bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: Utility of multiplexed biomarker analysis in non-small-cell lung cancer patients with discrepancies between FISH and immunohistochemical results of ALK testing
Authors: KIM TAE-JUNG , TERAI HIDEKI 
Published: May 2016

Abstract
Background: The clinical implications in Non-small cell lung cancer (NSCLC) patients with discrepancy between fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assessing ALK status are unclear.
Materials and Methods: From 1131 archived tissue samples, we identified 41 NSCLC patients with discrepant results showing positive or borderline ALK FISH and negative IHC using ALK1 antibody. Of these, 21 cases with sufficient tissue remaining for selected reaction monitoring (SRM) and an additional case within normal range FISH split (4%) were sent to confirm ALK IHC using other antibodies (5A4 and D5F3). Target protein levels measured by multiplexed SRM were correlated with records of clinical outcomes after treatment with crizotinib or cytotoxic chemotherapy.
Results: Of 22 cases with various ALK FISH results and negative IHC (ALK1), IHC using other antibodies (5A4 and D5F3) identified 4 positive cases, whereas the SRM assay identified 7 cases with tumor-specific ALK protein. IHC showed lower sensitivity in specimen with delayed fixation but SRM showed superior sensitivity in those samples as SRM is independent to modified epitope. Of 8 crizotinib-treated cases, 4 cases with detectable levels of either ALK or cMET proteins had complete or partial responses; cases without either of these proteins (n = 4) did not respond to crizotinib regardless of ALK FISH results. Cases with 3 or more predictive proteins specific to chemotherapeutic agents were found to be more responded to those agents and had a higher probability of progression-free survival.
Conclusions: The SRM assay showed superior sensitivity in poorly fixed specimens and can inform therapeutic decision-making in NCSLC patients with ALK screening discordances.
Citation Format: TAE-JUNG KIM, HIDEKI TERAI. Utility of multiplexed biomarker analysis in non-small-cell lung cancer patients with discrepancies between FISH and immunohistochemical results of ALK testing. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A33.
Abstract A39: 3,4',5- Trismethoxybenzophenone inhibits the growth of human hepatocarcinoma cells via cell-cycle arrest at the G2/M phase
Authors: Patton Christopher J. , Khadka Pritika , Kotturi Hari 
Published: May 2016

Abstract
3,4',5-trismethoxybenzophenone (TMBP) is an analogue of the natural dietary polyphenolic compound resveratrol (3,5,4'-trihydro-trans-stilbene, abbreviated as RVT). Natural RVT belongs to the phytoalexin class of phytochemicals that are antibiotics produced by plants in response to stimuli such as injury, ultraviolet irradiation, stress, and fungal attack. RVT and its analogues have also been shown to prevent hepatic steatosis. In this study we focused on TMBP which is a methylated derivative of RVT. Studies have shown that TMBP exhibits added biological effects and a better pharmacokinetic profile compared to RVT due to the presence of methoxy groups. The human hepatoma cell line (FCA4 cells) that harbors a subgenomic selectable HCV replicon was used for this study. The Huh7 cell line lacking the replicon served as the corresponding control. MTS assay was used to determine the cytotoxicity of TMBP at various concentrations. Wound healing assay was performed to determine the effect of the analogue on cell migration. Flow cytometry and magnetic levitation were used to measure the effect of compound on cell cycle and 3D spheroid formation. Our data showed that treating liver cancer cells with TMBP resulted in a significant dose and time dependent growth inhibition combined with G2/M-phase cell cycle arrest at 5 μM with (IC50) at 7.5 μM. TMBP at 5μM inhibited the formation of 3D spheroids, and also repressed the migration of cancer cells. Current therapies available for treating hepatocellular carcinoma (HCC) have a high incidence of recurrence and postoperative death in patients. Exploring different strategies with high pharmaceutical function and low toxicity is of great urgency for treating HCC. Our studies show that we have identified a promising analogue for treating HCC.
Citation Format: Christopher J. Patton, Pritika Khadka, Hari Kotturi. 3,4',5- Trismethoxybenzophenone inhibits the growth of human hepatocarcinoma cells via cell-cycle arrest at the G2/M phase. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A39.
Abstract A7: Drug resistant murine tumor models facilitate development of next generation anticancer therapeutics
Authors: Jin Ying , Zhang Juan , Zhu Dandan , Sun Yanmei , Mao Guanping , Wang Minxia , Shi Qian 
Published: May 2016

Abstract
Despite the success in the development of new anti-cancer drugs, all cancer therapeutics, either conventional cytotoxic chemo- or targeted therapeutics, are limited by the drug resistance. Resistance may be divided into two broad categories: intrinsic/de novo or acquired, involving various mechanisms. Certain patients are de novo resistant to a specific therapy, while others initially responded, but eventually recurred with resistant tumors that no longer respond to the original therapy. Even with the newly developed immunotherapies that promise to have long lasting tumor inhibitory effect in patients, a large percentage of patients still do not respond to the therapy. To overcome the resistance to the existing drugs, effective new strategies, e.g. next-generation selective inhibitors, rational drug combinations, and new drug delivery or formulation designs, are developed and under active preclinical and clinical investigations. To enable a more informative selection of resistant models for in vivo preclinical drug evaluation, here we set out to identify a series of animal models, which are intrinsically resistant to either chemotherapy, targeted therapy, or immunotherapy, from more than 200 CrownBio validated cell line xenograft and syngeneic tumor models. On another hand, we also validated a panel of acquired drug resistant models, covering the resistance to Doxorubicin, Imatinib, Elotinib, Quizartinib, Crizotinib or Androgen ablation (castration), etc. The possible mechanisms of some resistance were discussed. In conclusion, these resistant models provide a valuable platform for the development of new strategies to overcome the drug resistance.
Citation Format: Ying Jin, Juan Zhang, Dandan Zhu, Yanmei Sun, Guanping Mao, Minxia Wang, Qian Shi. Drug resistant murine tumor models facilitate development of next generation anticancer therapeutics. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A7.
Abstract A84: Intravital microscopy reveals biopsy induced local wound-healing response
Authors: Alieva Maria , Colak Burcin , Boquetale Carla , Van Rheenen Jacco 
Published: May 2016

Abstract
A biopsy is for most types of cancer the golden standard for a definitive cancer diagnosis, as it provides the most accurate analysis of tissues. However taking biopsies creates a wound thereby potentially changing the composition and architecture of the tissue. In non-pathological situations, wounded tissue ‘repairs’ itself by a cascade of cellular events, including the induction of an inflammatory response that promotes cell proliferation and migration of surrounding cells to close the wound. Proliferation and migration are two malignant processes that promote tumor progression and metastatic disease. Thus it is vital to identify the potential effect of biopsy on the behavior of cells that remain in the tumor.
By making use of repeated high-resolution intravital microscopy (IVM) we studied how the behavior of tumor cells locally changes upon biopsy. Our results showed that biopsy-like injury triggers a wound-healing response observed as increased tumor cell migration and proliferation. 24 hours after biopsy-like injury there was a 1.75 fold increase in migratory cells and a 1.52 fold increase in proliferating cells compared to the control group that did not received an injury. IVM showed that the observed effects were mediated by a CCL-2- dependent inflammation response. Interestingly, immune cell ablation by dexamethasone, a glucocorticoid commonly used to prevent inflammation resulted in decreased tumor cell motility and proliferation and suppressed the observed wound healing response. This result opens new therapeutic possibilities to prevent biopsy undesired effects on tumor cell behavior.
Taken together, our data show that biopsy induces a local wound-healing response in the tumor through an immune system mediated mechanism and illustrate that IVM is a powerful technique to study local and temporal changes in cell behavior that cannot be assessed by other techniques (e.g. immunohistochemistry) that only provide a snapshot of a dynamic tissue. Furthermore this tool can be useful to determine local and dynamic responses of (tumor) cells to other more aggressive clinical interventions, such as surgical resection or chemotherapeutic treatment.
Citation Format: Maria Alieva, Burcin Colak, Carla Boquetale, Jacco Van Rheenen. Intravital microscopy reveals biopsy induced local wound-healing response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A84.
Abstract B121: A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation
Authors: Grassilli Emanuela , Pisano Fabio , Cialdella Annamaria , Bonomo Sara , Missaglia Carola , Cerrito Maria Grazia , Masiero Laura , Ianzano Leonarda , Narloch Robert , D'Amato Filomena , Noli Barbara , Ferri Gian Luca , Leone Biagio E. , Stanta Giorgio , Bonin Serena , Helin Kristian , Giovannoni Roberto , Lavitrano Marialuisa 
Published: May 2016

Abstract
It is known that Bruton's tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel oncogenic isoform expressed in colon carcinomas.
Standard procedures were used for cloning the full length p65BTK-encoding mRNA and raise anti-p65BTK specific polyclonal antibodies. Quantitative PCR, western blot, RNA immunoprecipitation, silencing experiments and fluorescence assay upon transfection with bi-cistronic vectors were used to demonstrate post-transcriptional regulation of p65BTK expression. Immunohystochemistry was employed to study p65BTK expression in colon cancer patients specimens. Soft agar assay and foci assay were carried out to assess p65BTK oncogenic properties. Cell growth, cell viability and colony assays were performed to study the effects of p65BTK inhibition (by a specific kinase inhibitor) on colon cancer cells biology.
We found that p65BTK differs from the already known 77 kDa isoform for the lack of the N-terminal PH domain and is translated - through an IRES-dependent mechanism -from a transcript containing an alternative first exon in the 5'UTR. Moreover, p65BTK mRNA translation requires phosho-hnRNPK binding to its cognate sites (located in the alternative first exon) and is post-transcriptionally regulated, via hnRNPK, by the MAPK pathway. We demonstrate that p65BTK is endowed with strong transforming activity that depends on active ERK1/2 and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Finally we show that p65BTK inhibition affects growth and survival of colon cancer cells.
In conclusion, our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.
Citation Format: Emanuela Grassilli, Fabio Pisano, Annamaria Cialdella, Sara Bonomo, Carola Missaglia, Maria Grazia Cerrito, Laura Masiero, Leonarda Ianzano, Robert Narloch, Filomena D'Amato, Barbara Noli, Gian Luca Ferri, Biagio E. Leone, Giorgio Stanta, Serena Bonin, Kristian Helin, Roberto Giovannoni, Marialuisa Lavitrano. A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B121.
Abstract B142: A “moneyball” approach to predicting clinical trial failures and successes
Authors: Gayvert Kaitlyn , Madhukar Neel , Elemento Olivier 
Published: May 2016

Abstract
Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, drug attrition rates due to clinical trial failure have continued to substantially rise. Clinical trials can fail for various reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (sensitivity) (and drugs that fail clinical trials (specificity).
We introduce a novel data-driven approach (PrOCTOR) that integrates chemical properties of a compound, along with that of its targets, to provide a new measure, the PrOCTOR score, that helps predict whether drugs in clinical trials will fail for toxicity reasons. When trained on failed Phase I clinical trials and FDA approved drugs, the PrOCTOR score performs at a high accuracy, specificity and sensitivity (∼0.75), as well as high area under the ROC curve (&gt;0.80). In comparison, none of the drug-likeness approaches were able to successfully maintain both high sensitivity and specificity. Robust feature analysis of the model indicates that it is critical to consider properties of the drug target, with the target's network connectivity and liver toxicity as two of the most important features. The approach was further evaluated by testing the predictions of the trained model on an established independent dataset. We found that our method was able to significantly distinguish a representative set of bioavailable drugs from a representative set of toxic drugs (D = 0.2133, p&lt;2.2e-16, Kolmogorov-Smirnov test). Additionally, we found that the measure is strongly correlated with severe toxicity events, such as pleural effusion (ρ = −0.9792) and neutropenia (ρ = −0.9613). Altogether, our method provides a novel, data-driven and broadly applicable strategy that is able to identify drugs likely to possess manageable toxicity in clinical trials.
Citation Format: Kaitlyn Gayvert, Neel Madhukar, Olivier Elemento. A “moneyball” approach to predicting clinical trial failures and successes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B142.
Abstract B146: Preclinical pharmacokinetic studies of RPT835, an allosteric FGFR2 inhibitor
Authors: Tsimafeyeu Ilya , Byakhov Mikhail , Bencetić Mihaljević Vlatka , Padovan Jasna , Murillo Genoveva , Tjulandin Sergei 
Published: May 2016

Abstract
RPT835 (recommended INN, alofanib) is a novel allosteric FGFR2 inhibitor with activity in FGFR2-expressing women's cancers. Administration of RPT835 intravenously (iv) daily demonstrated dramatic effect in ovarian cancer xenografts compared with RPT835 orally daily [S. Tjulandin et al. AACR 2015]. Here we explore the pharmacokinetic (PK) profile of RPT835.
Three preclinical PK studies were conducted. In Study 1, RPT835 was administered to 49 male BALB/C mice via two routes (oral and iv). Mice in group 1 received a single iv injection of the RPT835 (30 mg/kg), while mice in group 2 received a single dose of RPT835 (30 mg/kg) via oral gavage. The aim of the Study 2 was to evaluate the PK for RPT835 in 24 male Sprague Dawley rats after a single iv dose of 22 mg/kg and oral dosing in capsules at three dose levels (22, 110 and 220 mg/kg). In Study 3, PK of pharmaceutical form of RPT835 in male Sprague Dawley rats after a single iv dose of 55.3, 113.8 and 218.7 mg/kg was evaluated. Six animals per dose group were dosed, with plasma samples collected from the tail vein up to 24 hours. Plasma concentrations were quantified by LC-MS/MS using a research qualified method. The PK data are summarized in Table.
Following oral administration, RPT835 appeared rapidly in plasma (within 30 min), but could not be detected after 2 hours. Bioavailability for oral administration could not be calculated but is estimated to be low (&lt;1%). Following single iv bolus dosing of RPT835, animals showed a moderate intra-individual variability in plasma levels. RPT835 plasma levels were quantifiable up to 8 hours post dose in all animals in Study 3. The compound resulted in a moderate and low clearance (32-12% of liver blood flow), small volume of distribution (0.26-0.5 L/kg) and short half-life (0.4-0.9 h). Based on results of PK, protocol of Phase IB study of continuous iv infusion of RPT835 via pump in patients with ovarian cancer was developed at the ECCO-AACR-EORTC-ESMO Workshop on Methods in Clinical Cancer Research (“Flims17”).
PK resultsStudyGroup (dose, mg/kg)C0/Cmax, ng/mlTmax, ht1/2AUC, h*ng/mLCL, mL/min/kgVss, L/kgF, %1iv, 3057739-0.93580386.76.9NC - Parameter cannot be calculatedoral/gavage, 3043.61-2NCNCNCNCNC2iv, 2279323-0.441423427.10.47-oral/caps, 2222.02.0NC68.0--0.36oral/caps, 11082.32.5NC1.0--0.18oral/caps, 220110.01.0NC1.0--0.183iv, 55.3246499-0.863710523.80.3-iv, 113.8432342-0.7313078814.80.29-iv, 218.7730496-0.6836314510.10.26-
Citation Format: Ilya Tsimafeyeu, Mikhail Byakhov, Vlatka Bencetić Mihaljević, Jasna Padovan, Genoveva Murillo, Sergei Tjulandin. Preclinical pharmacokinetic studies of RPT835, an allosteric FGFR2 inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B146.
Abstract B170: Discovery of tubulysin payloads for antibody drug conjugates with potent in vitro activity and in vivo efficacy in solid tumor models
Authors: Toader Dorin , Harper Jay , Lloyd Chris , Marwood Rose , Bannister David , Mao Shenlan , Chen Cui (Tracy) , Zhong Haihon (Helen) , Bedian Vahe , Wang Fengjiang , Gingipalli Lakshmaiah , Vasbinder Melisa , Thompson Pamela , Fleming Ryan , Bezabeh Byniam , Dimasi Nazzareno , Gao Changshou , Kamal Adeela 
Published: May 2016

Abstract
Antibody drug conjugates (ADCs) combine the specificity of antibodies with the potency of small molecule cytotoxic drugs and have the potential to provide significant efficacy as a treatment for cancer. The objective of this work was to identify potent new cytotoxic ADC payloads that can be used to target diverse tumor types. Here we report for the first time the discovery of fully synthetic tubulysin payloads which belong to a class of highly cytotoxic natural products that disrupt the cellular microtubule network leading to apoptosis of tumor cells. Our fully synthetic tubulysin payloads are comprised of: (i) a tubulysin warhead that displays pM potency, (ii) a protease cleavable amino-acid sequence and (iii) a tether bearing a reactive maleimide group. Tubulysin-based ADCs were generated via site-specific conjugation of these payloads to cysteines engineered into antibodies against cancer antigen target oncofetal protein 5T4. The resulting ADCs showed potent in vitro cell killing and in vivo efficacy in multiple solid tumor xenograft models including prostate cancer, non-small cell lung adenocarcinoma, breast cancer and gastric carcinoma. Furthermore, specific structural features of the tubulysin warhead, linker design and antibody engineering were shown to impact the overall in vitro and in vivo properties of the ADCs. Thus, these synthetic tubulysin payloads represent novel microtubule network disrupting compounds that display potent preclinical anti-tumor activity as an ADC that could be advanced to the clinic.
Citation Format: Dorin Toader, Jay Harper, Chris Lloyd, Rose Marwood, David Bannister, Shenlan Mao, Cui (Tracy) Chen, Haihon (Helen) Zhong, Vahe Bedian, Fengjiang Wang, Lakshmaiah Gingipalli, Melisa Vasbinder, Pamela Thompson, Ryan Fleming, Byniam Bezabeh, Nazzareno Dimasi, Changshou Gao, Adeela Kamal. Discovery of tubulysin payloads for antibody drug conjugates with potent in vitro activity and in vivo efficacy in solid tumor models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B170.
Abstract B186: ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma
Authors: Kuo Tsung-Keng , Lee On , Lin Mai-Wei , Lin Li-Zong , Liu Chun-Min , Hsieh Tai-ju , Wang Chun-Chung , Lin Shyh-Horng , Chang Chia-Ni , Hsu Hui-Chun , Chou Nien-Tzu , Lai Chin-Pen , Chen Chih-Hung , Tu Chia-Mu , Chen Shih-Ta , Tsai Yuan-Jang , Liu Chih-Peng , Hwang Jenn-Tsang , Huang Jui-Wen , Chen Yen-Chun , Hwang Chrong-Shiong , Tseng Hsiang-Wen 
Published: May 2016

Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and is also a leading cause of cancer-related deaths worldwide. Until now, treatments for HCC remain limited, especially for the shortage of promising systemic therapies to replace systemic chemotherapy. Sorafenib, the first drug applied in targeted therapy for HCC, was approved and drew considerable attention. However, the efficacy and side effects of sorafenib are still unsatisfied, which make sorafenib far from ideal for treatment of HCC. Thus, developing novel therapeutics for HCC is necessary. A novel compound, ITRI-2531, is developed to improve the efficacy from sorafenib. ITRI-2531 shows cytotoxicity in HCC cell lines (Huh-7 and PLC/PRF/5) and patient-derived HCC tissue cell lines. In studies of kinase activities, ITRI-2531 suppresses the phosphorylation of MEK and ERK in PLC/PRF/5 cells and shows inhibition of multiple kinases (FLT3, FLT4, PDGFRA, PGDFRB, and VEGFR2) in KINOMEscanTM study. In in vivo studies, oral treatment of ITRI-2531 repressed subcutaneous Huh-7 and PLC/PRF/5 tumor growth in severe combined immunodeficient (SCID) mice and shows better efficacy than sorafinib. Moreover, ITRI-2531 prolongs the survival of SCID mice with orthotopic patient-derived xenograft tumor and suppresses alpha-fetoprotein in serum. On the other hand, ITRI-2531 also has good pharmacokinetic profiles. According to these results, we believe that ITRI-2531 warrants further evaluation as a new anti-HCC drug.
Citation Format: Tsung-Keng Kuo, On Lee, Mai-Wei Lin, Li-Zong Lin, Chun-Min Liu, Tai-ju Hsieh, Chun-Chung Wang, Shyh-Horng Lin, Chia-Ni Chang, Hui-Chun Hsu, Nien-Tzu Chou, Chin-Pen Lai, Chih-Hung Chen, Chia-Mu Tu, Shih-Ta Chen, Yuan-Jang Tsai, Chih-Peng Liu, Jenn-Tsang Hwang, Jui-Wen Huang, Yen-Chun Chen, Chrong-Shiong Hwang, Hsiang-Wen Tseng. ITRI-2531 - A novel kinase inhibitor for treating hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B186.