bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A86: Preclinical refinement of a highly-penetrative polymeric nanoparticle drug delivery system for the treatment of glioblastoma multiforme.
Authors: Strohbehn Garth W. , Atsina Komli-Kofi , Patel Toral R. , Piepmeier Joseph M. , Zhou Jiangbing , Saltzman W. Mark 
Published: August 2014

Abstract
Survival statistics for glioblastoma multiforme (GBM) have remained static despite years of research. Two challenges must be overcome to extend survival: drug delivery and resistance to current therapies. Recently, we have developed a highly-penetrative polymeric nanoparticle system capable of being safely delivered to brain parenchyma using convection-enhanced delivery (CED). We have previously shown that this system is capable of protecting and releasing in a controlled manner agents with activity against glioma stem cells (GSCs), significantly improving survival in a rat xenograft model of GSC-derived GBM. We describe here our efforts to further refine this potential therapeutic.
First, utilizing high-throughput small molecule screening of a library of generic and FDA- and internationally-approved compounds against GSCs of varying morphologies and genetic composition, we describe the discovery of a novel class of compounds with profound anti-proliferative activity against GSCs but with only very limited activity against normal glial cells. Identified compounds are notably small and lipophilic, making them ideal candidates for translation in our highly-penetrative polymeric nanoparticle system.
Second, building upon recent advances in magnetic resonance imaging technology, we describe the incorporation of supraparamagnetic iron oxide (SPIO) in our highly-penetrative polymeric nanoparticle system. We show that incorporation of SPIO does not alter size or in vitro properties of these nanoparticles. Further, we show that SPIO-loaded nanoparticles can be safely delivered to brain parenchyma using CED and can stably release their contents in a controlled fashion over a matter of weeks. These results represent important steps toward clinical application of a promising drug delivery technology.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A86.
Citation Format: Garth W. Strohbehn, Komli-Kofi Atsina, Toral R. Patel, Joseph M. Piepmeier, Jiangbing Zhou, W. Mark Saltzman. Preclinical refinement of a highly-penetrative polymeric nanoparticle drug delivery system for the treatment of glioblastoma multiforme. [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 A86.
Abstract A87: Overcoming NSCLC to SCLC transformation as a resistance mechanism in EGFR mutant lung cancer.
Authors: Niederst Matthew J. , Sequist Lecia V. , Lockerman Elizabeth L. , Costa Carlotta , Borger Darrell R. , Mino-Kenudson Mari , Iafrate Anthony J. , Engelman Jeffrey A. 
Published: August 2014

Abstract
The EGFR TKIs gefitinib and erlotinib produce dramatic responses in NSCLC patients with EGFR activating mutations, however, the efficacy of these drugs is severely limited by the development of acquired resistance. Recently, we and others have found that a subset of these cancers transform from NSCLC to SCLC as they acquire resistance to EGFR TKI. Here we report an initial characterization of the molecular mechanisms underlying the transformation from NSCLC to SCLC in samples and cell lines derived from resistant patients. Much like de novo SCLC, Rb and p53 are altered in the resistant tumors that transformed to SCLC, although loss of p53 and Rb function alone were insufficient to drive the transformation in NSCLC cell lines. In addition, we demonstrate that EGFR expression is lost in resistant samples, suggesting that in switching to SCLC these cancers become a cell type that is no longer dependent on EGFR activity and providing an explanation for lack of EGFR TKI sensitivity. Finally, we find that SCLC transformed cells are uniquely sensitive to the Bcl-2/Bcl-XL inhibitor Abt-263, offering a potential therapeutic option for these patients. Together, these results represent the first insights into the molecular and genetic details regarding this novel type of resistance to targeted therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A87.
Citation Format: Matthew J. Niederst, Lecia V. Sequist, Elizabeth L. Lockerman, Carlotta Costa, Darrell R. Borger, Mari Mino-Kenudson, Anthony J. Iafrate, Jeffrey A. Engelman. Overcoming NSCLC to SCLC transformation as a resistance mechanism in EGFR mutant lung 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 A87.
Abstract A89: Loss of HLA molecules as melanoma resistance mechanism in immune checkpoint blockade therapy.
Authors: Anichini Andrea , de Braud Filippo G. , Montarini Roberta , Bersani Ilaria , Tragni Gabrina , de Cecco Loris , Canevari Silvana , Di Guardo Lorenza , Pilla Lorenzo , Del Vecchio Michele 
Published: August 2014

Abstract
Melanoma immunotherapy based on immune checkpoint blockade, by targeting of CTLA-4 or PD-1, has markedly improved the treatment of advanced disease, as shown by several recent trials. Monotherapy with CTLA-4-specific antibody (Ipilimumab) prolongs overall survival, while PD-1-specific antibodies (Nivolumab and Lambrolizumab) induce durable tumor regression in a large fraction of patients. Moreover, a recent trial based on combination checkpoint blockade (Ipilimumab plus Nivolumab) has shown an objective response rate of 53%, with tumor reduction of 80% in responding patients, without escalation of toxic effects. In spite of these highly relevant results, clinical benefit by immunotherapy targeting CTLA-4 or PD-1 remains limited to a fraction of patients. This points to the existence of immune escape mechanisms, which, in some tumors, may prevent effective elimination of neoplastic cells, in spite of the reactivated T cell immunity. This hypothesis was tested in a melanoma patient, treated with Ipilimumab, and that we recently reported (J. Clin. Oncol. 29:e783-8, 2011) to have a strong T cell infiltrate and evidence of T cell maturation/activation only in a regressing right adrenal metastasis, but not in the progressing controlateral lesion. To this end, we carried out DASL whole genome gene expression analysis and extensive immunohistochemistry (IHC) on paraffin-embedded neoplastic tissues. The results indicated that, in comparison to the progressing metastasis, the regressing lesion had a distinct gene expression profile characterized by enhanced expression of several genes involved in T cell differentiation to cytolytic effector stage. Most importantly, the regressing lesion retained expression of HLA molecules on neoplastic cells. In contrast, the progressing lesion showed almost complete loss of HLA class I and Class II molecules by the tumor, as documented by IHC. Taken together, these results suggest that lack/loss of expression of HLA molecules, by tumor cells, may represent a highly effective tumor resistance mechanism to immune checkpoint blockade. Moreover, pre-therapy IHC on tumor samples may allow to test whether HLA antigen expression/loss is a predictive marker for response/resistance to therapy targeting CTLA-4 or PD-1.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A89.
Citation Format: Andrea Anichini, Filippo G. de Braud, Roberta Montarini, Ilaria Bersani, Gabrina Tragni, Loris de Cecco, Silvana Canevari, Lorenza Di Guardo, Lorenzo Pilla, Michele Del Vecchio. Loss of HLA molecules as melanoma resistance mechanism in immune checkpoint blockade therapy. [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 A89.
Abstract A94: Understanding of differing sensitivity in EML4-ALK NSCLC patients to crizotinib and geldanamycin.
Authors: Rikova Klarisa , Hall Benjamin , Possemato Anthony , Mroszczyk Keri , Lee Kimberly A. , MacNeill Joan , Ren Jian Min , Guo Ailan , Mulhern Daniel , Wang Yi , Beausoleil Sean A. , Comb Michael J. 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer, afflicting nearly 200,000 people in the United States each year. Abnormal ALK is found in about 5% of NSCLC cases, meaning more than 5,000 new patients could benefit from the tyrosine kinase inhibitor (TKI) crizotinib. However, not all patients benefit from such treatment, with the clinical response to crizotinib differing among patients who harbor the same molecular abnormality. Similarly, patients with ALK fusion proteins have shown varying sensitivity to the HSP90 inhibitor geldanamycin in preclinical studies.
We have chosen two NSCLC cell lines, H3122 and H2228, as a model to address these questions. Both cell lines harbor EML4-ALK fusions with differing sensitivity to the inhibitors crizotinib and geldanamycin. We used the established method of TMT peptide labeling coupled with serial peptide immunoprecipitation. To observe the effects of crizotinib and geldanamycin on ALK sensitive H3122 and non-sensitive H2228 NSCLC cell lines quantitative analysis was performed. Phosphotyrosine, acetylation, methylation, ATM/ATR substrate (s/tQ), Akt/AMPK subs AGC/CAMK/STE, and MAPK family kinase motif antibodies were used for immunoprecipitation allowing us to characterize and quantify post translational modifications before and after treatment.
In this study, we identify extensive signaling networks downstream of ALK across multiple spaces, including phosphorylation, acetylation, and methylation. These differences may be clinically significant and highlight the possibility that ALK inhibitors alone may only be effective in a subset of NSCLC ALK-positive patients with EML4-ALK inversion.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A94.
Citation Format: Klarisa Rikova, Benjamin Hall, Anthony Possemato, Keri Mroszczyk, Kimberly A. Lee, Joan MacNeill, Jian Min Ren, Ailan Guo, Daniel Mulhern, Yi Wang, Sean A. Beausoleil, Michael J. Comb. Understanding of differing sensitivity in EML4-ALK NSCLC patients to crizotinib and geldanamycin. [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 A94.
Abstract A97: PPME1 is a novel target for synthetic lethal therapy in human gliomas.
Authors: Westermarck Jukka , Kaur Amanpreet 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is a devastating disease with very limited therapy choices. Although deregulated kinase pathways have been identified as drivers of GBM progression, inhibition of receptor tyrosine kinases or serine/threonine kinases has not been successful therapy mode for GBM. Therefore, there is an evident need for novel therapy strategies to overcome kinase inhibitor resistance in GBM.
Here we have identified a novel approach to induce very potent synthetic lethal cell killing in human glioma cells treated with multikinase inhibitors. We show that targeting of protein methylesterase PPME1, which functions as an inhibitor of human tumor suppressor protein phosphatase 2A (PP2A), causes dramatic cell killing in GBM cells in combination with structurally defined subgroup of indolocarbazole inhibitors currently in clinical trials. PPME1 silenced glioma cells are significantly sensitized to cell killing by indolocarbazole inhibitors both in vitro and in in vivo tumors. Synthetic lethality is specific for combination of PME-1-regulated PP2A activity and can be reversed by inhibition of specific PP2A complexes. Downstream of PP2A, PPME1 inhibition-elicited synthetic lethality involves regulation of HDAC4, a known survival factor in neuronal cells. Consequently, inhibition of HDAC4 phenocopies synthetic lethal cell killing seen in PME-1-depleted cells and expression of HDAC4 correlates with disease progression and with PME-1 status in human glioma. Biochemical evidence indicates that PPME1 and HDAC4 regulate expression and acetylation of same target proteins involved in regulation of cancer cell survival.
Thus, these results present novel synthetic lethal therapy approach for GBM via inhibition of PPME1 and HDAC4. These results also identify PME-1 as potential biomarker for glioma patient stratification for indolocarbazole inhibitors currently in clinical trials. Generally these results emphasize potential of concomitant inhibition of kinases and reactivation of their antagonist protein phosphatases as a cancer therapy approach.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A97.
Citation Format: Jukka Westermarck, Amanpreet Kaur. PPME1 is a novel target for synthetic lethal therapy in human gliomas. [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 A97.
Abstract B108: A genome-scale shRNA synthetic lethal screen identifies enhancers of sensitivity to RAF inhibition.
Authors: Whittaker Steven R. , Luo Flora , Hsiao Jessica , Cowley Glenn S. , Root David E. , Garraway Levi A. 
Published: August 2014

Abstract
Genome-scale RNA interference screens have identified a dependency on BRAF for the proliferation of BRAF-mutant colorectal cancer (CRC) cell lines. Despite this, small molecule RAF inhibitors, such as vemurafenib, have been unsuccessful in clinical trials of patients with CRC, with a response rate of only 5%. CRC cell lines demonstrate intrinsic resistance to RAF inhibitors, in some cases through EGFR or MET activity. We designed a genome-scale RNA interference screen to identify loss of function events that could synergize with pharmacologic RAF inhibition. We transduced a pooled lentiviral library encoding 90,000 shRNAs targeting over 16,500 genes into the RKO CRC cell line, which displays robust resistance to PLX470. The shRNA-infected population was divided into two experimental arms, one treated with DMSO, the other treated with PLX4720. Following 16 population doublings, the abundance of each hairpin was assessed by PCR amplification of barcoded hairpin DNA, followed by massively parallel paired-end sequencing. The log-fold change in shRNA abundance between the PLX4720- and DMSO-treated controls was determined and RNAi gene enrichment (RIGER) used to rank individual shRNAs and nominate candidate genes that were required for survival of RKO cells exposed to PLX4720. Top-ranking genes that displayed synthetic lethality with RAF inhibition were validated in an arrayed secondary screen. shRNAs targeting MET scored highly, consistent with recent reports implicating HGF-MET signaling in resistance to BRAF inhibition, validating our approach. Furthermore, we describe the characterization of additional genes that sensitize cells to inhibition of BRAF. Ultimately, these studies aim to nominate pharmacologically targetable events that mediate RAF-inhibitor resistance in colorectal cancers.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B108.
Citation Format: Steven R. Whittaker, Flora Luo, Jessica Hsiao, Glenn S. Cowley, David E. Root, Levi A. Garraway. A genome-scale shRNA synthetic lethal screen identifies enhancers of sensitivity to RAF inhibition. [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 B108.
Abstract B119: Mechanisms of drug resistance to molecular target therapeutics against tyrosine kinases as EGFR, c-Met, and PDGFR in GBM.
Authors: Tsuda Masumi , Wang Lei , Tanino Mishie , Kimura Taichi , Nishihara Hiroshi , Tanaka Shinya 
Published: August 2014

Abstract
Glioblastoma multiforme (GBM) is the most common and aggressive brain tumor. Despite technological advances in surgery, combined with regimens of radiotherapy and new generation chemotherapy, the median survival is still 15 months. Several molecular therapeutics targeting protein tyrosine kinases have recently been attempted; however, the emerging drug resistance is a crucial issue. Here, we established cell lines acquired drug resistance to individual inhibitor for major tyrosine kinase as EGFR, c-Met, or PDGFR that highly expressed in GBM, and characterized the underlying mechanisms. While initial 50 days starting inhibitor treatment, the cells exhibited distinct morphological changes of epithelial-mesenchymal transition (EMT) concomitant with up-regulation of Snail, Slug, and Mmp-2. Of note, further continuous drug treatment produced stemness-like properties in the cells. PCR array and microarray analysis have identified marked enhancement of several stemness-related genes including Sox2 and CXCL12. These findings show that suppression of EMT and/or stemness features of GBM may be an effective strategy to avoid the acquisition of resistance for molecular target therapy in GBM.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B119.
Citation Format: Masumi Tsuda, Lei Wang, Mishie Tanino, Taichi Kimura, Hiroshi Nishihara, Shinya Tanaka. Mechanisms of drug resistance to molecular target therapeutics against tyrosine kinases as EGFR, c-Met, and PDGFR in GBM. [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 B119.
Abstract B124: Selective inhibition of HER2 signaling pathway reveals novel functions of FOXA1 in breast cancer.
Authors: Katika Madhumohan , Martin Ruthmma , Siv Gilfillan , Børresen-Dale Anne Lise , Lopez Sandra , Hurtado Toni 
Published: August 2014

Abstract
Breast cancer cell proliferation results from many different factors that activate multiple cellular signaling pathways, which are currently target therapies. Yet, how genomic pathways are influenced upon cell-signaling disruption has been poorly assessed. We explored how the inhibition of HER2 signaling pathway influences the function of the transcription factor FOXA1. By means of specific inhibitors targeting the kinase activity of HER2 (Lapatinib) and its downstream kinase MEK (AZD6244) we have identified HER2/MEK signaling pathway as a key supervisor of FOXA1 function in HER2+ breast cancer subtype. The HER2/MEK pathway regulates the function of acetyltransferase enzymes through phosphorylation. These acetyltransferases in turn control the binding of FOXA1 towards key genes required for the proliferation in HER2+ cancer cells. Importantly, the same mechanisms of FOXA1 regulation are needed to induce cell proliferation in ER+ breast cancer cells that do not overexpress HER2.
We also explored the function of FOXA1 upon Herceptin treatment, which is a monoclonal antibody that binds to the extracellular domain of HER2. Here, we demonstrate that treatment of breast cancer cells with Herceptin produces the activation of cytokine signaling pathways. Importantly, the cytokine pathway activation reprograms the chromatin interactions of FOXA1 towards genes playing a key role in the initiation of the cell-mediated cytotoxicity. All together, these findings supports the idea that FOXA1 integrates input signals originating from multiple cell-signaling pathways to generate output responses that culminate in control of proliferation and the response to anti-cancer therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B124.
Citation Format: Madhumohan Katika, Ruthmma Martin, Gilfillan Siv, Anne Lise Børresen-Dale, Sandra Lopez, Toni Hurtado. Selective inhibition of HER2 signaling pathway reveals novel functions of FOXA1 in breast 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 B124.
Abstract B133: Regulation of the androgen receptor function by a metabolic kinase in prostate cancer.
Authors: asim Mohammad , Massie Charlie , Zecchini Heather , Baridi Ajoeb , Gomes Nelma , Mohammed Hisham , Zecchini Vincent , Madhu Basetti , Qureshi Arham , Russell Roslin , Hessenkemper Wiebke , Sriranjan Rouchelle , Yang Carrie , Lynch Andy , Gregorengko Elena , Stark Rory , Rennie Paul , Griffiths John , Baniahmad Aria , Carroll Jasol , Mills Ian , Neal David 
Published: August 2014

Abstract
In a recent genome-wide study to identify androgen receptor target genes we found that the AR promotes tumor growth by enhancing the expression and activity of enzymes required for metabolic biosynthesis. This raises the possibility for effective therapeutic approaches directed towards AR target genes. Kinases are well-established drug targets. In this study we identify androgen regulated kinome and show that an important androgen regulated metabolic kinase is a drug target in prostate cancer. Our proteome study shows that this kinase interacts with the androgen receptor and regulates AR stability. Inhibition of this kinase significantly reduces AR protein levels and suppresses prostate cancer growth in cell-lines and ex vivo cultures. In clinical prostate cancer this kinase is highly over-expressed in metastatic prostate cancers and inhibition represses metastatic potential of prostate cancer cells. Our study therefore establishes this kinase for the first time as an AR target gene that regualtes AR itself as part of feedback loop and makes a case for further investigation of its inhibitors as novel AR antagonists in both localised and advanced disease.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B133.
Citation Format: Mohammad asim, Charlie Massie, Heather Zecchini, Ajoeb Baridi, Nelma Gomes, Hisham Mohammed, Vincent Zecchini, Basetti Madhu, Arham Qureshi, Roslin Russell, Wiebke Hessenkemper, Rouchelle Sriranjan, Carrie Yang, Andy Lynch, Elena Gregorengko, Rory Stark, Paul Rennie, John Griffiths, Aria Baniahmad, Jasol Carroll, Ian Mills, David Neal. Regulation of the androgen receptor function by a metabolic kinase in prostate 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 B133.