bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 843: Influx of thiosemicarbazone NSC73306 is mediated by the cisplatin and copper transporter SLC31A1 (CTR1)
Authors: Fung King Leung , Tepede Abisola K. , Pluchino Kristen M. , Hall Matthew D. , Gottesman Michael M. 
Published: August 2012

Abstract
Multidrug resistance (MDR) mediated via the drug efflux pump P-glycoprotein (P-gp/ABCB1) overexpression is a major obstacle to the success of chemotherapy to combat many cancers. Clinically, P-gp expression correlates with poor clinical response to chemotherapy in patients, and its presence on the blood-brain barrier (BBB) can reduce the efficacy of otherwise promising agents targeted to the brain. Attempts to reverse drug resistance by inhibiting P-gp have not been successful, and we have been investigating alternative strategies for targeting multidrug-resistant (MDR) cancer cells. One such strategy is the use of NSC73306, a thiosemicarbazone compound that is selectively toxic towards P-gp-expressing cells. Here, we investigate the cellular uptake of NSC73306, and examine its interaction with P-gp and copper transporter 1 (SLC31A1, CTR1). In porcine kidney epithelial LLC-PK1 cells, cellular accumulation of NSC73306 is saturable, and overexpression of human P-gp in LLC-PK1 cells sensitizes them to NSC73306. Accumulation of [3H]NSC73306 in LLC-PK1 cells is inhibited by cyclosporin A (IC50 = 500 μM), verapamil (IC50= 700 μM) and cisplatin (IC50 = 77 μM). Among these compounds, we tested the effect of cisplatin on NSC73306. Selective toxicity of NSC73306 to P-gp-expressing LLC-PK1 cells was reversed by cisplatin in a dose-dependent manner (up to 40 μM). In contrast, the amount of cisplatin required to kill 50% of LLC-PK1 cells was not affected by increasing the amount of NSC73306 (up to 2μM). Since cisplatin could inhibit NSC73306 uptake, we hypothesize that these two compounds share a common uptake pathway, but cisplatin has additional routes of entry into cells. Cells transiently expressing CTR1 showed significantly higher [3H]NSC73306 accumulation. In contrast, CTR1 knockdown cells had lower [3H]NSC73306 uptake. Although cisplatin is a transport substrate of CTR1, we found that CTR1 protein was overexpressed in cisplatin-resistant KB-CP20 and BEL7404-CP20 cell lines. Compared to their parental cisplatin-sensitive cells, even though these resistance cells show decreased cisplatin accumulation, suggesting that CTR1 is not rate-limited for cisplatin uptake. These cell lines also showed higher [3H]NSC73306 uptake compared to their parental cells. In contrast, MDR cell lines overexpressing P-gp had unchanged CTR1 protein levels. Incubation with NSC73306 for 24 hours down-regulated CTR1 in a dose-dependent manner. These results suggest that NSC73306 is a transport substrate of CTR1.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 843. doi:1538-7445.AM2012-843
Abstract 855: The antileukemia drug nilotinib inhibits invasion and metastasis of colorectal cancer cells by targeting the receptor tyrosine kinase DDR1
Authors: Leroy Cédric , Tosti Priscillia , Simon Valérie , Robert Bruno , Sirvent Audrey , Roche Serge 
Published: August 2012

Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the Western world. Cancer that metastasizes to distant sites is usually not curable, although chemotherapy can extend survival. Recently, a novel immunotherapy approach based on targeting of the tyrosine kinase (TK) EGFR was shown to significantly improve the survival of patients with metastatic CRC (mCRC). However, only patients with a wild-type KRAS may hope respond to EGFR inhibition. The majority of patients expresses oncogenic components of Ras signaling and thus have hyperactive Ras cascade operating independently from EGFR. Therefore, there is an urgent need to discover new Ras-independent oncogenic targets that regulate tumor cell invasion and metastasis in patients with mCRC. Using a pharmacological screen, we uncovered an additional TK that regulates CRC cell invasion and metastasis induction irrespective of KRAS mutation. Specifically, the clinically available TK inhibitor nilotinib (Tasigna) originally developed to target imatinib-resistant Bcr-Abl alleles in leukemia, also inhibits invasive properties of CRC cells. Nilotinib also strongly reduces liver metastases that were induced after injection of mCRC cells in the spleen of nude mice. Remarkably, the potency of nilotinib to inhibit invasive activity of mCRC cells was similar to the one observed in leukemia. Since we could not detect Abl deregulation in CRC cells, we speculated the involvement of an alternative target to be identified. Interestingly, a previous chemical-proteomic approach identified DDR1 as the highest affinity target of nilotinib (Rix et al, Blood, 110:4055-63). DDR1 is a poorly-characterized TK and a receptor for collagen, the major component of the extracellular matrix. We found that DDR1 is overexpressed in CRC and regulates CRC cell-induced invasion in vitro and liver metastasis formation in vivo. Finally, we have obtained evidence supporting that the pharmacological activity of nilotinib in CRC cells is mediated by inhibition of DDR1. Indeed, introduction of the nilotinib resistant DDR1 T701I mutant into CRC cells renders these cells resistant to nilotinib. Overall, our data suggest that targeting DDR1 by nilotinib may be a therapeutic value in patients with mCRC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 855. doi:1538-7445.AM2012-855
Abstract 862: Pre-clinical and molecular analysis of Crizotinib in c-Met positive uveal melanoma
Authors: de Lange Mark J. , Versluis Mieke , Luyten Gre P.M. , Jager Martine J. , van der Velden Pieter A. 
Published: August 2012

Abstract
Uveal melanoma (UM) is an intraocular neoplasm with an annual incidence of 7 per million. UM originates from melanocytes just like cutaneous melanoma (CM) and similar to CM, the RAS/RAF/MEK/ERK pathway is involved in the development of UM. However, not all UM seem to depend on the activation of this pathway. Loss of ERK signalling may be correlated with progression as the ERK negative cells are derived from UM metastasis. In these tumours, cells apparently use a different pathway to proliferate and survive. In order to identify treatment targets for metastasis patients we set out to identify the pathway which stimulates proliferation in the ERK negative UM cells. Growth factor receptor screening revealed that activation of c-Met or HGF receptor, is inversely correlated with ERK activation leaving the metastatic UM, halfway progression to metastasis, with both c-Met and ERK activated. In this study, we tested the efficacy of c-Met inhibitor Crizotinib and investigated primary and downstream targets to delineate the role of c-Met signalling in UM progression. Crizotinib was shown to specifically inhibit c-Met positive UM and this was most clear when cells were grown anchorage independent, in line with a role in dissemination for c-Met. With phospho-proteomics we showed that c-Met is the primary target of Crizotinib in UM while FAK emerges as the prime downstream target. Moreover, Src was shown to be the downstream kinase that transmits the c-Met signal to both FAK and ERK in metastatic UM. In UM metastasis, lacking active ERK, Src is absent and FAK is directly activated by c-Met. Combined, our data support the use of Crizotinib in late stage UM and reveals altered c-Met signalling in uveal melanoma progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 862. doi:1538-7445.AM2012-862
Abstract 863: Tyrosine kinase activity profiling of metastatic malignant melanoma: Identification of possible therapeutic targets and markers predicting response to therapy
Authors: Tahiri Andliena , Roe Kathrine , Busch Christian , Lonning Per Eystein , Ree Anne H. , Kristensen Vessela N. , Geisler Juergen 
Published: August 2012

Abstract
Metastatic melanoma is an aggressive form of skin cancer that is highly resistant to conventional chemotherapy. Thus, novel approaches to improve the current treatment of advanced melanoma are urgently needed. Kinases are key regulators of cellular processes, and since nearly half of the tyrosine kinase complement is implicated in cancer, the information of kinase activity in tumors give important tumor-specific information on affected pathways and potential targets for treatment. With this in mind, we performed tyrosine kinase activity profiling of 26 tissue samples obtained from patients suffering from metastatic stage IV melanoma, prior to dacarbazine (DTIC) treatment, using Tyrosine Kinase PamChip® microarrays. Each sample lysate generated an individual phospho-substrate signature, representing the state of the kinase signalling cascades, which allowed us to compare affected targets in responders and non-responders to DTIC treatment. Further, we attempted to evaluate the kinase activity in response to BRAF inhibitor, PLX4032 (Vemurafenib), which has shown dramatic and positive effects in advanced melanoma tumors, and has recently been approved for the treatment of late stage melanoma. In this case, incubation was carried out on all samples with and without PLX4032. Our preliminary results showed that although the compound is mainly directed against a serine/threonine kinase, BRAF, PLX4032 also showed inhibitory effects on the activity of multiple tyrosine kinases. Since the drug is only beneficial for melanoma patients with BRAF V600E mutations, we compared the activated kinase pathways in patients with and without this mutation in order to identify alternative survival pathways in patients with wild type BRAF. The technology used in this study is based on a unique 3D flow-through microarray format that allows monitoring of the reaction in real time, ideal for the characterization of pathways. Each array contained 144 peptide substrates with sites for phosphorylation, representing about 100 different proteins. The use of kinase inhibitors will cause inhibition of corresponding kinases of activated signalling pathways; hence, providing us leads to therapeutic targets and possible prediction markers for response to therapy. The detailed effects of both PLX4032 and sunitinib in the chosen test system are currently prepared for presentation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 863. doi:1538-7445.AM2012-863
Abstract 87: Micropapillary breast carcinoma is characterized by deregulation of genes involved in cell division control
Authors: Gruel Nadege , Benhamo Vanessa , Popova Tatiana , Gauthier Arnaud , Cascone Ilaria , Arnould Laurent , Fréneaux Paul , Cedenot Aurelie , Mariani Odette , Bhalshankar Jaydutt , Pierron Gaëlle , de Cremoux Patricia , Reyal Fabien , Alran Severine , Cottu Paul , Fourquet Alain , Sastre Xavier , Stern Marc-Henri , Camonis Jacques , Delattre Olivier , Vincent-Salomon Anne 
Published: August 2012

Abstract
This study provides insight into the biological specificities of invasive micropapillary carcinoma of the breast (IMPC), an entity characterized by cell polarity inversion and frequent lymphovascular invasion and axillary lymph node metastasis compared to invasive ductal carcinoma (IDC). Morphological review was combined with copy number analyses, genotyping (SNP6.0 Affymetrix), TP53 and PIK3CA sequencing and transcriptomic analysis in a series of 39 pure IMPC and the results were compared to those of 19 IDC with positive estrogen receptors, and positive axillary lymph node and lymphovascular invasion (ER+, N+, LVI+). The presence of numerous bi-nucleated cells was identified as a morphological pattern of IMPC. This specific trait was underlined by deregulation of the expression of genes involved in cell division. IMPC and IDC exhibit common genomic alterations including 8p-, 8q+, 16q-, 17p13- and 22q- and mutations of PIK3CA (10% for IMPC and 11% for IDC) and TP53 (13% in IMPC vs 33% in IDC). In contrast, IMPC were specifically characterized by frequent 17q23.2-q24.1 gains (54%), chromosomes 17q 23.1 (26%), 17q12 (22%), 8q22.1 (21%) amplifications and 6q16.1-q22.31 losses (43%). Within the IMPC group, unsupervised analysis of genomic data distinguished two distinct subsets: one subset (16 IMPC) exhibited a significant increase in 16p gains associated with near-diploid cells and the second subset (19 IMPC) characterized by a high frequency of 8q, 17q and 20q amplifications associated with near-tetraploid cells. This analysis showed that IMPC constitutes a distinct entity from ER+ N+ LVI+ IDC with, in particular, high frequencies of bi-nucleated cells, 17q gains and amplifications associated with 6q losses of heterozygosity. This study also showed that IMPC comprises two genomic subsets that may suggest the existence of different oncogenic mechanisms giving rise to the same morphological entity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 87. doi:1538-7445.AM2012-87
Abstract 870: Synergistic antitumor activity of AKT inhibitor MK2206 and FUS1-nanoparticles in LKB1 mutant NSCLC
Authors: Meng Jieru , Lara-Guerra Humberto , Ji Lin , Roth Jack A. 
Published: August 2012

Abstract
FUS1, a novel tumor suppressor gene in the human chromosome 3p21.3 region, is deleted in many cancers. A phase I clinical trial assessing FUS1-mediated molecular therapy has reported antitumor activity in lung cancer patients. Previous studies showed that FUS1 regulates the activation of multiple oncogenic kinases. MK2206 is a highly selective non-ATP-competitive allosteric inhibitor of AKT currently being evaluated in early-phase clinical trials for treatment of patients with lung cancer. In this study, we evaluated the combined effects of the tumor suppressor gene FUS1 and MK2206 on tumor cell growth and apoptosis induction in NSCLC cells and explored the molecular mechanism of their mutual action. We found that exogenous expression of FUS1 sensitized the response of NSCLC cells to MK2206, resulting in a marked increase in growth suppression and apoptosis in LKB1-mutant NSCLC cells. However, FUS1 had no effect on the response of LKB1-wild-type NSCLC cells to MK2206. Systemic treatment with a combination of FUS1-nanoparticles and MK2206 in an LKB1 mutant H322 lung cancer subcutaneous xenograft mouse model enhanced the therapeutic efficacy of MK2206. The mice receiving the combination of MK2206 and FUS1-nanoparticles showed a significantly reduced mean tumor volume (364±164 mm3) compared with mice receiving empty vector/MK2206 (728±101 mm3), MK2206 alone (926±250 mm3), FUS1 alone (1171±294 mm3), or empty vector (2405±737 mm3) by day 21 (P&lt;0.01 for all three comparisons). Our results show that FUS1 may play a role in modulating the sensitivity of lung cancer cells to AKT inhibition, and suggests that a combination of FUS1-nanoparticles and MK2206 may be an effective treatment strategy for LKB1 mutant human lung cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 870. doi:1538-7445.AM2012-870
Abstract 877: Identification of novel genes critical to survival of MPNST cells via medium throughput screening using lentiviral shRNA
Authors: Patel Ami , Ratner Nancy 
Published: August 2012

Abstract
Malignant peripheral nerve sheath tumor (MPNST) is a soft tissue sarcoma that is highly invasive and eventually lethal. About 50% of MPNSTs have mutation and/or loss of the NF1 gene, while the rest are spontaneous. Many MPNST also show mutations in p53 and/or homozygous deletion of CDKN2. In an effort to identify novel genes that play key roles n MPNST tumorigenesis, we performed a genome wide micro-array analysis using human neurofibroma and MPNST (Miller et al., 2009). This analysis identified 130 genes that are up-regulated &gt;3 fold in MPNSTs as compared to normal human Schwann cells. Over expression of these genes in tumors as compared to normal cells suggested that some might be critical for survival of MPNST cells. This hypothesis was directly tested by studying effects on survival of MPNST cells in vitro post down regulation of the 130 genes using lentiviral short hairpin (sh) RNA. For each shRNA experiment a sh non-targeting lentivirus was used as a negative control and shSOX9, a construct previously shown to kill MPNST cells in vitro, was used as a positive control for an effect on cell survival. Screening was performed sequentially allowing for selection of genes with significant effects on survival. In screen I, T265 MPNST cells were exposed to each shRNA virus. In screen II, shRNAs were tested for effects on adenocarcinoma cells (A549) vs T265 cells. These two round of screens identified 10/130 genes specific for survival of T265 cells. Screen III was performed on four different MPNST cell lines, including T265 (NF1-/-), 8814 (NF1-/-), S462TY (NF1-/-) and SSTS26T (sporadic MPNST wild-type for NF1), to identify shRNA's with similar or different effects on cell survival in the presence or absence of wild-type NF1 gene. No significant difference in survival was observed for NF null MPNST cells vs sporadic MPNST cell line for any gene. This approach facilitates a streamlined pathway from genome wide gene expression analysis to identification of novel genes critical to survival of cancer cells in vitro. Future studies will be directed toward testing the identified genes for roles in tumor formation and growth, and as potential MPNST therapeutic targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 877. doi:1538-7445.AM2012-877
Abstract 878: In vitro selection of metastatic breast cancer cells based on their adaptability
Authors: Singh Balraj , Raythatha Milan R. , Cady Amanda M. , Madan Simran , Tai Karen , Irving LaTashia R. , Lucci Anthony 
Published: August 2012

Abstract
The success of cancer depends on ongoing generation of genetic and epigenetic heterogeneity in cancer cells, and the selection of cells that are most adaptable at surviving numerous obstacles in the body. Current approaches of personalized therapy, mostly designed to inhibit cell proliferative function of a single protein, may not succeed unless we target adaptability of cancer cells as well. We reported recently that it is possible to isolate highly metastatic rare cancer cells (&lt; 0.01% in SUM149 inflammatory breast cancer cell line) based on their adaptability to survive without glutamine in culture medium. These studies also provided evidence of a high COX-2 expression in such Gln-independent cells and in subpopulations that survived lack of serum and attachment. To determine the usefulness of our new function-based selections, we compared different COX-2 overexpressing subpopulations with the parental SUM149 cell line for their adaptability to survive lack of Gln- 1) COX-2 overexpressing cells that survive lack of serum and attachment (designated SWS), and 2) a pre-existing COX-2 overexpressing clone (clone 5) isolated by picking individual colonies. We found that the SWS variants yielded significantly more colonies (2-3 fold) than the parental cell line upon Gln withdrawal. In contrast, clone 5 failed to yield any Gln-ind colony. Further investigation into the adaptability of Gln-ind cells revealed that they are better able to survive exposure to hypoxia than the parental cell line. We obtained similar results with hypoxia caused by cell culture in 0.5% oxygen or with hypoxia caused by exposure to cobalt chloride. These results support a model in which rare cells that drive metastasis are proposed to be adaptable in multiple ways. Our studies suggest that the function-based selection of adaptable cancer cells is able to select unique cancer cells from a heterogeneous population that may not be selectable on the basis of specific biomarkers. We conclude that it is feasible to isolate rare metastatic breast cancer cells with a function-based robust selection of adaptable metabolic state. In vitro assays utilizing such adaptable and metastatic cancer cells will likely aid anti-cancer drug discovery efforts.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 878. doi:1538-7445.AM2012-878