panitumumab interacts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine
Authors: Kazuhide Nakamura, Yuji Baba, Toshiya Tamura, Yoshihiko Satoh, Masamitsu Gotou, Hiroshi Sawada, Shunsuke Ebara, Kazunori Shibuya, Jumpei Soeda
Journal: Cancer Research (2017)

Abstract Panitumumab is a monoclonal antibody raised against the human epidermal growth factor receptor (EGFR). TAS-102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS-102 have been approved for the treatment of metastatic colorectal cancer (mCRC). In this study, we show the mechanism underlying the anti-cancer effects of the panitumumab/TAS-102 combination in preclinical models. Co-treatment with panitumumab and FTD exerted additive and synergistic anti-proliferative effects in LIM1215 and SW48 colon cancer cells, respectively. Consistent with the in vitro effects, panitumumab/TAS-102 combination led to tumor regression in LIM1215 and COL-01-JCK colon cancer patient-derived xenograft models. In LIM1215 cells, FTD induced ERK/Akt/STAT3 phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed the FTD-induced ERK/Akt/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD together with the basal activity of the EGFR tyrosine kinase induced downstream pro-survival signaling through ERK/Akt/STAT3. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR-mediated adaptive responses, thereby exerting anti-cancer effects in combination with TAS-102. These preclinical findings provide a compelling rationale to evaluate anti-EGFR antibodies combined with TAS-102 against mCRC. Citation Format: Kazuhide Nakamura, Yuji Baba, Toshiya Tamura, Yoshihiko Satoh, Masamitsu Gotou, Hiroshi Sawada, Shunsuke Ebara, Kazunori Shibuya, Jumpei Soeda. Panitumumab interacts with TAS-102 leading to combinational anti-cancer effects by blocking EGFR-mediated tumor response to trifluridine [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 26. doi:10.1158/1538-7445.AM2017-26
Abstract 2690: MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion
Authors: Anita L. Ray, Amanda S. Peretti, Wade Johnson, Gregory Gan, Ellen J. Beswick
Journal: Cancer Research (2017)

Abstract Introduction: Colorectal cancer is the third most common malignancy diagnosed for both men and women in the United States of America. High levels of inflammatory cytokines in colorectal tumors cause increased growth and invasion and carry a higher risk of metastasis. Identifying new targets to control inflammation is important for developing improved treatment approaches. Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a regulator of pro-inflammatory cytokines that may promote colorectal tumor progression. MK2 signaling is known to induce IL-1, IL-6, and TNF-α production. These pro-inflammatory cytokines are associated with CRC development, invasion, and metastasis. We hypothesized that the MK2 pathway could be an important component of CRC growth, invasion and tumor regrowth. Methods: To investigate this pathway, CT26 CRC cells were examined. Cells were flank-injected into Balb/c mice with and without MK2 inhibitor treatment. At day 19 after tumor injection, tumors were harvested and measured using calipers. Cytokines were quantitated by multiplex bead array in organ culture supernatants and in supernatants from tumor cells plated in fibronectin coated wells. In culture, tumor cell invasion was measured in scratch wound assays containing matrigel. Results: Treating CT26 cells with MK2 inhibitors markedly reduced tumor growth in mice by a mean of 60% compared to vehicle control treated cells. Inflammatory cytokines were also dramatically decreased with MK2 inhibition compared to controls by up to 80%. Cytokines affected included both known MK2 downstream cytokines (IL-1, IL-6, and TNF-α) and also chemokines such as MIP-1α and MCP-1 in both supernatants from cultured tumor cells and in organ culture supernatants. MK2 inhibition also decreased invasion of tumor cells in a cytokine dependent manner. Conclusions: The MK2 pathway regulates production of multiple pro-inflammatory cytokines in colorectal tumors, including several previously unreported chemokines. Inhibition of this pathway markedly decreases tumor growth and invasion. Thus, MK2 may be a promising tumor target to prevent colorectal cancer progression. Citation Format: Anita L. Ray, Amanda S. Peretti, Wade Johnson, Gregory Gan, Ellen J. Beswick. MK2 pathway blockade inhibits inflammatory cytokine production and colorectal cancer growth and invasion [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 2690. doi:10.1158/1538-7445.AM2017-2690
FBW7 Loss Promotes Chromosomal Instability and Tumorigenesis via Cyclin E1/CDK2–Mediated Phosphorylation of CENP-A
Authors: Mamoru Takada, Weiguo Zhang, Aussie Suzuki, Taruho S. Kuroda, Zhouliang Yu, Hiroyuki Inuzuka, Daming Gao, Lixin Wan, Ming Zhuang, Lianxin Hu, Bo Zhai, Christopher J. Fry, Kerry Bloom, Guohong Li, Gary H. Karpen, Wenyi Wei, Qing Zhang
Journal: Cancer Research (2017)

The centromere regulates proper chromosome segregation, and its dysfunction is implicated in chromosomal instability (CIN). However, relatively little is known about how centromere dysfunction occurs in cancer. Here, we define the consequences of phosphorylation by cyclin E1/CDK2 on a conserved Ser18 residue of centromere-associated protein CENP-A, an essential histone H3 variant that specifies centromere identity. Ser18 hyperphosphorylation in cells occurred upon loss of FBW7, a tumor suppressor whose inactivation leads to CIN. This event on CENP-A reduced its centromeric localization, increased CIN, and promoted anchorage-independent growth and xenograft tumor formation. Overall, our results revealed a pathway that cyclin E1/CDK2 activation coupled with FBW7 loss promotes CIN and tumor progression via CENP-A-mediated centromere dysfunction. Cancer Res; 77(18); 4881-93. ©2017 AACR.