bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3880: Peptide-targeted chemotherapy for pancreatic cancer
Authors: Lin Chin-Tarng , Wu Chen-Der , Lee Jen-Chieh , Wu Han-Chung , Lee Chung-Wei , Lin Chin-Feng , Hsu Ming-Chieh 
Published: August 2018

Abstract
The purpose of this abstract was to assess the efficacy of peptide targeted chemotherapy for pancreatic carcinoma. Previously we have constructed four peptides that bind specifically to cancer cell lines, which were derived from three different carcinoma cell lines and their vascular endothelia: L-peptide: (L-P, anti-cancer cell membrane), RLLDTNRPLLPY; SP-94-P (anti-hepato-pancreatic cancer cell membrane), SFSHHTPILP; PC5-52-peptide (anti-tumor endothelia), SVSVGMKPSPRP; and control peptide, RLLDTNRGGGGG. These peptides were linked to pegylated liposomal iron oxide nanoparticles to identify the targeted tumor cells and vascular endothelia using MRI analysis, and were also linked to dextran coated liposomal doxorubicin (L-D) for treatment of non-obese diabetic, severe combined immunodeficiency (NOD-SCID) mice bearing pancreatic cancer cell (PANC-1) xenografts. Our results demonstrated that the tumor intensity of MRI is clearly decreased after SP-94-P-iron oxide was applied, and that in combination of application of L-P linked L-D (L-P-L-D) plus SP-94-P linked L-D (SP-94-P-L-D) and PC5-52-P linked L-D (PC5-52-P-L-D), they could inhibit pancreatic tumor growth with very mild adverse events. The use of the control peptide linked L-D also led to a decrease of the xenograft size, but also induced marked apoptotic change of their visceral organs. It is concluded that the combination of L-P-L-D, SP-94-P-L-D and PC5-52-P-L-D to treat pancreatic cancer xenograft in NOD SCID mice can clearly inhibit pancreatic cancer growth with minimal adverse events.
Citation Format: Chin-Tarng Lin, Chen-Der Wu, Jen-Chieh Lee, Han-Chung Wu, Chung-Wei Lee, Chin-Feng Lin, Ming-Chieh Hsu. Peptide-targeted chemotherapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3880.
Abstract 3882: Functional validation of a genome-wide association study (GWAS) SNP associated with anthracycline-induced congestive heart failure
Authors: Wu Xi , Xue Gloria , Gardner Laura , Shen Fei , Jiang Guanglong , Philips Santosh , Cunningham Geneva , Schneider Bryan P. 
Published: August 2018

Abstract
Anthracyclines are commonly used chemotherapies for the treatment of breast cancer, but they can cause dose-related cardiotoxicities and lead to congestive heart failure (CHF) in ~2% of patients. There are no clinically available predictive biomarkers for this toxicity. Previously we have identified and validated the association of a single nucleotide polymorphism (SNP), rs28714259, with CHF in three large adjuvant phase III breast cancer trials. rs28714259 locates in a putative glucocorticoid receptor (GR) binding site and the risk (minor) allele is predicted to disrupt GR binding. Interestingly, activation of GR-signaling by dexamethasone has been shown to protect cardiomyocytes from doxorubicin-induced apoptosis in rat. To test whether the risk allele affects GR binding efficiency in vitro, we performed electrophoretic mobility shift assay (EMSA) in MCF-7 and A549 cells. 100nM of dexamethasone for 4 hours induced a prominent band shift in either the major- or risk-allele probes. Notably, we observed a ~50% reduction in the shifted band intensity of risk-allele probes compared to major-allele probes, suggesting decreased binding in risk-allele probes. No additional supershift was detected after the binding reaction was co-incubated with a GR antibody. However, the previously shifted band was significantly diminished in both the major- and risk-allele probes, probably due to a conformational change induced by GR antibody and leading to the disruption of GR/DNA binding, which in turn suggests the observed shift was specifically caused by GR. Further validations are ongoing using cardiomyocytes derived from human induced pluripotent stem cells (iPSCs). These studies provide further insight into the function and role of rs28714259 in anthracycline-induced CHF.
Citation Format: Xi Wu, Gloria Xue, Laura Gardner, Fei Shen, Guanglong Jiang, Santosh Philips, Geneva Cunningham, Bryan P. Schneider. Functional validation of a genome-wide association study (GWAS) SNP associated with anthracycline-induced congestive heart failure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3882.
Abstract 3893: Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity
Authors: Nie Qian , Shrestha Shikshya , Tapper Erin E. , Trogstad-Isaacson Colbren S. , Bouchonville Kelly J. , Offer Steven M. , Diasio Robert B. 
Published: August 2018

Abstract
5-Fluorouracil (5-FU) has remained a widely prescribed anti-cancer drug for decades. However, 5-FU–based treatments show inter-individual variability, with up to 34% of 5-FU–treated patients developing severe (grade 3+) adverse toxicity. Dihydropyrimidine dehydrogenase (DPD; DPYD gene) is the rate-limiting enzyme of 5-FU catabolism and converts 80–85% of 5-FU into its inactive metabolites. Three deleterious genetic variations in DPYD are well-established predictors of severe 5-FU toxicity (i.e., *2A, p. I560S, and p. D949V); however, these variants only explain 30–35% of adverse cases. Recently, an intronic variant (rs75017182) has been suggested to contribute to 5-FU–related toxicity by promoting the alternative splicing of DPYD. However, clinical studies are conflicting as to the degree to which rs75017182 affects DPD enzyme function, and the true contribution of the rs75017182 variant towards DPD function and 5-FU toxicity remains unclear and inconclusive. In the present study, we directly examined the effect of the intronic SNP rs75017182 on DPYD mRNA splicing, DPYD expression, and DPD enzyme function. We genotyped 3950 healthy Caucasian volunteers from the Mayo Clinic Biobank to identify the rs75017182, *2A, p.I560S, and p.D949V variants. From the initial cohort, 204 volunteers who were rs75017182 heterozygous carriers were recruited as our study population. Alternative splicing and DPD activity in rs75017182 carriers were measured. The findings were confirmed using a novel mini-gene reporter system in vitro. A moderate, but significant, reduction (30%) was detected in canonically spliced DPYD expression in rs75017182 carriers compared to non-carriers. A correlative reduction (35%) in DPD enzyme activity was observed in those carriers, which was similar to that of D949V carriers (31%). The results demonstrated an association of this deep intronic variant with decreased DPD activity and suggested that rs75017182 may be a predictor of 5-FU toxicity similar to D949V.
Citation Format: Qian Nie, Shikshya Shrestha, Erin E. Tapper, Colbren S. Trogstad-Isaacson, Kelly J. Bouchonville, Steven M. Offer, Robert B. Diasio. Quantitative contribution of rs75017182 to dihydropyrimidine dehydrogenase mRNA splicing and enzyme activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3893.
Abstract 3901: Characterizing antibody-drug conjugate cytotoxicity using four different real-time assays
Authors: Niles Andrew L. , Kupcho Kevin , Duellman Sarah , Vidugiriene Jolanta , Lazar Dan , Cali James J. 
Published: August 2018

Abstract
Recent clinical successes using antibody drug conjugates (ADC) directed to hematological or solid tumor cancers have re-invigorated immunotherapeutic drug development interest. Unfortunately, efficacious ADC are inherently complex entities comprised of a targeting antibody, a stable but cleavable linker, and a toxic payload, for which the best combinations are often identified through iterative trial and error. Therefore, an efficient and systematic method for rank ordering ADC candidates is sought to evaluate their intrinsic pharmacodynamic properties. We chose SKBR3 (Her2+) and T47D (Her2-) cell models to define the on- and off-target cytotoxic potential of trastuzumab emtansine. We employed a suite of four, newly developed real-time assays to measure exposure-dependent changes in viability, caspase activation, phosphatidylserine (PS) exposure and loss of membrane integrity to define potency and magnitude of response, as well as primary mode of cell death. We discovered that trastuzumab emtansine mediated dose-dependent effects on SKBR3, with cytostasis beginning at 17h near 1μg/ml, caspase induction at 20h, which led to PS exposure at about 21h and secondary necrosis at 30h. During this same time course, full dose-response curves were generated for each biomarker as EC50 values evolved and matured to their respective maximal responses. Conversely, the T47D non-target cell population exhibited only minor cytotoxicity at the latest time points, presumably owing to linker degradation and non-specific payload release. Taken together, these data define the in vitro pharmacological disposition of trastuzumab emtansine, including the kinetic component of functionality related to antigen/antibody engagement, internalization, linker mediated payload release and resulting toxicity. This study may provide a tangible roadmap for the critical evaluation of other ADC under development.
Citation Format: Andrew L. Niles, Kevin Kupcho, Sarah Duellman, Jolanta Vidugiriene, Dan Lazar, James J. Cali. Characterizing antibody-drug conjugate cytotoxicity using four different real-time assays [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3901.
Abstract 3902: A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo
Authors: Brin Elena , Wu Katherine , He Yudou , Shia Wei-Jong , Kuo Mario M. , Chen Li-Chang , Dagostino Eleanor , Hickey Richard , Almassy Bob , Showalter Richard , Thomson Jim 
Published: August 2018

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have shown good safety profile and efficacy in preclinical cancer models. However, clinical success has been limited due to poor PK and/or development of resistance to death receptor-induced apoptosis. To address these issues we have conceived and produced a fusion protein of arginine deiminase (ADI) and TRAIL. ADI is an enzyme that converts arginine into citrulline. Arginine deprivation can inhibit growth of arginine auxotrophic cancers that lack key enzymes enabling normal cells to produce arginine from citrulline. ADI is currently being evaluated in clinical trials and is well-tolerated. We (and others) observed synergy between ADI and TRAIL in inducing apoptosis in a number of cancer cell lines including those that are otherwise resistant to rhTRAIL. We have explored potential mechanisms of synergy and will present our findings. Using in silico modeling we predicted structural complementarity between ADI and TRAIL with each modality stabilized when part of the fusion protein. We were able to produce multiple ADI-TRAIL fusion protein variants and have tested their activity in enzymatic and cell-based assays. Our experimental data confirmed in silico predictions of the structural advantages for ADI and TRAIL in the fusion protein. ADI enzymatic activity improved when part of the fusion protein and the fusion protein appeared to have higher potency than the combination of the two separate proteins in inducing cancer cell death. In mice ADI-TRAIL fusion protein exhibited extended half-life and was efficacious in HCT116 xenograft model, superior to rhTRAIL administered at the same molar amounts. Serum concentrations of the fusion protein had an inverse correlation with the tumor volume. ADI-TRAIL is a novel biologic that benefits from structural and functional synergies between its components and is showing promise as a cancer therapeutic in preclinical studies.
Citation Format: Elena Brin, Katherine Wu, Yudou He, Wei-Jong Shia, Mario M. Kuo, Li-Chang Chen, Eleanor Dagostino, Richard Hickey, Bob Almassy, Richard Showalter, Jim Thomson. A novel biologic ADI-TRAIL fusion protein benefits from structural and functional complementarity of its components arginine deiminase and TRAIL, induces cancer cell apoptosis in vitro, and inhibits tumor growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3902.
Abstract 3926: Discovering a novel microtubule inhibitor overcoming tumor multidrug resistance
Authors: Ning Nannan , Wu Chengyong , Wu Min , Yu Yamei , Zhu Changjun , Benes Cyril , Zhang Jianming , Deng Xianming , Chen Qiang , Ren Ruibao 
Published: August 2018

Abstract
Microtubule inhibitors, as chemotherapeutic drugs, are widely used for cancer treatment in clinic. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in its clinical implementation. From a high throughput drug screening using cells transformed by oncogenic RAS, we identified a small molecule AR8-1006 that blocks cell proliferation. The analysis of structure-activity relationship indicated that this serial of scaffold represents a potent inhibitor of tumor cell growth. AR8-1006 shows activities against a larger panel of more than 1000 human cancer cell lines with a wide variety of tissue origins. Further analysis showed that this compound depolymerizes microtubules and affects formation of the spindle. Interestingly, it induces the spike-like conformation of microtubules in vitro and in vivo, which is different from typical microtubule modulators. Structural analysis revealed that this serial of compounds binds to the colchicine pocket at the intra-dimer interface, though mostly not overlapping with colchicine binding. More importantly, AR8-1006 displays favorable pharmacological properties on overcoming tumor MDR both in vitro and in vivo. Taken together, our data reveal a novel scaffold represented by AR8-1006 that could be developed as cancer therapeutics, especially for tumor multidrug resistance.
Citation Format: Nannan Ning, Chengyong Wu, Min Wu, Yamei Yu, Changjun Zhu, Cyril Benes, Jianming Zhang, Xianming Deng, Qiang Chen, Ruibao Ren. Discovering a novel microtubule inhibitor overcoming tumor multidrug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3926.
Abstract 3932: Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma
Authors: Umemura Shigeki , Makinoshima Hideki , Ishii Genichiro , Sasaki Takehiko , Esumi Hiroyasu , Goto Koichi , Tsuchihara Katsuya 
Published: August 2018

Abstract
Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. We analyzed the phosphatidyl lipid profile including the acyl groups of 11 SCLC cell lines using electrospray ionization mass spectrometry. We found that a specific phosphatidylinositol (3,4,5)-triphosphate (PIP3) subspecies lipid product, PIP3 (38:4), is predictive in assessing sensitivity to gedatolisib. We generated a large-scale metabolomic dataset for 28 SCLC cell lines. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine led to resistance to PI3K pathway inhibition. The levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1 (HPRT1), a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Loss of HPRT1 in SCLC cells decreased cellular proliferation in the presence of gedatolisib compared with a control. Further, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the mechanism of resistance to PI3K pathway inhibitors is mediated by activation of the purine salvage pathway, which supplies purine resources for nucleotide biosynthesis. Metabolic profiles of clinical samples of SCLC revealed that purine-related metabolites were higher in SCLC tumor tissues, suggesting that higher amounts of purine-related aqueous metabolites might be characteristic of SCLC biology. Metabolomics is a powerful approach for identifying novel therapeutic biomarkers applicable to SCLC treatment.
Citation Format: Shigeki Umemura, Hideki Makinoshima, Genichiro Ishii, Takehiko Sasaki, Hiroyasu Esumi, Koichi Goto, Katsuya Tsuchihara. Metabolic biomarkers predict the sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3932.
Abstract 3933: Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index
Authors: Schnell Christian R. , Ferrat Thomas , Wyss Daniel , Tinetto Walter , Tobler Sonja , Fritsch Christine , Jensen Michael 
Published: August 2018

Abstract
The gene encoding for the catalytic subunit of the phosphatidylinositol-3-kinase (PI3K), p110a (PIK3CA) is the most frequently mutated kinase in cancer. This discovery triggered the development of small molecule anti-PI3K inhibitors, such as NVP-BYL719. However, the PI3K / Akt signaling pathway plays not only an important role in promoting cell growth, proliferation and survival but also in regulating glucose homeostasis by directly mediating insulin-stimulated glucose uptake into insulin sensitive tissues (adipocytes and muscles). NVP-BYL719 (a selective inhibitor of the class Ia PI3K isoform alpha) given in the morning is facing on-target tolerability challenge (hyperglycemia) in clinical trials limiting the dose being administered to patient (1). As glucose metabolism is highly impacted by circadian rhythms in patients and rodents, we have decided to adopt an integrative circadian-timing approach in our pre-clinical models to interrogate the benefit of morning vs evening dosing for BYL719. By using a newly developed radio-telemetry technology (2), we were able to record in real time and 'around-the-clock' blood glucose levels in stress-free, freely moving rats dosed with NVP-BYL719 at different regimens. The dynamic profile of hyperglycemia observed after active or inactive period dosing of NVP-BYL719 (50 mg/kg qd p.o.) were similar. Dosing before the inactive phase (10 a.m.) allowed blood glucose to normalize in between 2 doses, which could not be achieved when dosing before the active phase (5 p.m.). After treatment discontinuation a significant hyperglycemia remained for a period up to 12h in the group dosed before the active phase (5 p.m.). Circadian “evening” NVP-BYL719 dosing is associated with a better control of glycaemia. Clinically this could potentially translate to better compliance and longer time on treatment hence better efficacy for patient. Based on these findings we could recommend optimized treatment schedules for future combination experiments in the clinic with NVP-BYL719. 1) Juric et al, “Phase I study of the PI3Kα Inhibitor BYL719, as a Single Agent in Patients with Advanced Solid Tumors (AST)”, Annals of Oncology (2014), 25 (Supp. 4) 2) Brockway et al, “Fully Implantable Arterial Blood Glucose Device for Metabolic Research Applications in Rats for Two Months”, J Diabetes Sci Technol (2015), 9(4):771-81
Citation Format: Christian R. Schnell, Thomas Ferrat, Daniel Wyss, Walter Tinetto, Sonja Tobler, Christine Fritsch, Michael Jensen. Circadian timing regimen for alpelisib (NVP-BYL719), a selective inhibitor of the class Ia PI3K isoform alpha to maximize therapeutic index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3933.
Abstract 3936: Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes
Authors: Wang Xin , Hamdan Feda H. , Sen Madhobi , Kutschat Ana P. , Johnsen Steven A. 
Published: August 2018

Abstract
Esophageal cancer is one of the most malignant cancers, ranking as the sixth leading cause of cancer-related deaths worldwide. The poor survival rate and prognosis highlight the limitations in the biological understanding of esophageal cancer and the urgent need for identification of novel targeted molecular therapies. Recently, large scale genomic analyses have revealed the extensive alternations of epigenetic regulators which may be used as a basis for developing new “epigenetic drugs “. BRDT, bromodomain testis-specific protein, is a member of the bromodomain and extra-terminal (BET) family of epigenetic reader proteins. BET proteins can regulate gene expression by recognizing acetylated lysines, thus playing important roles in both normal development and disease progression. Inhibition of BET proteins has emerged as a potential therapy for many types of cancer. In normal human tissues, unlike the other members of BET family, BRDT is exclusively highly expressed in testes where it drives the meiotic and post-meiotic gene expression to promote spermatogenesis. We have identified BRDT to be expressed in over 20% of esophageal squamous cell carcinoma (ESCC), a predominant subtype of esophageal cancer. Knockdown of BRDT does not affect cell proliferation, but leads to alterations in the expression of differentiation markers. In addition, RNA-seq following BRDT knockdown also supports a role of BRDT in cell differentiation. Depletion of BRDT does not alter the cellular response to BET inhibition. Surprisingly, we also identified BRDT transcripts encoding two truncated isoforms lacking the first bromodomain, which could potentially alter its epigenetic reader function. The genome occupancy profile of BRDT showed a significant enrichment at transcription start site (TSS), which is distinct from BRD4. It also showed potential interactions between BRDT and E2F family and SMAD family. Together, we showed that BRDT is overexpressed in ESCC cell lines and may influence ESCC development or progression in a subset of tumors by regulating cell differentiation-associated genes.
Citation Format: Xin Wang, Feda H. Hamdan, Madhobi Sen, Ana P. Kutschat, Steven A. Johnsen. Bromodomain testis-specific protein BRDT is expressed in a subset of esophageal squamous cell carcinomas and controls expression of differentiation-associated genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3936.