bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4759: Identification of ALK, ROS1, FGFR2 and NRG1 fusions and validation with targeted inhibitors in lung and ovarian PDX models
Authors: Tang Xuzhen , Dong Hua , Gao Yibo , Zhang Zhixiang , Qiang Xiangnan , Zhang Baoyuan , Qin Yuxin , Yang Shuqun , Yan Yunbiao , Gu Qingyang , Zhang Norman , He Jie , Ji Qunsheng 
Published: July 2016

Abstract
Chromosomal rearrangement mediated gene fusions and activation of oncogenic signaling pathways have become druggable targets for therapeutic intervention, with successful development of Imatinib as an inhibitor of Bcr-Abl in treatment of Philadelphia chromosome positive chronic myelogenous leukemia. A recent study by Stransky et. al. reported systemic analysis of the transcriptome of nearly 7000 human tumor samples from the Cancer Genome Atlas and revealed the landscape of near twenty kinase fusions across twenty solid tumor types. Identification of corresponding PDX models that carry given kinase fusions would be of paramount interest for preclinical validation of candidate inhibitors. We have established about 1000 PDX models across 20 tumor types. Here we report the identification of ALK, ROS1, FGFR2 fusions in lung cancer PDX models and a NRG1 fusion in the ovarian cancer models by RNA using Sequencing data combined with the Chimerascan and Star-Fusion software for fusion calling.. The gene fusions, as validated by PCR and Sanger Sequencing, led to over-expression of the affected kinases, supporting the notion that kinase activation may be the oncogenic driver in the corresponding tumors. We further validated that ALK inhibitors Crizotinib, AP26113 and LDK378 exhibited robust antitumor activities in the ALK fusion model. Current works on validation of ROS1, FGFR2 and NRG1 inhibitors in the pertinent fusion models are under progression. These models should provide means for pre-clinical validation of novel kinase inhibitors and for experimenting novel combinatorial therapeutic strategies.
Citation Format: Xuzhen Tang, Hua Dong, Yibo Gao, Zhixiang Zhang, Xiangnan Qiang, Baoyuan Zhang, Yuxin Qin, Shuqun Yang, Yunbiao Yan, Qingyang Gu, Norman Zhang, Jie He, Qunsheng Ji. Identification of ALK, ROS1, FGFR2 and NRG1 fusions and validation with targeted inhibitors in lung and ovarian PDX models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4759.
Abstract 4766: Establishment of drug sensitivity and resistance testing using focused drug libraries to develop targeted therapies for patients with leukemia
Authors: Patel Apurvi , Montoya Justin J. , Wai Daniel H. , Arceci Robert J. , Azorsa David O. 
Published: July 2016

Abstract
Despite major advancements in pediatric leukemia therapy, toxicities and morbidity from chemotherapy regimens have been detrimental. Advances in genomic research as well as precision medicine have helped identify specific mutations that may be susceptible to targeted therapy in leukemic patients. Overall, the use of targeted drug therapy is rising in the pediatric oncology field. To complement genomic analysis of leukemia patients, our laboratory is working on the development of a drug sensitivity and resistance screening library, that would provide functionally relevant drug response data of the patient's leukemia cells. Development of this assay included the preparation of pre-dosed library plates allowing for rapid initiation of the assay. Cells were treated for 72 hours and cell viability was determined. Preliminary work in our laboratory used a library of 56 anti-cancer and targeted agents, which were tested on 16 AML cell lines and 10 ALL cell lines. Biological replicates were preformed for each cell line and drug response data in the form of IC50s and Area Under the Curve (AUC) were calculated. Hierarchical clustering was performed to determine similar responses between cell lines. Our results identified several cell lines that showed hypersensitivity to specific drugs. Among them, the AML cell line KG-1a showed sensitivity to three FGFR inhibitors including Ponatinib, which was previously reported. Validation of the screening results was done using a 10-concentration drug dose response assay. Further testing will include expansion of our drug library and application to ex vivo patient samples. The results from these studies can lead to the establishment of a drug sensitivity and resistance assay that could provide specifically engineered therapies for each patient. This form of personalized therapy would lead to diminished toxicities from systemic therapies as well as allow increased cure rates.
Citation Format: Apurvi Patel, Justin J. Montoya, Daniel H. Wai, Robert J. Arceci, David O. Azorsa. Establishment of drug sensitivity and resistance testing using focused drug libraries to develop targeted therapies for patients with leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4766.
Abstract 4768: Determination of Rab GTPase-mediated pathways critical for the antimyeloma activity of Rab GGTase inhibitors
Authors: Dykstra Kaitlyn M. , Allen Cheryl L. , Holstein Sarah A. 
Published: July 2016

Abstract
Multiple myeloma (MM) is a plasma cell malignancy characterized by the production of high levels of monoclonal protein (MP). This leads to an increased protein folding burden in the endoplasmic reticulum (ER) in MM cells, resulting in a constitutively upregulated unfolded protein response (UPR) and a lower threshold for ER stress-mediated apoptosis. We have previously shown that inhibitors of Rab GGTase, the enzyme responsible for Rab GTPase geranylgeranylation, disrupt MP trafficking in MM cells, leading to an accumulation of MP in the ER and induction of the UPR and apoptosis. There are over 60 different Rab GTPases in mammalian cells involved in regulating a wide range of membrane trafficking events including exocytic, endocytic, and lysosomal pathways. In this study, we aimed to further define how disruption of RabGTPase function in MM cells leads to apoptosis by knocking down individual Rab proteins. Given the accumulation of MP and induction of UPR, our initial focus was on secretory Rabs. Knockdown of Rab1A/B (&gt;50%) using siRNA in RPMI 8226 cells lead to moderate increases in intracellular lambda light chain in Rab1A/B knockdowns after 72 hours (∼120-140% of control levels by ELISA). However, despite the increase in intracellular MP, no increases in UPR or apoptosis markers were seen by western blot analysis or annexin-V/propidium iodide flow cytometry. Extended time course experiments (up to 120 hours) also did not exhibit any increase in UPR or apoptosis. Knockdown of Rab6A (&gt;60%), another RabGTPase associated with the secretory pathway, did not lead to increases in intracellular lambda light chain or induction of apoptosis. These results suggest that although individual knockdown of Rab1 is sufficient to partially disrupt MP trafficking, either more complete knockdown of the individual Rabs or knockdown of multiple Rabs is necessary for induction of the UPR and apoptosis. Additional optimization of the knockdowns will be performed in order to verify these results. These studies support the further development of Rab GGTase inhibitors that globally effect Rab GTPase geranylgeranylation as a novel anti-myeloma strategy.
Citation Format: Kaitlyn M. Dykstra, Cheryl L. Allen, Sarah A. Holstein. Determination of Rab GTPase-mediated pathways critical for the antimyeloma activity of Rab GGTase inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4768.
Abstract 477: Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC tumors
Authors: Quon Chenglu C. , Xia Xiaoling , Manriquez Lupe , Schemp Crystal , Sloane Dawn , Alabagi Shahad , Abdelwahab Mohammed G. , Gu Pengfei , Pang Lizhen , Hanif Khalid , Schechter Nicole 
Published: July 2016

Abstract
Dysregulation of the immune checkpoints has been identified as one of the mechanisms tumor cells employ for immune escape. Human papillomavirus (HPV) plays an important role in the etiology of one subset of Head and Neck Squamous Cell Carcinomas (HNSCC). Recent studies reported that PD-1/PD-L1 pathway may be correlated with HPV-associated HNSCC. The degree of PD-L1 expression has been reported to be increased in those patients with HPV-positive disease. Also, PD-L1 expression in HNSCC was observed in the primary, recurrent, and metastatic disease setting. However, the clinicopathological implications associated with PD-L1 in HNSCC, as well as in disease metastasis, remain largely unclear.
Using immunohistochemistry (IHC) and In situ hybridization (ISH) on VENTANA BenchMark ULTRA automated stainers, 40 cases of HNSCC, with matching primary and metastatic cancer stages, were evaluated for expression of PD-L1, p16, a surrogate marker of transforming HPV infections, and presence of HPV. Formalin-fixed paraffin-embedded tumor samples were subjected to PD-L1- and p16-IHC as well as HPV-ISH. A potential association between PD-L1 expression and HPV status among primary tumors and matched metastases was analyzed.
Our data show that expression of PD-L1 or p16 is concordant in the majority of HNSCC primary vs metastatic tumor cases tested. Agreement rate of p16 expression among 40 case pairs of primary vs metastatic tumor was 88.2% with a 95% Confidence Interval (CI) of (73.4-95.3). PD-L1 expression was 76.9% (61.7-87.4) concordant among the 40 case pairs. Agreement rate between PD-L1 and p16 was 77.1% (61.0-87.9) in primary cases and 51.3% (35.9-66.6) in metastatic cases. No obvious association between PD-L1 and p16 expression was observed.
Citation Format: Chenglu C. Quon, Xiaoling Xia, Lupe Manriquez, Crystal Schemp, Dawn Sloane, Shahad Alabagi, Mohammed G. Abdelwahab, Pengfei Gu, Lizhen Pang, Khalid Hanif, Nicole Schechter. Correlation of PD-L1 expression and HPV status among primary and metastasized HNSCC tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 477.
Abstract 4772: Addiction to chaperones: Investigating the role of HSP70 isoforms in cancer
Authors: Suckling Lorna AB , Powers Marissa , Sharp Swee , Workman Paul 
Published: July 2016

Abstract
The heat shock protein 70kDa (HSP70) family of molecular chaperones are critical for the survival of cancer cells due to their antiapoptotic activity and role in protein homeostasis. Our laboratory has previously shown that silencing two members of this family (HSP72 and HSC70) causes tumour cell specific apoptosis and also sensitises cancer cells to HSP90 inhibitors. HSP70 has therefore become an appealing therapeutic target. The human HSP70 family comprises 17 genes and the individual roles of the isoforms in cancer are poorly understood. Here we use a systematic approach to determine the importance of HSP70 isoforms, and a selection of HSP70 binding partners, for the growth of cancer cells under stress. It was hypothesised that cancer cells are more dependent on HSP70 proteins when under stressed conditions, as encountered in the tumour environment. We used RNA interference (RNAi) to determine the effect of silencing HSP70 isoforms and binding partners on cancer cell viability, as measured by CellTiter-Blue®. The siRNA screens were carried out in human colon (RKO) and breast (BT474) cancer cells under serum deprivation, oxidative stress and hypoxia. The silencing of several HSP70 genes, including the HSP70 isoform HSPA5 (also known as BiP/Grp78), were found to cause a reduction in cancer cell viability under stress. Detailed validation of hits has been carried out to confirm their importance for cancer cell survival and validated hits may provide potentially important therapeutic targets for cancer drug discovery.
Citation Format: Lorna AB Suckling, Marissa Powers, Swee Sharp, Paul Workman. Addiction to chaperones: Investigating the role of HSP70 isoforms in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4772.
Abstract 4778: Covalent bonding of a C8-conjugated pyrrolobenzodiazepine (PBD) monomer and dimer to a terminal guanine residue of DNA duplex and hairpin fragments
Authors: Mantaj Julia , Jackson Paul J. M. , Jackson Khondaker Miraz , Thurston David E. 
Published: July 2016

Abstract
The pyrrolobenzodiazepines (PBDs) are a family of covalent-binding DNA-interactive minor-groove binding agents that are of growing interest due to their potential as stand-alone anticancer agents, and for their use as payloads in Antibody Drug Conjugates (ADCs). For example, one PBD Dimer, SJG-136 has reached Phase II evaluation in the clinic for ovarian and haematological cancers, and a number of PBD-based ADCs are now being evaluated in pre-clinical, Phase I and II clinical trials (e.g., SGN-CD19B, SGN-CD33A [vadastuximab talirine], SGN-CD70A, SGN-CD123A, SC16LD6.5 [Rova-T, rovalpituzumab tesirine] and ADCT-402).
Until now, PBDs, which bind in the minor groove of DNA and covalently bond to a guanine residue through its C2-NH2 functional group, were thought to require a three-base-pair recognition sequence prior to covalent bonding to the central guanine (with a thermodynamic preference for binding to 5’-Pu-G-Pu-3’ sequences but a kinetic preference for 5’-Py-G-Py-3’; Pu = Purine, Py = Pyrimidine). Using HPLC/MS methodology with designed hairpin and duplex oligonucleotides, we have now demonstrated that the PBD dimer SJG-136 and the C8-conjugated PBD Monomer GWL-78 can covalently bond to a terminal guanine of DNA, with the PBD skeleton spanning only two base pairs. Control experiments with the non-C8-conjugated anthramycin along with molecular dynamics simulations suggest that the C8-substituent of a PBD monomer, or one-half of a PBD Dimer, may provide stability for the adduct.
This observation highlights the importance of PBD C8-substituents, and also suggests that PBDs may bind to terminal guanines within stretches of DNA in cells, thus representing a potentially novel mechanism of action at the end of DNA strand breaks.
Citation Format: Julia Mantaj, Paul J. M. Jackson, Khondaker Miraz Jackson, David E. Thurston. Covalent bonding of a C8-conjugated pyrrolobenzodiazepine (PBD) monomer and dimer to a terminal guanine residue of DNA duplex and hairpin fragments. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4778.
Abstract 478: A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors
Authors: Contractor Tanupriya , Kobayashi Shinta , Clausen Richard , da Silva Edaise , Tang Laura , Chan Chang , Harris Chris R. 
Published: July 2016

Abstract
Pancreatic neuroendocrine tumors are generally classified as functioning or nonfunctioning. Patients with functioning tumors can have severe hypoglycemia because their tumors express high amounts of insulin as well as chromogranin A; fortunately, these tumors are seldom metastatic. Patients with nonfunctioning tumors express high amounts of chromogranin A but little insulin; unfortunately these tumors are highly metastatic to the liver. Nonfunctioning tumors are more common, and a more severe health issue. The highly studied RT2 B6 mouse, in which the SV40 T antigen is expressed from an insulin promoter in an inbred C57Bl/6 genetic background, is a model for functioning pancreatic neuroendocrine tumors: liver metastasis is uncommon in RT2 B6 mice, which are very hypoglycemic and often die when tumors are very small. We have changed the genetic background and are studying RT2 AB6F1 hybrid mice, which have a C57Bl/6 father and a mother from an A/J inbred background. RT2 AB6F1 mice are much less hypoglycemic, and these mice develop liver metastasis with high frequency. We have mated the hybrid AB6F1 mice to their littermates in order to map metastasis genes by F2 analysis, and have discovered that a locus at mouse chromosome 2qG1 links tightly to liver metastasis. One gene within this locus, InsM1, is less expressed in the primary tumors of mice with liver metastatic disease. InsM1 is also less expressed in primary tumors from humans with liver metastatic disease. Previous studies of InsM1 have shown that this protein maintains the differentiated status of pancreatic beta cells. We find that tumors from mice with low expression of InsM1 also express lower amounts of several distinctive markers of differentiated beta cells, but higher amounts of several markers of liver cells. These data suggest that dedifferentiation to stem cells, which can then redifferentiate to other cell types such as liver cells, promotes metastasis of pancreatic beta cell tumors. Intratumoral expression of liver markers may be a useful predictor of metastatic disease in these patients. Dedifferentiation of mature beta cells is also a mechanism by which type 2 diabetes occurs, so there may be similarities between these two diseases.
Citation Format: Tanupriya Contractor, Shinta Kobayashi, Richard Clausen, Edaise da Silva, Laura Tang, Chang Chan, Chris R. Harris. A mouse model for highly metastatic, nonfunctioning pancreatic neuroendocrine tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 478.
Abstract 4788: Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action
Authors: Deng Yongqi , Samatar Ahmed , Shipps Gerald , Cooper Alan , Long Brian , Carr Donnar , Xiao Li , Hruza Alan , Wang Tong , Zhu Liang , Nan Yang , Patel Mehul , Muppalla Kiran , Zhu Hugh , Boga Babu Sobhana , Gao Xiaolei 
Published: July 2016

Abstract
Activation of the RAS/MAPK pathway occurs via a cascade of protein phosphorylation events which culminate in the phosphorylation & activation of ERK 1/2. Aberrant activation of this pathway has been demonstrated in several human tumor types. Inhibitors of this pathway in clinical development target upstream kinases, BRAF or MEK. Only a few ERK 1/2 has been reported. The goal of the ERK program was to develop a targeted therapy that is guided by a clear patient selection / responder identification plan based on BRAF and K/NRAS mutations.
Utilizing an affinity based high-throughput screening strategy (ALIS), we discover a novel class of small molecule ERK 1/2 inhibitors. Optimization of this chemical series led to the discovery of SCH 772984, which is highly selective ERK1/2 inhibitor, inhibiting cell proliferation selectively in tumor cell lines with an activated MAPK pathway and causes significant tumor regression in vivo in BRAF & RAS mutant xenograft models. Based on insights gained through crystallographic analysis, SCH 772984 and related compounds have a unique ERK binding mode which results in a novel dual mechanism of inhibition, blocking ERK phosphorylation by MEK as well as inhibiting ERK kinase activity. This novel mechanism enables the use of ERK phosphorylation as a target engagement biomarker. Biological differences between pathway inhibition at the level or ERK vs. inhibition of upstream kinases are being examined. The SAR and crystal structures of this series ERK inhibitors will be reported.
Citation Format: Yongqi Deng, Ahmed Samatar, Gerald Shipps, Alan Cooper, Brian Long, Donnar Carr, Li Xiao, Alan Hruza, Tong Wang, Liang Zhu, Yang Nan, Mehul Patel, Kiran Muppalla, Hugh Zhu, Babu Sobhana Boga, Xiaolei Gao. Discovery of potent and selective inhibitors of ERK1/2 with a unique mechanism of action. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4788.
Abstract 4805: In vitro characterization of novel inhibitors of ROCK and MRCK kinases as anticancer agents
Authors: Desai Dhimant H. , Kale Vijay P. , Hengst Jeremy A. , Dick Taryn E. , Colledge Ashley L. , Amin Shantu G. , Yun Jong K. 
Published: July 2016

Abstract
Metastatic cancers are the second leading cause of deaths in the USA. RhoA and Cdc42 play critical roles in the regulation of plasticity of cancer cell migration/invasion and cell proliferation. ROCK1/2 and MRCKá/â are downstream kinases in the signaling pathways associated with cancer cell migration and invasion. Hence, we hypothesized that simultaneous targeting of these two kinase families would be an effective therapeutic strategy to block migration, invasion, and growth of metastatic cancers. We have identified DJ4 as a novel inhibitor of ROCK and MRCK kinases. In the cellular functional assays, DJ4 treatment significantly blocked stress fiber formation, and inhibited migration and invasion of multiple cancer cell lines in a concentration dependent manner. To study the critical functional groups required for its activity, we have modified the chemical structure of DJ4 at various functional groups and synthesized several analogs of DJ4 to perform the structural activity relationship (SAR) study for their ROCK1 inhibition. The effectiveness of these compounds were further investigated using National Cancer Institute's drug screening program in 60 human cancer cell lines representing nine different cancer types. These compounds effectively inhibit migration and invasion of multiple cancer cell types. Selected analogs were tested for their anti migration, pro-apoptotic, and anti-proliferative effects in breast cancer cells. Our studies strongly indicate that DJ4 and its analog, DJ110, are potent inhibitors of ROCK1, ROCK2, MERKá and MRCKâ. The results of our finding will be discussed.
Citation Format: Dhimant H. Desai, Vijay P. Kale, Jeremy A. Hengst, Taryn E. Dick, Ashley L. Colledge, Shantu G. Amin, Jong K. Yun. In vitro characterization of novel inhibitors of ROCK and MRCK kinases as anticancer agents. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4805.