bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A164: The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel
Authors: Milhollen Michael A. , Shi Judi , Traore Tary , Huck Jessica , Sappal Darshan , Duffy Jennifer , Lightcap Eric , Ishii Yuko , Ciavarri Jeff , Fleming Paul , Bence Neil , Hyer Marc L. 
Published: May 2016

Abstract
Clinical results of VELCADE® (bortezomib) For Injection have prompted evaluation of other enzymes within the ubiquitin proteasome system (UPS) as druggable targets for human cancer. We have identified a first in class investigational drug, TAK-243 (MLN7243), which targets the ubiquitin activating enzyme, UAE (UBA1), an essential cellular enzyme responsible for activating &gt; 99% of all cellular ubiquitin. Ubiquitin is involved in multiple cellular processes including ubiquitin-dependent protein turnover, cell cycle progression, regulation of apoptosis, protein localization and response to DNA damage. Experiments combining targeted siRNA knockdown with TAK-243 identified DNA damage repair genes necessary for UAE inhibitor-induced cell death. A more focused approach revealed TAK-243 treatment blocked essential monoubiquitination events within the Translesion synthesis (TLS), Fanconi Anemia (FA) and Homologous recombination (HR) pathways. Inhibition of UAE prevented mono-ubiquitin signaling of key mediators within these pathways, including PCNA and FANCD2, by blocking formation of their specific E2-ubiquitin thioesters. In vitro cell-based assays combining TAK-243 with ultraviolet (UV) and radiation, both known to induce DNA damage, yielded inhibition of cell growth and enhanced DNA damage as observed through colony formation assays and Comet assay detection, respectively. Xenograft tumor bearing mice were treated with carboplatin or docetaxel, combined with TAK-243, to evaluate combination benefits in vivo. Synergistic and additive anti-tumor combination benefits were observed in animals treated with TAK-243 + carboplatin and TAK-243 + docetaxel. These important mechanistic in vitro and in vivo studies indicate the dependency of ubiquitination signaling in DNA damage repair and provide a mechanistic rationale for combining radiation, carboplatin or docetaxel with TAK-243 in the clinical setting. Currently, TAK-243 is being evaluated in a solid tumor phase I clinical trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity (ClinicalTrials.gov identifier: NCT02045095).
Citation Format: Michael A. Milhollen, Judi Shi, Tary Traore, Jessica Huck, Darshan Sappal, Jennifer Duffy, Eric Lightcap, Yuko Ishii, Jeff Ciavarri, Paul Fleming, Neil Bence, Marc L. Hyer. The small molecule UAE inhibitor TAK-243 (MLN7243) prevents DNA damage repair and reduces cell viability/tumor growth when combined with radiation, carboplatin and docetaxel. [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 A164.
Abstract A174: RXDX-105 demonstrates potent RET inhibitory activity with therapeutic potential in multiple preclinical models of RET-rearrangement driven cancer
Authors: Joseph James , Franovic Aleksandra , Schairer Anni , Martin Eric , Wei Ge , Murphy Danielle , Christiansen Jason , Shoemaker Robert , Multani Pratik , Wild Robert , Li Gang 
Published: May 2016

Abstract
Genomic alterations in RET, encoding the RET (rearranged in transformation) kinase, have been identified as bona fide oncogenic drivers in numerous tumor types. Activating RET point mutations are typically associated with multiple endocrine neoplasia (types A and B) and familial medullary thyroid carcinoma. Although activating RET rearrangements can be found in up to 40% of papillary thyroid cancers, they are only present in up to 2% of non-small cell lung cancers and at lower frequencies in multiple other malignancies. As a result of the relatively low prevalence of molecular alterations in multiple tumor types, diagnostics-driven therapeutic selection strategies are being developed to identify patients with RET alterations. There also remains a clinical need for a potent, selective and safe RET inhibitor that demonstrates robust efficacy in malignancies harboring RET rearrangements and other oncogenic alterations.
RXDX-105 (formerly CEP-32496) is a potent, orally available, small molecule kinase inhibitor that potently binds and antagonizes several known oncogenic driver proteins, including RET, while sparing VEGFR2. RXDX-105 is currently in clinical trial in patients with solid tumors. To evaluate the therapeutic potential of RXDX-105 in malignancies bearing RET alterations, we first assessed the ability of RXDX-105 to antagonize RET activity in vitro. In biochemical and cell based assays, RXDX-105 potently antagonizes the activity of RET-fusion proteins and RET activating point mutations, resulting in a dose dependent inhibition of downstream signaling events and cell proliferation. In vivo, RXDX-105 displays potent and dose dependent anti-tumor activity with significant tumor growth regressions in several patient derived xenograft models harboring RET-rearrangements.
These pre-clinical studies support the inclusion of patients bearing RET alterations in future diagnostics-based clinical trials exploring RXDX-105 efficacy across a variety of tumor types.
Citation Format: James Joseph, Aleksandra Franovic, Anni Schairer, Eric Martin, Ge Wei, Danielle Murphy, Jason Christiansen, Robert Shoemaker, Pratik Multani, Robert Wild, Gang Li. RXDX-105 demonstrates potent RET inhibitory activity with therapeutic potential in multiple preclinical models of RET-rearrangement driven cancer. [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 A174.
Abstract A185: Combined treatment strategies for microtubule interfering agent-resistant tumors
Authors: Broggini-Tenzer Angela , Sharma Ashish , Bender Sabine , Nytko-Karouzakis Katarzyna , Pruschy Martin 
Published: May 2016

Abstract
Treatment resistances to specific anticancer agents and radiotherapy are often linked to the mutated genetic background of tumor cells. Their activities towards co-targeted tumor microenvironment-related cells are thereby also abrogated but could be reestablished as part of rationally-designed combined treatment modalities. Here we mechanistically investigate in two clinically relevant microtubule-interfering agent (MIA)-refractory tumor models the potency of combined treatment modalities of MIAs, inhibitors of angiogenesis and ionizing radiation to overcome MIA-resistance.
Single and combined treatment regimens of ionizing radiation, microtubule stabilizing and de-stabilizing agents and anti-angiogenic compounds (everolimus, bevacizumab) were investigated in genetically defined MIA-sensitive and tubulin-mutated or P-glycoprotein/MDR1-overexpressing MIA-resistant lung and colon adenocarcinoma carcinoma cell systems (A549, SW480) and in the corresponding tumor xenografts. MIAs potently inhibited A549wt and endothelial cell proliferation, while no anti-proliferative effect was observed in the corresponding MIA-resistant tumor cells. More important, MIAs did not downregulate anymore HIF-1α transcriptional activity and subsequent secretion of HIF-1α-mediated growth factors and cytokines from these MIA-resistant tumor cells. Continuous pro-survival auto- and paracrine signaling from these resistant tumor cells resulted in an additional level of treatment resistance towards MIAs and ionizing radiation as determined in tumor xenografts derived from MIA-resistant tumor cells. However rationally-designed combined treatment of MIAs with mTOR-signaling- or VEGF-antagonists strongly re-sensitized treatment-resistant tumors to the corresponding MIA.
These data demonstrate that the interaction between the tumor cell compartment and the tumor microenvironment strongly determines the treatment response to different anticancer treatment modalities.A combined treatment modality of MIAs with antiangiogenic agents is potent to overcome tumor cell-linked MIA-resistance and should be considered as clinical strategy for MIA-refractory tumor entities.
Citation Format: Angela Broggini-Tenzer, Ashish Sharma, Sabine Bender, Katarzyna Nytko-Karouzakis, Martin Pruschy. Combined treatment strategies for microtubule interfering agent-resistant tumors. [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 A185.
Abstract A22: PanDrugsDB: Identifying druggable genetic dependencies for personalized cancer therapy
Authors: Piñeiro-Yáñez Elena , Reboiro-Jato Miguel , Perales-Patón Javier , Glez-Peña Daniel , Tejero Héctor , Shimamura Takeshi , Carretero Julián , Valencia Alfonso , Hidalgo Manuel , Al-Shahrour Fátima 
Published: May 2016

Abstract
The paradigm of personalized medicine is the identification of the appropriate drug for the right patient, using molecular profiles. In Oncology, it is well established that the anticancer drugs are effective in only a small subset of patients. Moreover, many of the new targeted therapies inhibit specific proteins, and they are only effective in tumors that are genetically altered. Consequently, the success of personalized treatment depends on each individual molecular profile, which a priori can be considered as very heterogeneous.
Here, we present a new computational approach (PanDrugsDB) based on the analysis and integration of genomic data (mutations, copy number variations or gene expression levels), with functional data (proteins essentiality) and pharmacological data. This tool is able to identify those molecular alterations that drive tumor progression and could be druggable based on the patient's molecular profile, and propose an individualized therapeutic strategy to guide clinical decision making for cancer patients. We have tested this approach, in publicly available data (ICGC and TCGA cancer genome projects) and patient's tumor genomic data that are analyzed in our institution as part of CNIO Personalized Medicine initiative.
Citation Format: Elena Piñeiro-Yáñez, Miguel Reboiro-Jato, Javier Perales-Patón, Daniel Glez-Peña, Héctor Tejero, Takeshi Shimamura, Julián Carretero, Alfonso Valencia, Manuel Hidalgo, Fátima Al-Shahrour. PanDrugsDB: Identifying druggable genetic dependencies for personalized cancer therapy. [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 A22.
Abstract A40: MicroRNA-494 inhibits growth of the gastrointesintal stromal tumor by targeting multiple cell cycle regulatory genes
Authors: Yun SeongJu , Kim Won Kyu , Kim Hoguen 
Published: May 2016

Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms occurring throughout the entire region of the gastrointestinal tract. Two oncogenes of the receptor tyrosine kinase family, KIT and PDGFRA, have gain-of-function mutations in approximately 70% and 15% of GISTs. Mutations of these 2 genes cause sustained activation, resulting in constant stimulation of the downstream signaling pathways of KIT and platelet-derived growth factor receptor, alpha polypeptide. Although KIT mutations are present in approximately 70% of GISTs,KIT overexpression is observed in more than 90% of GISTs. Dysregulation of microRNAs(miRNA)-494 was demonstrated to be a major cause for the overexppression of mutatnt KIT proteins in GISTs. It was also demonstrated that miR-494 treatment inhibits proliferation of GISTs and promotes apoptosis however, no details mechanisms are not known.
The purpose of this study was to provide evidence regarding the roles of miR-494 in GIST suppression. To elucidate the specific pathways affected by miRNA-494 treatment on GIST cell lines, transcriptome analysis of GIST430 and GIST882 cells transfected with nontargeting microRNA or with miR-494 was performed and subsequently validated by qRT-PCR. Based on the transcriptome analysis, we found that multiple cell cycle relevant pathways were down-regulated by miR-494 treatment and importantly, core genes such as KIT, CASP2, CDCA2, AURKB, CDCA8, E2F7, BIRC5 and CKS1B involved in the regulation of cell cycle pathways were identified as novel targets by miR-494. Using reporter assays, we further validated that miR-494 directly binds to the 3'UTR regions of BRAC5, CKS1B and E2F7 and induces biological alterations. To demonstrate the perturbation of cell cycle pathways by miR-494, FACS analysis using five GIST cell lines was performed and we found that all of the five GIST cell lines transfected with miR-494 subjected to cell cycle arrest and apoptosis. Colony forming and proliferation assays also demonstrated that miR-494 treatment induced the growth inhibition of GIST cells which was derived from the alterations of cell cycle pathways. Taken together, our findings suggest that the efficient suppression of GISTs by miR-494 is driven not only by targeting KIT, but also multiple genes involved in cell cycle pathways
Citation Format: SeongJu Yun, Won Kyu Kim, Hoguen Kim. MicroRNA-494 inhibits growth of the gastrointesintal stromal tumor by targeting multiple cell cycle regulatory genes. [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 A40.
Abstract A44: Inhibition of Foxm1 transcription factor diminished Kras-mutated tumor development
Authors: Wang I-Ching , Chien Hsin Chih , Chao Sheng-Yang , Li Chien-Cheng 
Published: May 2016

Abstract
Increased expression level of the Forkhead Box M1 (FOXM1) transcription factor is found in multiple types of cancers, and its expression is correlated with poor prognosis in patients with cancers, including non-small cell lung cancers and pancreatic cancers. We and others have shown that FoxM1 transcriptionally regulates a variety of genes essential for cell cycle progression, inflammation, angiogenesis, tumor cell invasiveness and survival. Published studies demonstrated that genetic deletion of Foxm1 gene from SPC-rtTA/tetO-KrasG12D/Foxm1 fl/fl mouse lung epithelial cells conferred resistance to tumorigenesis caused by oncogenic KrasG12D, indicating Foxm1 is a critical regulator of Kras signaling pathway during lung cancer initiation. When treated SPC-rtTA/tetO-KrasG12D/tetO-FOXM1 mice with Doxycycline, lung epithelial cell-specific expressed transgenic FOXM1 and Kras cooperate to promote tumor growth in mouse lungs. In the present study, we determine whether expression of FoxM1 affects proliferation of human cancer cells harboring oncogenic Kras. Here, we show that depletion of FOXM1 expression using inducible shFOXM1 diminished proliferation of Kras-mutated human non-small cell adenocarcinoma (A549 and NCI-H23) and pancreatic cancer (PANC-1 and AsPC-1) cell lines. In contrast, increased expression of FOXM1 caused increased proliferation of Kras mutated cancer cells. Scratch wound healing assay demonstrated that FOXM1 stimulates the migration of these cells, which is associated with elevated epithelial-mesenchymal transition (EMT) markers. Our studies demonstrate that FOXM1 transcription factor is required for Kras mutated human cancer cells proliferation during tumor progression.
Citation Format: I-Ching Wang, Hsin Chih Chien, Sheng-Yang Chao, Chien-Cheng Li. Inhibition of Foxm1 transcription factor diminished Kras-mutated tumor development. [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 A44.
Abstract A6: RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy
Authors: Zhang Lan , Zhang Juan , Shi Qian 
Published: May 2016

Abstract
Background: Syngeneic tumor models have long been used in cancer research. Recently, the clinical success of anti-CTLA4 and anti-PD1 antibodies resulted in increased interests in using syngeneic models to evaluate cancer immunotherapeutics. Furthermore, as researchers discovered many of the existing or developing inhibitors of the canonical signaling pathways may interact with immune-environment, thus may synergize with cancer immunotherapies, they are looking for suitable models that may evaluate the combination of those therapies. More importantly, in the clinic it is still unknown why some patients respond to certain immunotherapies while others do not. We set out to utilize syngenetic models to address those questions.
Material and methods: Syngeneic cell lines models, such as B16, CT26, MC38, 4T1, were used to evaluate anti-PD1, PD-L1 and CTLA4 antibodies efficacies. Tumors were collected before the treatment for RNAseq analysis. Biomarkers were analyzed with the RNAseq data to predict treatment response to different immune checkpoint inhibitors.
Results: Crown has established a large collection of syngeneic models that covers most of the tumor types. Those models have been extensively profiled in vivo using anti-PD1, anti-CTLA4 antibodies, providing information necessary for selecting models and doses for combination therapy. Mostly recently, we have generated detailed maps of the expressional and mutational profiles of those models, as well as identified the alternative gene spliced transcripts, and gene fusion using RNA-seq. Mutational analysis indicated a number of syngeneic models harbor mutations that may be useful for combination studies of targeted and immuno-therapy. Using proprietary algorithms, we have also identified a set of biomarkers that may be useful to predict response to different immunotherapies in mouse models.
Conclusions: These data will enable selection of models based on researchers' specific targets for combination studies with immunotherapy. In addition, predictive biomarkers obtained from the analysis may be useful in understanding patient response in the clinic.
Citation Format: Lan Zhang, Juan Zhang, Qian Shi. RNAseq and immune profiling analysis of syngeneic mouse models treated with immune checkpoint inhibitors enable biomarker discovery and model selection for cancer immunotherapy. [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 A6.
Abstract A77: Repression of mTORC1 activity in NOTCH1 mutant T-ALL results in sensitivity to the BCL-2 inhibitor ABT-263
Authors: Dastur Anahita , Faber Anthony , Costa Carlotta , Benes Cyril 
Published: May 2016

Abstract
There is no effective molecularly targeted therapy for T-cell Acute Lymphoblastic Leukemias (T-ALL) and prognosis for relapsed or chemotherapeutic refractory cases remains poor. A large unbiased drug screen performed across cell lines from a broad spectrum of cancers revealed that NOTCH1 mutant T-ALL cells, including lines resistant to gamma-secretase inhibitors are very sensitive to the Bcl-2/xL inhibitor ABT-263. We found that NOTCH1 up regulates the mTOR suppressor REDD1, leading to suppression of the mTOR Complex 1. This in turn results in low MCL-1 levels and ABT-263 sensitivity. Inhibition of NOTCH1 activity in this context leads to robust and sustained up regulation of mTOR signaling which could limit the activity of gamma-secretase inhibitors. Analysis of a small set of patient samples support the findings that NOTCH1 mutant T-ALL have low MCL-1 levels. Most importantly, we show that suppression of mTORC1 by a small molecule inhibitor further sensitizes NOTCH1 mutant T-ALL to ABT-263 resulting in massive apoptosis and in vivo efficacy.
SIGNIFICANCE: This study uncovers a previously unappreciated link between two major oncogenic pathways, the NOTCH and mTOR pathways, with NOTCH1 repressing mTORC1 through REDD1. Further, we show that this suppression results in low MCL-1 levels and that combining mTORC inhibition with BCL-2 inhibition is a promising therapeutic strategy for GSI-resistantNOTCH1-mutant T-ALL.
Citation Format: Anahita Dastur, Anthony Faber, Carlotta Costa, Cyril Benes. Repression of mTORC1 activity in NOTCH1 mutant T-ALL results in sensitivity to the BCL-2 inhibitor ABT-263. [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 A77.
Abstract A81: Identification of reversion mutation by next-generation sequencing in PARP-inhibitor resistant BRCA2 associated breast cancer: Defects in mis-match repair and acquired chemoresistance in breast cancer
Authors: GHEEYA JINESH S. , Tang Jeremy , Ho Joseph , Wong Serena , Toppmeyer Deborah , HIrshfield Kim , Rodriguez Lorna , Ganesan Shridar 
Published: May 2016

Abstract
Women harboring germline mutations in BRCA2 have an increased risk of developing breast and ovarian cancers. The cancers that arise have undergone loss of the wildtype BRCA2 allele, consistent with BRCA2 functioning as a tumor suppressor. The DNA repair defect present in BRCA2-associated cancers renders them highly sensitive to certain classes of DNA damaging agents including platinum agents and PARP inhibitors. BRCA2-mutant cancers have shown acquired resistance to platinum agents through reversion mutations, in which a second mutation in BRCA2 restores an open reading frame that can partially or completely restore functional protein. This kind of functional restoration is often achieved by genomic deletions that excise the exon containing the deleterious germline mutation and place the gene back in frame.
Here we report a case of a BRCA2-mutation associated breast cancer that progressed after a prolonged response to PARP inhibitor- based therapy and became chemoresistant. The patient was positive for germline BRCA2 Q2899 * mutation. Next-generation sequencing of the chemoresistant tumor revealed a secondary mutation in BRCA2 that altered BRCA2 Q2899* to Q2899L_converting a non-sense mutation into a missense mutation. In addition to BRCA2 mutation, the tumor had a deletion in MLH1, suggesting that an acquired defect in mis-match repair may have allowed reversion of BRCA2 Q2899* by a point-mutation in this tumor. Analysis of serial specimens from this patient allows reconstruction of the evolution of this tumor, and points to a novel mechanism of reversion mutation due to defects in mismatch repair. This finding suggest how mismatch repair defects can functionally affect BRCA2 mutant cancers, and raise possible therapeutic strategies.
Citation Format: JINESH S. GHEEYA, Jeremy Tang, Joseph Ho, Serena Wong, Deborah Toppmeyer, Kim HIrshfield, Lorna Rodriguez, Shridar Ganesan. Identification of reversion mutation by next-generation sequencing in PARP-inhibitor resistant BRCA2 associated breast cancer: Defects in mis-match repair and acquired chemoresistance in breast cancer. [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 A81.