bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C99: Wogonin enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by Nrf2 suppression in HepG2 cells.
Authors: Qian Chen , Hu Rong 
Published: August 2014

Abstract
Abstract: Cancer cells, compared to normal cells, are under increased oxidative stress with higher level of ROS. When exposed to environmental or intracellular stresses like ROS, NFE-related factor 2 (Nrf2) is the key to antioxidant response by transcriptionally activate various detoxification and antioxidant enzymes. We have previously shown that wogonin (5,7-Dihydroxy-8-methoxy-2-phenyl-4H-1-benzopyran-4-one), a flavonoid isolated from the root of Scutellaria baicalensis Georgi, could reverse drug resistance in MCF-7/ DOX cells through blocking the translocation of Nrf2 into nucleus, however, the effects of wogonin on Nrf2 signaling pathway have not previously been reported. In our study, we observed that wogonin reduced Nrf2 nuclear translocation, and therefore elevated the level of intracellular ROS to accomplish the purpose of killing malignant cells. In order to confirm the roles of Nrf2, it was activated by tBHQ and knocked down by the Nrf2 siRNA, and the results demonstrated that the activation of Nrf2 was involved in the wogonin-induced accumulation of ROS and cell death. Furthermore, the suppression of Nrf2 by wogonin can potentiate cytotoxic effects of chemotherapeutic agents in HepG2 cells. On one hand, down-regulation of Nrf2 lead to reduction of cytoprotective effect through inducing phage II enzymes which sensitize cells to chemotherapeutic agents. On the other hand, inhibition of multidrug resistance-associated protein (MRPs) by wogonin to enhance the effective drug level in cancer cells is another way to potentiates chemotherapeutic effects. At last, we found that the down-regulation of Nrf2 is associated with over-expression of p53. Using p53 siRNA to knock down the endogenous p53 expression, the level of both c-Myc and Nrf2 in nucleus increased when exposed to wogonin. The present study indicated that wogonin can be used in chemotherapy not only because its own antitumor ability, but also due to the enhanced cytotoxic effects of chemotherapeutic agents.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C99.
Citation Format: Chen Qian, Rong Hu. Wogonin enhanced reactive oxygen species-induced apoptosis and potentiated cytotoxic effects of chemotherapeutic agents by Nrf2 suppression in HepG2 cells. [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 C99.
Abstract CN02-01: CTCs in small cell lung cancer: Biomarkers and biology.
Authors: Dive Caroline 
Published: August 2014

Abstract
Tumor biopsies from lung cancer patients are challenging, particularly so in metastatic disease and development of informative minimally invasive biomarkers are much needed. In this presentation I will review the current status of CTCs in lung cancer as prognostic, predictive and pharmacodynamic biomarkers. The presentation will then focus on Small Cell Lung Cancer (SCLC), an aggressive, neuroendocrine tumor with early dissemination and dismal prognosis accounting for 15-20% lung cancer cases and ∼200,000 deaths globally each year. Most cases are inoperable and biopsies to interrogate SCLC biology are rarely obtained. Improved treatment outcomes for SCLC patients requires new approaches to interrogate the biology and genetics of the disease, appropriate methods to investigate the rapid onset of acquired resistance to current chemotherapy and tractable, patient derived models with which to test new therapies. Circulating tumor cells (CTCs) are prevalent in SCLC. I will describe how we isolate a molecularly profile single CTCs and discuss the development of our new CTC mouse. These new models that can be generated longitudinally from patients at diagnosis and at relapse, together with an analysis of CTC heterogeneity will facilitate a thorough investigation of the mechanisms of acquired drug resistance, and may identify new targets for improved therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN02-01.
Citation Format: Caroline Dive. CTCs in small cell lung cancer: Biomarkers and biology. [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 CN02-01.
Abstract CN04-02: Discovery of Mcl-1 inhibitors using fragment-based methods.
Authors: Fesik Stephen W. 
Published: August 2014

Abstract
Mcl-1, a member of the Bcl-2 family of proteins, is overexpressed and amplified in several cancers and causes the aberrant survival of tumor cells that would otherwise undergo programmed cell death and resistance to many chemotherapeutic agents. Down-regulation of Mcl-1 by RNA interference inhibits cell growth, induces apoptosis in cancer cells, and decreases tumorgenicity in mouse xenograft models. Although very potent inhibitors of Bcl-2/Bcl-xL (ABT-263, Navitoclax) and Bcl-2 (ABT-199) have progressed to the clinic, no Mcl-1 inhibitors have entered clinical trials. In this presentation, the discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design will be described.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN04-02.
Citation Format: Stephen W. Fesik. Discovery of Mcl-1 inhibitors using fragment-based methods. [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 CN04-02.
Abstract ED01-01: Somatic alterations in human cancer genomes.
Authors: Meyerson Matthew L. 
Published: August 2014

Abstract
The advent of high-throughput genome sequence analysis has enabled systematic discovery of somatic genome alterations through genome, exome, and transcriptome sequencing of paired human cancer and germline nucleic acids. These discoveries have led to the identification of somatic genome alterations in new pathways including epigenetic regulators, RNA splicing factors, and immune response regulators, in addition to previously known signal transduction, cell cycle, and transcriptional pathways. I will discuss alterations in these pathways by copy number disruption, mutation, and re-arrangement, especially as seen through the lens of recent and ongoing large-scale studies of lung adenocarcinoma and squamous cell lung carcinoma genomes, from The Cancer Genome Atlas and beyond– and will discuss the implications for the understanding of cancer pathogenesis and for the development of targeted and immunomodulatory therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):ED01-01.
Citation Format: Matthew L. Meyerson. Somatic alterations in human cancer genomes. [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 ED01-01.
Abstract PL05-04: Temporal evaluation of cancer heterogeneity.
Authors: Mardis Elaine R. 
Published: August 2014

Abstract
Next-generation, massively parallel sequencing is enabling an exploration of how cancer genome heterogeneity is changing over time. This approach provides the rough equivalent of techniques that explore species evolution by monitoring the ebb and flow of genomic profiles in the tumor cell population under various influences. One such influence is the application of therapy, which takes many forms from cytotoxic chemotherapy to hormone therapy to targeted, small molecule therapy. Another influence is the temporal study of tumor evolution as the primary evolves to established metastases. I will provide examples from our work of each of the aforementioned scenarios, illustrating how deep sequencing can aid in tracking the evolution of tumor cell genomic profiles.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL05-04.
Citation Format: Elaine R. Mardis. Temporal evaluation of cancer heterogeneity. [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 PL05-04.
Abstract PL06-01: Liquid biopsies to monitor response and resistance to targeted therapies.
Authors: Bardelli Alberto 
Published: August 2014

Abstract
The advent of the EGFR-targeted monoclonal antibodies cetuximab and panitumumab paved the way to the individualized treatment of metastatic colorectal cancer (mCRC). In the last 5 years it has become evident that mCRCs respond differently to EGFR-targeted agents and that the tumor-specific response has a genetic basis. After the initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of anti-EGFR therapies. Understanding the molecular bases of secondary resistance to cetuximab and panitumumab is required to design additional therapeutic options. We found that molecular alterations in KRAS, NRAS, BRAF, and MET are causally associated with the onset of acquired resistance to anti-EGFR blockade in colorectal cancers. We optimized a diagnostic platform to identify resistance-associated genetic alterations in the blood of patients (liquid biopsy) months before radiographic documentation of disease progression. Preclinical models of relapse including cell lines and patient-derived xenografts (xenopatients) allowed us to assess new lines of therapy. Overall our results provide the rationale for delaying or reversing resistance to anti EGFR therapies in mCRCs and support the initiation of innovative– molecularly driven– clinical trials.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL06-01.
Citation Format: Alberto Bardelli. Liquid biopsies to monitor response and resistance to targeted 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 PL06-01.
Abstract PL07-03: Mechanisms of protective tumor immunity.
Authors: Dranoff Glenn 
Published: August 2014

Abstract
Efficacious cancer immunotherapies will likely require combinations of strategies that enhance tumor antigen presentation and antagonize negative immune regulatory circuits. We demonstrated that vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF followed by antibody blockade of CTLA-4 accomplishes clinically significant tumor destruction with minimal toxicity in a majority of stage IV metastatic melanoma and some advanced ovarian carcinoma patients. The extent of tumor necrosis in post-treatment biopsies was linearly related to the natural logarithm of the ratio of infiltrating CD8+ effector T cells to FoxP3+ Tregs, suggesting that further Treg inhibition might increase the frequency of clinical responses. Through an analysis of cytokine deficient mice, we delineated a critical role for GM-CSF in Treg homeostasis. GM-CSF is required for the expression of the phosphatidylserine binding protein MFG-E8 in antigen presenting cells, whereas the uptake of apoptotic cells by phagocyte-derived MFG-E8 maintains peripheral Treg activity. The pharmacologic inhibition of MFG-E8 function through genetic or engineering-based approaches blocks Treg induction, which intensifies vaccine-induced responses, leading to the regression of established tumors in mice. The clinical translation of these therapeutic strategies to Phase I testing in humans is underway.
The detailed analysis of patients achieving sustained clinical benefits from irradiated, autologous GM-CSF secreting tumor cell vaccines and CTLA-4 antibody blockade also affords a rich opportunity to identify antigens associated with immune-mediated tumor destruction and to delineate mechanisms of therapeutic immunity. We elucidated several of the molecular pathways that underlie these antitumor effects, including the NKG2D system and multiple secreted/or cell surface proteins that contribute to tumor promoting inflammation. The therapy-induced antibodies manifest functional activity in vitro, antagonizing tumor cell survival, invasive potential, and angiogenesis. These findings support a key role for humoral immunity in tumor destruction, and highlight interest in more detailed characterization of the antitumor B cell repertoire in vaccinated patients.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL07-03.
Citation Format: Glenn Dranoff. Mechanisms of protective tumor immunity. [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 PL07-03.
Abstract PR01: Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.
Authors: Burns Michael , Sun Qi , Daniels Richard , Kennedy J. Phillip , Camper DeMarco , Phan Jason , Olejniczak Edward , Lee Taekyu , Waterson Alex , Rossanese Olivia , Fesik Stephen 
Published: August 2014

Abstract
Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active receptor tyrosine kinases (RTKs) results in the deregulation of cellular signals governing growth and survival in cancer. The guanine nucleotide exchange factor Son of Sevenless (SOS) catalyzes the rate-limiting step in the activation of Ras by exchanging GDP for GTP. SOS is therefore a key control point for the propagation of RTK and Ras signaling. Here we report the discovery of small molecules that bind to a unique pocket on the Ras:SOS:Ras complex, increase SOScat-catalyzed nucleotide exchange, and perturb Ras signaling pathways in cells. X-ray crystallographic studies of Ras:SOS:Ras complexed with these small molecules reveal that they bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of the x-ray structures of multiple co-complexes. In addition, structure-based mutational analyses indicate that this newly identified pocket is essential for compound activity. As predicted, these molecules increase Ras-GTP levels in cells. However, they unexpectedly inhibit MAPK and PI3K signaling. Our studies suggest a novel way to target K-Ras and offer possible starting points for the discovery of compounds that could be used to treat Ras-driven tumors.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR01.
Citation Format: Michael Burns, Qi Sun, Richard Daniels, J. Phillip Kennedy, DeMarco Camper, Jason Phan, Edward Olejniczak, Taekyu Lee, Alex Waterson, Olivia Rossanese, Stephen Fesik. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. [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 PR01.
Abstract PR02: LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer.
Authors: Kim Sunkyu , Loo Alice , Chopra Rajiv , Caponigro Giordano , Huang Alan , Vora Sadhna , Parasuraman Sudha , Howard Steve , Keen Nicholas , Sellers William , Brain Christopher 
Published: August 2014

Abstract
The tumor suppressor Retinoblastoma protein (Rb) is often inactivated in cancer. In many tumors, the Rb protein itself is retained but functionally inactivated by increased CDK4/6 kinase activity. A number of key oncogenic aberrations can result in this increased activity, including inactivation of CDKN2A (p16), translocation or amplification of D-cyclins, amplification of CDK4/6 and mutations/deletions upstream of cyclin D, such as activating mutations of BRAF/PIK3CA and PTEN deletion. Abolishing CDK4/6 kinase activity and subsequent reactivation of Rb in these tumors has been demonstrated to inhibit tumor initiation and growth. Here we will describe LEE011- an orally bioavailable, selective small molecule inhibitor of CDK4/6 kinases. LEE011 inhibits CDK4/6 kinase activity with nM IC50 and is highly selective for these targets. In a number of preclinical tumor models, LEE011 demonstrates a dose dependent anti-tumor activity that tracks well with CDK4/6 inhibition. The primary mechanism for growth inhibitory effect appears to be G1 arrest in vitro, although, in some sensitive in vivo models, regressions are observed. Importantly, given the role of CDK4/6 downstream of other oncogenic driver mutations, LEE011 shows single agent activity in melanomas with activating mutations of BRAF or NRAS, and in breast cancers with intact estrogen receptor and/or activating aberrations of PIK3CA/Her-2. Combining LEE011 with LGX818, a V600E BRAF specific inhibitor, leads to robust anti-tumor activity in melanoma models that are both sensitive and, importantly, those that are resistant to LGX818. Furthermore, combining LEE011 with BYL719, a PIK3CA specific inhibitor, also leads to significant anti-tumor activity in breast cancer models both sensitive and resistant to BYL719. Several clinical studies evaluating LEE011 as single agent and in combinations are underway.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR02.
Citation Format: Sunkyu Kim, Alice Loo, Rajiv Chopra, Giordano Caponigro, Alan Huang, Sadhna Vora, Sudha Parasuraman, Steve Howard, Nicholas Keen, William Sellers, Christopher Brain. LEE011: An orally bioavailable, selective small molecule inhibitor of CDK4/6– Reactivating Rb in cancer. [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 PR02.
Abstract 1750: Identification of genes involved in chemoradiation response of head and neck cancer by functional genetic screens
Authors: Martens-de Kemp Sanne R. , Brink Arjen , van der Meulen Ida H. , Kuik Dirk J. , Menezes Renee , Braakhuis Boudewijn JM , van Beusechem Victor W. , Brakenhoff Ruud H. 
Published: August 2014

Abstract
Introduction: Patients with advanced head and neck squamous cell carcinoma (HNSCC) are treated with cisplatin-containing chemoradiation protocols, but tumor responses can be short-lasting. For these patients surgery combined with postoperative radiotherapy is preferred over chemoradiation. Currently, there are no strong predictors of chemoradiation response that would allow to personalize treatment. We performed a functional genetic siRNA screen to identify genes that can be used to predict upfront which tumors are likely to respond to chemoradiation.
Methods: A large panel of HNSCC cell lines was characterized for cisplatin sensitivity. A suitable HNSCC cell line was selected and forward transfected with a genome-wide library of short interfering RNAs (siRNAs), followed by cisplatin (IC20 and IC80) or mock treatment. Genes influencing cellular response to cisplatin were identified by comparing cell viability between the different conditions. The screen was carried out in duplicate and data were analyzed by Z-score calculation using two independent statistical methods.
Results: Scrambled siRNAs and siRNAs targeting genes known to influence cell viability or cisplatin sensitivity were included as controls and gave the expected results: less than 10% toxicity and &gt;80% knock-down. Hit lists obtained with both methods of data analysis revealed 86 siRNAs that appeared to influence cisplatin response significantly. Some of these 86 siRNAs target genes that are known to cause sensitivity to cisplatin, thereby confirming the reliability of the approach. We also obtained a list of 80 genes that influenced basic cell viability of HNSCC cells independent of cisplatin.
Conclusion: By specifically knocking down all human genes in HNSCC cells, we obtained an unbiased list of at least 86 candidate genes that seem to influence the cellular response to cisplatin. Refined statistical analysis combined with bioinformatics, the exclusion of off-target effects, as well as confirmation of the hits in multiple cell lines is needed to validate these results. Validated hits will be evaluated as predictive markers in clinical samples.
This research was supported by the Center for Translational Molecular Medicine (AIRFORCE project).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1750. doi:10.1158/1538-7445.AM2011-1750
Abstract 1751: Engineered toxin bodies with specific cell kill activity against mesenchymal cells
Authors: Higgins Jack P. , Robinson Lee , Higley John , Grant Kari , Null Bill , Zhu Keng , Kim Jason , Cunningham Casey , Poma Eric 
Published: August 2014

Abstract
The epithelial-to-mesenchymal transition is associated with progression and poor outcome in numerous cancers. Discovery of selective agents that target mesenchymal cancer cells has been an area of significant interest. Here we describe the identification of several novel compounds that specifically recognize and kill H358 Non-small cell lung carcinoma (NSCLC) cells that have been transitioned to a mesenchymal phenotype while showing no activity against H358 epithelial cells. These compounds were identified from a screen of a novel biologic library derived from a de-immunogenized Shiga-like toxin 1 A subunit (SLT1A); SLT1A has no intrinsic binding ability of its own but can drive internalization, retrograde transport to the cytosol, and enzymatic inhibition of ribosome activity. This modified library of engineered toxin bodies (ETBs) was created through the insertion of random amino acids near the C-terminus of the SLT1A scaffold to confer selective binding ability of SLT1A while preserving the therapeutic PK and ADME profile of the scaffold. This library of approximately 10⁁15 variants was pre-cleared against epithelial H358 cells and then screened against mesenchymal H358 cells. The screen was performed in an etiology driven manner where the receptor was not known a priori and selection was based on variants ability to induce cell-kill. Sequence convergence was observed as a result of the biopanning and further characterization of a selected group of mesenchymal-specific ETBs is on-going.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1751. doi:10.1158/1538-7445.AM2011-1751