bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1627: Requirement for the Src family kinase, Fyn, in proliferation of BCR-ABL1 transduced bone marrow and aneuploidy in CML
Authors: Lu Xiaolin , Howard Adrienne , Gao Yin , Singh Melissa , Chandra Joya 
Published: February 2011

Abstract
Oncogenic signals stemming from the BCR/ABL kinase drive the development and progression of chronic myeloid leukemia (CML). Hence, therapies blocking kinase activity have proven extremely successful at managing this hematological malignancy. However, treatment of the terminal and progressed state of CML, blast crisis, remains difficult. Previous work from our group has identified the Src family kinase, Fyn, as being upregulated in blast crisis CML. We also reported that knockdown of Fyn slowed CML growth in vitro and in vivo and sensitized cells to BCR-ABL1 kinase inhibition with imatinib. Recent work using microarray profiling of kinase inhibitor resistant cells from a separate group has shown that imatinib resistance is associated with Fyn expression. In the current study, we utilized bone marrow cells from Fyn deficient mice to test the requirement for Fyn in p210 BCR-ABL1 mediated survival. Bone marrow cells from Fyn knockout and Fyn wildtype mice were harvested and transduced with a GFP expressing retroviral construct (MigR1) or MigR1-p210 BCR-ABL1. Cells were sorted for GFP expression and BCR-ABL1 expression was confirmed by Western blotting. Cell growth in culture was monitored over the course of three weeks in Fyn deficient and wildtype cells expressing BCR-ABL1. Fourteen days post sorting, the number of cells lacking Fyn were more than 50% lower than Fyn wildtype cells transduced with BCR-ABL1. Clonogenic assays further indicated that Fyn significantly promotes BCR-ABL1 induced bone marrow cell growth. Colony numbers in Fyn deficient cells expressing BCR-ABL1 were less than half that seen in Fyn wildtype cells. To address the role for Fyn kinase activity in these effects, constitutively active and dominant negative Fyn constructs have been transduced into BCR-ABL1 expressing cells. Constitutively active Fyn caused a high degree of chromosomal aberrations, fusions and aneuploidy suggestive of genomic instability. Taken together, these data highlight a significant role for Fyn in BCR-ABL1 mediated proliferation and secondary chromosomal aberrations, which are both features characteristic of blast crisis CML. Our results indicate that strategies to inhibit Fyn expression and kinase activity will be therapeutically relevant for progressed and/or refractory CML patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1627.
Abstract 1637: The MEK/Erk pathway is required for PC3 cell survival following FdUMP[10] treatment
Authors: Gomes Evan , Jennings-Gee Jamie , Gmeiner William H. 
Published: February 2011

Abstract
We have demonstrated that the novel polymeric fluoropyrimidine (FP) antitumor agent FdUMP[10] is efficacious towards prostate tumor (PC3) xenografts at well-tolerated doses while 5-fluorouracil (5FU) is not efficacious. FdUMP[10] treatment of PC3 cells results in complete inhibition of thymidylate synthase and S-phase arrest with generation of extensive DNA double-strand breaks as detected from γH2AX phosphorylation. S-phase arrest was confirmed by Western blots evaluating cyclin expression. In addition, we show that although cell-cycle arrested, FdUMP[10]-treated PC3 cells are not quiescent as indicated by extensive levels of DNA synthesis. The elevated DNA synthesis levels are likely indicative of futile repair. Although approximately 90% of cells are non-viable as assessed by a clonogenic assay, only about 30% of cells undergo apoptosis as assessed by Annexin V+ cells. The observation that FdUMP[10] treatment resulted in potent anti-tumor activity with minimal induction of apoptotic events lead us to assess to what extent activation of cell survival pathways inhibited cell death. The phosphoinositide 3-kinase PI3K/Akt and the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinases (MEK/ERK1/2) signal transduction pathways play critical roles in mammalian cell survival and have been shown to be activated in various cancers. Previous studies have shown that inhibition of PI3K/Akt or MEK/ERK1/2 can each enhance the effectiveness of cytotoxic chemotherapy. Our results show that FdUMP[10] treatment reduced phosphorylated Akt levels suggesting FdUMP[10] treatment inactivates the PI3K/Akt pro-survival pathway. However, inhibition of PI3K/Akt with LY294002 alone promoted a significant loss in the clonogenic capacity of PC3 cells independent of FdUMP[10] treatment while co-treatment did not provide an enhanced therapeutic effect. In contrast to these findings, inhibition of the MEK/ERK1/2 pathway with U0126 showed a significant decrease in viability only in combination with FdUMP[10] treatment. Here, we demonstrate that the potent effects of FdUMP[10]-induced cytotoxicity towards prostate cancer cells may be exacerbated by impairment of the MEK/ERK1/2 but not the PI3K/Akt cell survival pathway. Altogether, our studies suggest advanced prostate cancer may be amenable to treatment with FdUMP[10] in combination with inhibitors of MAPK signaling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1637.
Abstract 1644: Sunitinib primarily acts on tumor endothelium but not tumor cells to inhibit renal cell carcinoma tumor growth
Authors: Huang Dan , Ding Yan , Li Yan , Luo Wang-Mei , Zhang Zhong-Fa , Snider John , VandenBeldt Kristin , Qian Chao-Nan , Teh Bin Tean 
Published: February 2011

Abstract
Sunitinib, a small-molecule inhibitor of multiple receptor tyrosine kinases (RTKs), is considered the standard of care for first line therapy of advanced clear cell renal cell carcinoma (ccRCC). However, a complete understanding of its targets and mechanism of action in the treatment of ccRCC remains incomplete. We aimed to evaluate the primary targets of sunitinib in the treatment of ccRCC (i.e. tumor cells versus endothelial cells) and to determine which RTK(s) specifically contribute to the therapeutic effect of sunitinib. Microarray gene expression profiling of human ccRCC samples showed that, of the known RTK targets of sunitinib, only PDGFR-β and VEGFR-2 were overexpressed in ccRCC relative to normal tissues. Western blotting of ccRCC and endothelial cell lines confirmed that PDGFR and VEGFR, but not other sunitinib targets, were expressed in these cells. In vitro studies found that sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (∼0.1 μM) which inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and invasion at these concentrations through suppression of VEGFR-2 signaling. Sunitinib inhibited growth of ccRCC xenografts and decreased tumor microvessel density as soon as 12 hours post-treatment; however, sunitinib showed no significant effects on tumor cell proliferation or apoptosis after up to 72 hours post-treatment. Our studies indicate that sunitinib inhibits ccRCC growth primarily through an anti-angiogenic mechanism and not through direct targeting of ccRCC tumor cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1644.
Abstract 1645: The phosphorylation status of BAD pathway influence to chemo-sensitivity
Authors: Chon Hye Sook , Marchion Douglas C. , Xiong Yin , Chen Ning , Bicaku Elona , Apte Sachin , Wenham Robert , Lancaster Johnathan M. 
Published: February 2011

Abstract
Objective: Patients with advanced or recurrent endometrial cancer have a poor prognosis in part due to lack of efficacy of currently available chemotherapies and incomplete understanding of the biology that underlies chemo-response. In the current study we used genomic expression data to identify molecular signaling pathways associated with endometrial cancer cell resistance to cisplatin, doxorubicin chemotherapy and further characterized the role of the BAD apoptosis pathway as a therapeutic target and determinant of chemo-response.
Methods: Eight endometrial cell lines were subject to genome-wide expression analysis using Affymetrix HG-U133Plus GeneChips and in parallel, ranked by relative sensitivity to cisplatin and doxorubicin using MTS cell proliferation assays. Gene array data from sensitive versus resistant cell lines was compared by student's t-test and Pearson's correlation to identify those genes associated with drug resistance and further evaluated by GeneGo Metacore software for representation of molecular signaling pathways. Furthermore, the role of the BAD pathway in chemo-resistance was evaluated by selective inhibition of BAD pathway members, PKA, PP2C, AKT1, AKT2 and AKT3 by siRNA or pharmacologic agents in the presence and absence of cisplatin. Cell death and growth arrest in the presence of cisplatin were evaluated by Western blot for PARP cleavage as well as nuclear condensation and fragmentation and MTS assays.
Results: Student's t-test and Pearson's correlation identified the expression of 325 and 1136 genes to be associated with cisplatin (p&lt;0.01) and doxorubicin (p&lt;0.01) resistance, respectively. Pathway analysis of genes associated with both cisplatin and doxorubicin resistance indicated significant representation of the BAD apoptosis pathway (p&lt;0.002). Selective depletion of the phosphatase, PP2C by siRNA resulted in increased phosphorylation of BAD, serine 118 and increased resistance to cisplatin induced cell growth arrest and cell death. In contrast, depletion of the kinase, PKA resulted in decreased phosphorylation of BAD, serine 118 and increased cell death in the presence of cisplatin. In addition, depletion of AKT1 using siRNA as wells as treatment of cells with the AKT inhibitor, triciribine, increased cisplatin-induced growth arrest and cell death, whereas depletion of AKT2 or AKT3 did not affect cisplatin sensitivity.
Conclusions: The phosphorylation status BAD may influence endometrial cancer cell sensitivity to chemotherapy and represents a compelling target for future therapeutic development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1645.
Abstract 1647: Imatinib mesylate leads to modulation of regulators of tumor cell quiescence in gastrointestinal stromal tumors (GIST) cells
Authors: Seneviratne Danushka S. , Parry Joshua A. , Baron Julianne L. , Duensing Stefan M. , Duensing Anette U. 
Published: February 2011

Abstract
Gastrointestinal stromal tumors (GISTs) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. While GISTs can successfully be treated with imatinib mesylate, many patients retain detectable tumor mass during treatment and experience relapse following termination of treatment. We wanted to determine whether these clinical observations result from direct, imatinib-induced effects on GIST cells. We have shown that imatinib can directly induce tumor cell quiescence in a proportion of GIST cells through an increase of nuclear CDH1, an activator of the anaphase-promoting complex (APC). This event was associated with downregulation of the F-box protein SKP2 and subsequent upregulation of its target, the CDK inhibitor p27(Kip1). Exit from the cell division cycle was reflected by reduced BrdU incorporation and reduced cyclin A protein expression. Quiescent tumor cells were able to re-enter the cell division cycle five days after removal of imatinib as indicated by enhanced BrdU incorporation, decrease in p27(Kip1) expression and increase of cyclin A expression. Furthermore, high SKP2 and low p27(Kip1) levels correlated with an increased risk of progression. Mechanistically, imatinib was found to modulate components of the human DREAM complex, a key regulator of quiescence. Imatinib treatment resulted in upregulation of p130 and downregulation of E2F4 as well as LIN37 and LIN9. After removal of imatinib, levels of p130 decreased, whereas E2F4, LIN37 and LIN9 levels increased, as a reflection of the cells re-entering the cell cycle. Our results indicate that GIST cells that do not undergo apoptosis in response to imatinib enter quiescence and are hence temporarily removed from the proliferative pool However, cells were found to readily re-enter the cell division cycle in the absence imatinib. Our results encourage further studies to target the quiescence pathway in GISTs therapeutically.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1647.
Abstract 1648: SCH 1473759, a novel aurora inhibitor, demonstrates enhanced antitumor activity in combination with taxanes and KSP inhibitors
Authors: Basso Andrea D. , Gray Kimberly , Tevar Seema , Ponery Samad , Lee Suining , Liu Ming , Smith Elizabeth , Yu Tao , Tagat Jay , Doll Ronald , Belanger David , Siddiqui Arshad , Zhang Yonglain , Xiao Yushi , Esposite Sara , Monsma Fredrick , Hicklin Dan , Kirschmeier Paul 
Published: February 2011

Abstract
Aurora kinases are required for orderly progression of cells through mitosis. Inhibition of these kinases by siRNA or a small molecule inhibitors results in aberrant endoreduplication and cell death. SCH 1473759 is a novel Aurora inhibitor with potent mechanism based cell activity. The compound is active against a large panel of tumor cell lines from different tissue origin and genetic backgrounds. We found that asynchronous cells require 24 hour exposure to SCH 1473759 to induce maximal endoreduplication and cell kill. However, following a taxane or KSP inhibitor mitotic arrest, less than 4-hour exposure was sufficient to induce endoreduplication. This finding correlated with the ability of SCH 1473759 to accelerate exit from mitosis in response to taxane and KSP induced arrest, but not that of a nocodazole arrest. SCH 1473759 demonstrated single agent biomarker and anti-tumor activity in A2780 ovarian xenograft models. Further, efficacy was enhanced in combination with taxotere and found to be most efficacious when SCH 1473759 was dosed 12-hours post taxotere. These findings could have clinical implications for the development of Aurora inhibitors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1648.
Abstract 1654: Compensatory insulin receptor (IR) activation upon inhibition of insulin-like growth factor receptor (IGF-1R): Rationale for co-targeting IGF-1R and IR in cancer
Authors: Buck Elizabeth , Gokhale Prafulla , Koujak Susan , Eyzaguirre Alexandra , Wild Robert , Epstein David , Pachter Jonathan , Miglarese Mark 
Published: February 2011

Abstract
The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) and a critical mediator of signaling through the PI3K-AKT pathway. IGF-1R is required for oncogenic transformation and tumorigenesis, and inhibiton of IGF-1R results in reduced proliferation and survival of tumor cells. These observations have spurred intense drug discovery and development efforts for both biologic and small molecule IGF-1R inhibitors for the treatment of cancer.
The ability for one RTK to compensate for another to maintain growth and survival signaling in tumor cells is emerging as a common mechanism of resistance to anti-tumor agents that selectively target individual RTKs. As IGF-1R is structurally and functionally related to the insulin receptor (IR), and IR can also activate tumor cell AKT signaling and cellular transformation, we asked whether IR signaling can contribute to resistance to IGF-1R inhibition in tumor cells.
In a panel of human tumor cell lines, IGF-1R/IR crosstalk was observed after treatment with a selective anti-IGF-1R monoclonal antibody, MAB391. Tumor cells treated with MAB391 responded with a compensatory increase in phospho-IR, which was also associated with an inability to fully inhibit phospho-IRS1 and phospho-AKT. In contrast, treatment with OSI-906, a small molecule dual kinase inhibitor of IGF-1R and IR, resulted in enhanced inhibition of the IRS1-AKT signaling pathway. OSI-906 showed superior efficacy compared to MAB391 in human tumor xenograft models where both phospho-IR and phospho-IGF-1R were detectable, and presumably both receptors were required by tumor cells for growth and/or survival. Both insulin and IGF-2 can activate the IR-AKT pathway and we show that treatment with either growth factor resulted in decreased sensitivity of tumor cells to MAB391, but not OSI-906. In tumor cells with an autocrine IGF-2 signaling loop, both OSI-906 and an anti-IGF-2 neutralizing antibody reduced phospho-IR and phospho-AKT levels, whereas MAB391 was ineffective. Collectively, these data indicate that OSI-906, which co-targets IGF-1R and IR, may provide superior efficacy as compared to agents that selectively target only IGF-1R.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1654.
Abstract 1658: Fenretinide induces lethal autophagy in pancreatic cancer cells
Authors: Messner Maria C. , Cabot Myles C. 
Published: February 2011

Abstract
Background: Recent studies show that the synthetic vitamin A analog fenretinide (4-HPR) is cytotoxic in a number of human tumor cell lines and is a chemopreventative agent that is well-tolerated clinically. 4-HPR has been shown to augment intracellular levels of reactive oxygen species (ROS) and ceramides, and to activate the MAPK family of kinases. Pancreatic cancer cells are sensitive to increased levels of ROS, ceramides, and MAPK phosphorylation, suggesting 4-HPR will be an effective agent against this disease.
Results: 4-HPR exposure markedly decreased viability of MIA PaCa-2 and PANC-1 cells, as shown by a dose-dependent decrease in absorbance from an MTS assay and a 3-fold increase in propidium iodide staining. A 50% reduction in [3H]thymidine incorporation showed that cell proliferation was halted as well. 4-HPR treatment caused a 3-fold increase in de novo ceramide production at 24 h and a time- and dose-dependent generation of ROS. 4-HPR led to a minor increase in caspase 3/7 activity and in FITC-Annexin V-positive cells. However, other measures of apoptosis were lacking, suggesting apoptosis was not the major death pathway elicited by 4-HPR. Further investigation of the mechanism of cell death suggests that the dominant pathway triggered by 4-HPR is lethal autophagy. After 4-HPR treatment, microscopic analysis of cells exposed to acridine orange showed bright red autophagic vesicles, and Western blot showed a robust increase in LC3 II protein expression. Pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) or the ROS scavenger vitamin E (VE) abrogated the increase in LC3 II expression caused by 4-HPR exposure, and both 3-MA and VE partially preserved viability. A sustained, dose-dependent increase in phosphorylation of the stress kinases JNK and p38 was observed following incubation with 4-HPR, whereas phosphorylation of the mitogenic kinase ERK 1/2 decreased. Pretreatment with myriocin (an inhibitor of de novo ceramide production), 3-MA, or VE attenuated the increase in JNK and p38 phosphorylation caused by 4-HPR. Additionally, VE pretreatment blocked the decrease in ERK 1/2 phosphorylation elicited by 4-HPR.
Conclusions: These data suggest that 4-HPR induces lethal autophagy in human pancreatic cancer cells by a mechanism that involves generation of ROS and engagement of the MAPK and sphingolipid signaling pathways. 4-HPR used alone or in combination with current therapies or signaling pathway modulators may be a promising avenue for future pancreatic cancer therapies. [Support: NIH/NIGMS grant no. GM077391]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1658.
Abstract 1666: Regorafenib (BAY 73-4506): preclinical pharmacology and clinical identification and quantification of its major metabolites
Authors: Zopf Dieter , Heinig Roland , Thierauch Karl-Heinz , Hirth-Dietrich Claudia , Hafner Frank-Thorsten , Christensen Olaf , Lin Tiffany , Wilhelm Scott , Radtke Martin 
Published: February 2011

Abstract
Regorafenib is a novel diphenylurea oral multikinase inhibitor of angiogenic, stromal, and oncogenic kinases with potent preclinical antitumor activity and long-lasting antiangiogenic activity (as measured by dynamic contrast-enhanced magnetic resonance imaging).
Regorafenib treatment has recently shown to result in a 31% partial response (PR) rate and 50% stabilization rate in patients with metastatic renal cell carcinoma in a Phase II study. Promising clinical activity was shown in a Phase I study in 27 evaluable patients with advanced refractory colorectal cancer (median 4 prior regimens) with a 74% overall disease control rate (PR + stable disease).
The biotransformation of regorafenib was investigated in vitro with liver microsomes and hepatocytes, and in vivo in the plasma of several species. In man, the N-oxide (M-2) and the demethylated N-oxide (M-5) appear significant as both metabolites show systemic exposure (area under the curve [AUC], mg*h/L) at steady state similar to regorafenib (the parent compound) in patients at a dose of 160 mg in a 3 weeks on/1 week off Phase I study.
Characterization of both M-2 and M-5 demonstrated potent pharmacologic activities. In biochemical kinase assays, M-2 and M-5 showed an inhibition profile similar to but distinct from regorafenib. In cellular assays, M-2 and M-5 inhibited key targets such as vascular endothelial growth factor (VEGF) receptor 2, TIE-2, and mutant and wild-type c-KIT and B-RAF, with IC50 values very similar to regorafenib for M-2 and somewhat higher for M-5.
Regorafenib and both M-2 and M-5 dosed iv at 1 mg/kg showed significant activity in a rat VEGF hypotensive pharmacodynamic model. Both metabolites dosed orally exhibited potent dose-dependent tumor growth inhibition (TGI) in preclinical murine HT-29 colorectal and MDA-MB-231 breast cancer xenografts, achieving significant TGI of 62/58% and 54/50%, respectively, compared with vehicle controls at 10 mg/kg. Regorafenib revealed 66-77% TGI at 10 mg/kg in these models. On oral administration of regorafenib to mice, the N-oxide (M-2) plasma level accounted for ∼20% of the AUC of regorafenib; conversely, on administration of M-2, regorafenib exposure reached ∼20% of M-2 exposure, indicating that oxidation to and reduction of the N-oxide are metabolic pathways in vivo.
In summary, these data demonstrate that the metabolites M-2 and M-5, exhibiting similar exposure as regorafenib, their parent compound, in man, are pharmacologically active and therefore most likely contribute to the clinical antitumor activity of regorafenib.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1666.