bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR03: Genome-wide screens for Wnt signaling in human haploid cells
Authors: Lebensohn Andres , Hughes Casey , Marceau Caleb , Rohatgi Rajat , Carette Jan 
Published: August 2014

Abstract
Wnt signaling is at the core of human development and stem cell biology. Defective Wnt signaling leads to several forms of cancer, most notably colorectal cancer. Using HAP1 cells, a human haploid cell line, we conducted a set of genome-wide forward genetic screens to identify new Wnt pathway components. We constructed a HAP1 line harboring a GFP reporter driven by the Wnt-responsive TCF promoter, we mutagenized the cells by insertion of a gene-trap retrovirus throughout the haploid genome, and we sorted the mutagenized population for cells exhibiting phenotypes of interest using FACS. In order to find 1. negative regulators, 2. positive regulators and 3. feedback modulators of the pathway, we sorted for 1. cells expressing GFP in the absence of Wnt, 2. cells with reduced GFP expression after strong Wnt stimulation and 3. cells with enhanced GFP expression after mild Wnt stimulation, respectively. Deep sequencing of amplified genomic DNA flanking the retroviral insertion sites in the sorted cell populations revealed genes whose disruption may have led to the phenotype of interest. Among the most frequently disrupted genes (some with over 150 unique retroviral insertions) we found many of the known components of the canonical Wnt pathway, including LRP6, casein kinase I, APC, β-catenin, DOT1-L, TCF4 and the recently discovered negative feedback regulator ZNRF3. Unexpectedly, the screen for positive regulators revealed retroviral insertions in AXIN2 (a scaffold protein found in the β-catenin destruction complex) predicted to yield a C-terminally truncated form that appears to act as a dominant negative. We are currently assessing hits not previously known to be involved in Wnt signaling.
This abstract is also presented as Poster A40.
Citation Format: Andres Lebensohn, Casey Hughes, Caleb Marceau, Rajat Rohatgi, Jan Carette. Genome-wide screens for Wnt signaling in human haploid cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR03.
Abstract PR09: Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS-mutant cancer models
Authors: Corcoran Ryan B. , Cheng Katherine A. , Hata Aaron N. , Faber Anthony C. , Ebi Hiromichi , Coffee Erin M. , Greninger Patricia , Brown Ronald D. , Godfrey Jason T. , Cohoon Travis J. , Song Youngchul , Lifshits Eugene , Shioda Toshi , Dias-Santagata Dora , Singh Anurag , Settleman Jeffrey , Benes Cyril H. , Mino-Kenudson Mari , Wong Kwok-Kin , Engelman Jeffrey A. 
Published: August 2014

Abstract
Although KRAS is the most commonly mutated oncogene in human cancer, KRAS has proven difficult to target pharmacologically, and no effective therapies exist for KRAS-mutant cancers. Recently, there has been evidence that targeted therapy combinations inhibiting multiple downstream effectors of KRAS may be a promising approach for KRAS-mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to kill KRAS-mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in the vast majority of KRAS-mutant cell lines tested from different tissue types. Mechanistic studies revealed that MEK inhibition led to marked induction of the pro-apoptotic protein BIM in KRAS-mutant cancer cells, but that BIM remained bound and inhibited by BCL-XL. Pharmacologic inhibition of BCL-XL with ABT-263 disrupted this inhibitory complex, allowing BIM to trigger apoptosis. Epithelial differentiation and E-cadherin expression correlated with increased sensitivity to this inhibitor combination across a panel of 30 KRAS-mutant cell lines, while epithelial-to-mesenchymal transition (EMT) correlated with resistance. This combination also caused marked in vivo tumor regressions in three independent KRAS-mutant xenografts and in established lung tumors in two genetically-engineered KRAS-driven lung cancer mouse models. These data support combined BCL-XL/MEK inhibition as a promising therapeutic approach for evaluation in future clinical trials for patients with KRAS-mutant cancers.
This abstract is also presented as Poster B19.
Citation Format: Ryan B. Corcoran, Katherine A. Cheng, Aaron N. Hata, Anthony C. Faber, Hiromichi Ebi, Erin M. Coffee, Patricia Greninger, Ronald D. Brown, Jason T. Godfrey, Travis J. Cohoon, Youngchul Song, Eugene Lifshits, Toshi Shioda, Dora Dias-Santagata, Anurag Singh, Jeffrey Settleman, Cyril H. Benes, Mari Mino-Kenudson, Kwok-Kin Wong, Jeffrey A. Engelman. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS-mutant cancer models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR09.
Abstract PR14: Targeting the GATA2 transcriptional network in K-Ras driven lung adenocarcinoma
Authors: Kumar Madhu S. , Downward Julian 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) is the most prevalent histological cancer subtype in terms of both incidence and mortality, with nearly 1.4 million deaths per year worldwide. Nearly one-third of all NSCLCs have activating mutations in the KRAS oncogene. In spite of thirty years' knowledge of KRAS mutations in lung cancer, it has proven therapeutically intractable, leaving KRAS mutant NSCLC to serve as a marker of poor prognosis. Thus, there is a substantial unmet clinical need to find treatment options for this subset of lung cancers.
By RNA interference screening, we previously discovered a transcription factor, GATA2, is necessary for the survival of KRAS mutant lung cancer cells, but not wild type lung cancer cells. Through an integrative genomic analysis of gene expression and chromatin occupancy, we discovered a GATA2-regulated transcriptional network consisting of the proteasome, IL-1 and Rho pathways. Functional analyses revealed that each of these pathways, though not individually necessary, is partially sufficient to restore viability in response to GATA2 depletion. Using two different genetically engineered mouse models (GEMMs), we found Gata2 is necessary for oncogenic Kras driven lung tumourigenesis. In addition, systemic Gata2 loss, while well tolerated, significantly extended survival in a Kras mutant NSCLC GEMM. Intriguingly, we found that combined treatment of Kras driven mouse models with clinically available inhibitors of the proteasome (bortezomib) and Rho kinase (fasudil) induced tumour regression.
We have now begun exploring and extending these initial therapeutic strategies to the Kras; Trp53 (KP) mouse model. Upon delivery of Cre recombinase to the lungs, KP mice undergo progression from low-grade adenomas to high-grade, invasive metastatic lung adenocarcinoma, more faithfully recapitulating the human disease. We have assessed our GATA2 network therapies through in vivo imaging of incipient lesions by micro-computed tomography, treatment cycles and subsequent re-imaging to determine efficacy. Using this approach, we observed substantial response when combining treatment with bortezomib and fasudil in the KP model. Moreover, introduction of a next-generation inhibitor of Rho kinase (AT13148), an agent in early-stage clinical development, combines with bortezomib to cause significant regression of lung adenocarcinomas in vivo. Taken together, we have elucidated a gene expression network necessary for Ras-driven lung cancer and have devised novel approaches to suppress this network with therapeutically tractable agents.
This abstract is also presented as Poster A14.
Citation Format: Madhu S. Kumar, Julian Downward. Targeting the GATA2 transcriptional network in K-Ras driven lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR14.
Abstract PR16: Targeting cancer-specific kinase dependency for precision therapy
Authors: Kothari Vishal , Iris Wei , Shankar Sunita , Kalyana-Sundaram Shanker , Wang Lidong , Ma Linda W. , Vats Pankaj , Grasso Catherine S. , Robinson Dan R. , Wu Yi-Mi , Cao Xuhong , Simeone Diane M. , Chinnaiyan Arul M. , Kumar-Sinha Chandan 
Published: August 2014

Abstract
Precision/ personalized cancer therapy based on clinical sequencing is premised on the identification of genomic aberrations in actionable therapeutic targets. Protein kinases represent the most accessible therapeutic targets across cancers, albeit only very small subsets of cancers harbor canonical targetable aberrations in kinases. Considering that kinases represent the predominant drivers of oncogenesis, functioning directly or downstream of other oncogenic aberrations, we hypothesize that most cancers harbor distinct “kinase dependencies” and thus provide a potent therapeutic avenue in individual cancers. Here, we test the hypothesis that the kinase(s) that display an “off the chart” Outlier Expression in individual cancer samples, impart a dependency on growth and survival that can be exploited therapeutically. Analyzing RNA-Seq data from a compendium of 482 cancer and benign samples belonging to 25 different tissue types we defined sample-specific ‘kinome’ expression profiles. Comparing the expression of kinases within a sample and across sample sets, we identified distinct ‘outlier kinases’ in individual samples, defined as genes showing the highest statistically significant levels of absolute and differential expression. Frequently observed outlier kinases in breast cancer included known therapeutic targets like ERBB2 and FGFR4, distinct from MET, AKT2, and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specific dependencies in various cell lines as assessed by siRNA knockdown or pharmacologic inhibition in vitro and in vivo. Outlier expression of polo-like kinases (PLKs) observed in a subset of KRAS-dependent pancreatic cancer cell lines conferred increased sensitivity to the PLK inhibitor BI 6727. Together, our results suggest that outlier kinases represent effective personalized therapeutic targets that are readily identifiable through RNA-sequencing of tumors. Next, to help translate these observations into treatment options, we are optimizing ex vivo culture of tumor tissues from surgical resections that will be used to test combinations of therapeutics including outlier kinase inhibitors.
This abstract is also presented as Poster B21.
Citation Format: Vishal Kothari, Wei Iris, Sunita Shankar, Shanker Kalyana-Sundaram, Lidong Wang, Linda W. Ma, Pankaj Vats, Catherine S. Grasso, Dan R. Robinson, Yi-Mi Wu, Xuhong Cao, Diane M. Simeone, Arul M. Chinnaiyan, Chandan Kumar-Sinha. Targeting cancer-specific kinase dependency for precision therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR16.
Abstract A104: A screening method for the identification of potentially effective drug-drug combinations reveals a synergistic interaction between Aurora-A inhibitor MK-5108 and Bcl-xL inhibitor navitoclax.
Authors: Gong Xueqian , Jin Shaoling , Merzoug Farhana , Ye Xiang S. , Lallena MaryJo , Du Jian , Webster Yue , Ma Xiwen , Reinhard Christoph , Iversen Phillip , Buchanan Sean G. 
Published: August 2014

Abstract
Recent developments in understanding the molecular mechanisms of cancer, coupled with large genomic datasets that detail the heterogeneity of the disease, have together led to a wealth of new cancer targets and therapeutic options. However, the restricted efficacy of these new agents and the emergence of resistance suggest that broader and more durable responses may be achieved through combination of these new drugs. To identify drug-drug combinations that may be effective in particular tumor types, we have developed an unbiased "synthetic lethal" screening approach to survey combination space across a diverse panel of tumor cell lines. We used this approach to test a panel of targeted drugs in all-versus-all fashion across 63 cell lines. Synergistic interactions were observed with the combination of an Aurora-A inhibitor, MK-5108, with navitoclax, an inhibitor of Bcl-2 family survival proteins. This combination, which was synergistic in a subset of the tumor cells, was further examined to identify the molecular determinants of synergy. Several features emerged from this analysis including the observation that Bcl-xL expression levels predict resistance to the single agent Aurora-A inhibitor and to synergy of combined MK-5108 and navitoclax.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A104.
Citation Format: Xueqian Gong, Shaoling Jin, Farhana Merzoug, Xiang S. Ye, MaryJo Lallena, Jian Du, Yue Webster, Xiwen Ma, Christoph Reinhard, Phillip Iversen, Sean G. Buchanan. A screening method for the identification of potentially effective drug-drug combinations reveals a synergistic interaction between Aurora-A inhibitor MK-5108 and Bcl-xL inhibitor navitoclax. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A104.
Abstract A106: Utilization of low passage adenoid cystic carcinoma (ACC) models to identify novel therapies.
Authors: Meade Justin , Wick Michael J. , Vaught Teresa L. , Carlile Jennifer , Tolcher Anthony W. , Rasco Drew , Patnaik Amita , Kaufman Jeffrey , Moskaluk Chris , Papadopoulos Kyriakos P. 
Published: August 2014

Abstract
Background: Adenoid Cystic Carcinoma (ACC) is an uncommon cancer of the head and neck which typically originates in the salivary glands. Treatment options for ACC resection and local radiation therapy although chemotherapy is sometimes used to control metastatic or locally recurrent disease. Patients with ACC may survive for years due to latent tumor growth and lack of lymph node metastasis; however, the high rate of recurrence and metastasis to the lungs lead to a poor prognosis beyond ten years. While no standard of care currently exists, improved understanding of ACC tumor biology and oncogenesis has provided some molecular targets for its treatment. Mutations and alterations of MYB, NFIB and molecules in the FGF, IGF, PI3K and NOTCH signaling pathways amongst others, may serve as targets for current and future therapies. Due to a lack of ACC derived cell lines, a panel of low passage ACC xenograft models designated ACCx5M1, ACCx6, ACCx9, ACCx14 and ACCx16 have been established and through the Adenoid Cystic Carcinoma Research Foundation (ACCRF) are routinely utilized to test agents which target pathways important in ACC.
Methods: Low passage ACC models were established in immune-deficient mice from primary or metastatic patient tissue and once established were confirmed by histologic comparative analysis. Drug sensitivity studies are performed evaluating models towards chemotherapy and targeted agents. Study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition and regression reported at study completion.
Results: To date over seventy FDA-approved and investigational therapies have been evaluated and data has been generated that have contributed to the initiation of two Phase 2 clinical trials in ACC. In addition to chemotherapies, therapies targeting FGF, IGF, VEGF and NOTCH pathways have been tested and we are currently evaluating agents targeting MYB dysregulation.
Conclusion: Low passage ACC models have been used to identify agents potentially useful in the treatment of ACC and models are available through the ACCRF to evaluate potential therapies for the treatment of adenoid cystic carcinoma.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A106.
Citation Format: Justin Meade, Michael J. Wick, Teresa L. Vaught, Jennifer Carlile, Anthony W. Tolcher, Drew Rasco, Amita Patnaik, Jeffrey Kaufman, Chris Moskaluk, Kyriakos P. Papadopoulos. Utilization of low passage adenoid cystic carcinoma (ACC) models to identify novel therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A106.
Abstract A112: Combined targeting of HER2 and HER3 inhibits tumor growth in both trastuzumab-sensitive and trastuzumab-resistant breast cancer models.
Authors: Steiner Philipp , Wetzel Leslie , Schifferli Kevin , Rothstein Raymond , Tammali Ravinder , Rebelatto Marlon , Xiao Zhan , Pierce Andrew , Hollingsworth Robert 
Published: August 2014

Abstract
HER3 (ERBB3) is a tumor driver in divergent cancer types with high HRG levels or heightened EGFR or HER2 kinase activity via growth signal coupling to the PI3K-AKT pathway. HER3 lacks intrinsic tyrosine kinase activity but is capable of signaling after heterodimerizing with tyrosine kinase ERBB family members EGFR or HER2. Heterodimer formation is driven either by the binding of heregulin (NRG1/HRG) to HER3 (ligand dependent - LD), or alternatively, by overexpression of EGFR or HER2 (ligand-independent - LI). Preclinical evaluation of MEDI3379, a human IgG1 modified monoclonal anti-HER3 antibody that antagonizes both LD and LI signaling, demonstrated tumor growth inhibition in the HER2-expressing MDA-MB-361 breast cancer xenograft model. Anti-tumor activity of MEDI3379 in this model was increased in combination with the HER2-targeting drug trastuzumab to a greater extent than MEDI3379 when combined with either lapatinib or pertuzumab. Combined inhibition of HER2 and HER3 led to strong reduction in pHER3. Unexpectedly, co-administration of MEDI3379 together with trastuzumab in MDA-MB-361 tumor-bearing mice but not in naïve mice resulted in reduced serum levels of trastuzumab. A control antibody combined with trastuzumab in MDA-MB-361 tumor bearing mice did not have this effect. Furthermore, in the trastuzumab-resistant JIMT-1 breast cancer xenograft model which has high HRG and pHER3 levels MEDI3379 but not pertuzumab resensitized JIMT-1 tumors to trastuzumab resulting in synergistic anti-tumor activity and a reduction of pHER3. In vivo resistance to this regimen appeared with prolonged treatment of JIMT-1 tumors and was accompanied by a decrease in homogenous expression of HER2. In conclusion, the use of MEDI3379 in combination with trastuzumab in HER2-amplifed breast cancer cell lines has demonstrated additional tumor growth inhibition over single agent trastuzumab and overcoming trastuzumab-resistance mechanisms. This combination warrants further evaluation in preclinical and clinical studies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A112.
Citation Format: Philipp Steiner, Leslie Wetzel, Kevin Schifferli, Raymond Rothstein, Ravinder Tammali, Marlon Rebelatto, Zhan Xiao, Andrew Pierce, Robert Hollingsworth. Combined targeting of HER2 and HER3 inhibits tumor growth in both trastuzumab-sensitive and trastuzumab-resistant breast cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A112.
Abstract A12: Small molecule inhibitor of BCL2 in combination with RCHOP is effective in CD20 negative DLBCL.
Authors: Dutta Chaitali , Mayo Michele , Collins Mike , Brueckner Christopher , Lawson Deborah , Lai Zhongwu , Bao Larry , Reimer Corinne 
Published: August 2014

Abstract
Rituximab alone or in combination with chemotherapeutics is the first-line therapy for diffuse large B cell lymphomas (DLBCL). Although the complete response rate is quite impressive, vast majority of patient presents recurrent disease. The association between CD20 expression and clinical outcome in patients strongly suggests that reduced CD20 expression leads to inferior response to RCHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone). In order to understand how loss of CD20 leads to development of RCHOP resistance, we developed rituximab resistant DoHH2 model in vivo by chronic exposure to rituximab. Characterization of several resistant in vivo xenografts revealed one model that maintained resistance to an acute dose of rituximab and demonstrated loss of CD20. Further characterization of the model demonstrated a loss of CD20 is associated with over expression of BCL2 and BIM. In vivo efficacy studies showed resistant line is insensitive to acute dose of RCHOP and treatment with an inhibitor of BCL2 (ABT199) in combination with chemotherapy resulted in better efficacy than RCHOP alone. We have identified an in vivo model of DLBCL where loss of CD20 and over expression of anti-apoptotic protein BCL2 leads to RCHOP resistance. These data suggest the addition of BCL2 inhibitor to chemotherapy might be effective in treating CD20 negative lymphomas.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A12.
Citation Format: Chaitali Dutta, Michele Mayo, Mike Collins, Christopher Brueckner, Deborah Lawson, Zhongwu Lai, Larry Bao, Corinne Reimer. Small molecule inhibitor of BCL2 in combination with RCHOP is effective in CD20 negative DLBCL. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A12.