bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A229: BRAF inhibitors upregulate EGFR ligands: A molecular link to RAF inhibitor-induced cutaneous squamous cell carcinomas.
Authors: Ma Yan , Zhang Chao , Habets Gaston , Burton Elizabeth A. , Wong Bernice , Nguyen Hoa , Spevak Wayne , zhang Jiazhong , Cho Hanna , Wu Guoxian , Lin Jack L. , Ewing Todd , Zhang Ying , Shi Songyuan , Nespi Marika , Tsang Garson , Marimuthu Adhirai , Light Emily , Powell Ben , Shellooe Rafe , Tsai James , West Brian L. , Ibrahim Prabha N. , Hirth Peter , Bollag Gideon 
Published: June 2012

Abstract
Selective inhibitors of BRAF such as vemurafenib (PLX4032) and GSK2118436 show remarkable efficacy in melanoma patients with tumors harboring BRAF V600 mutations. However these compounds paradoxically activate the MAPK pathway in RAS-mutant cells and are associated clinically with appearance of skin tumors such as cutaneous squamous cell carcinomas (cuSCC), particularly of the keratoacanthoma subtype. Here we further investigated the molecular links between BRAF inhibitor treatment and skin neoplasm. In soft agar, BRAF inhibitors induced growth of HRAS-mutant cuSCC B9 cells via upregulation of several EGFR ligands. The EGFR inhibitor Tarceva antagonized this transforming effect. The “Paradox Breakers,” a class of BRAF inhibitors recently discovered at Plexxikon, did not activate the MAPK pathway in cells with RAS mutation or EGFR family kinase activation and failed to upregulate EGFR ligands or induce soft agar growth of B9 cells. Also when tested in vivo, subcutaneous B9-tumor growth was accelerated by a structural analog (PLX4720) of vemurafenib but not by an equally effective BRAF inhibitor of the Paradox Breaker class. Taken together, a novel mechanism responsible for BRAF inhibitor-induced cuSCC was uncovered. Our data suggest that combination treatment of EGFR inhibitors with BRAF inhibitors might prevent skin tumor growth and that Paradox Breakers represent a new generation of BRAF inhibitors that have fewer unwanted side effects and the potential for greater clinical efficacy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A229.
Abstract A241: Targeting FGFR4 for rhabdomyosarcoma therapy.
Authors: Cheuk Adam Tai Chi , Khan Javed 
Published: June 2012

Abstract
Rhabdomyosarcoma (RMS) is a soft tissue sarcoma in children. Despite advances in modern therapy, metastatic patients with this disease have a very poor clinical prognosis. FGFR4 is a tyrosine kinase receptor which plays a role in cell division, regulating cell growth and maturation. FGFR4 also involves in myogenesis and is a direct downstream target of PAX3-FOXO1A found in the majority of alveolar RMS subtype, and suggests its oncogenic role in RMS. Our and other's studies have shown that this gene is activated by amplification, over-expression and/or by mutation. Our previous data showed that activated FGFR4 promotes RMS tumor progression and inhibiting FGFR4 suppresses RMS tumor growth and metastasis. Ponatinib (Ariad, Cambridge, MA) is a multiple tyrosine kinase inhibitor that potently inhibits FGFR4 and is currently undergoing a pivotal phase 2 trial in adults with CML. Using a BaF3 TEL-FGFR4 model system, ponatinib was found to inhibit FGFR4 TK domain autophoshorylation and resulted in cell death. Five RMS cell lines that we have tested were all sensitive to ponatinib and the sensitivity was proportion to expression level of FGFR4. When treated with ponatinib, RMS cell line harboring the FGFR4 mutations K535 or E550, discovered by our group to be commonly mutated, were more sensitive to ponatinib compared to wild type as demonstrated by increase in active caspase 3/5 and in sub G1 population. Western blot confirmed that ponatinib inhibited autophosphorylation of FGFR4 K535 and E550 in a dose dependent manner. Furthermore, our pilot study also showed that the growth of subcutaneously injected RMS cells with the FGFR4 K535 mutants were suppressed after treating with ponatinib. Therefore our data suggest that ponatinib may be an effective therapy for patients with RMS and a clinical trial is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A241.
Abstract A33: Pan erbB inhibition enhances lysosomal dysfunction-induced death in malignant peripheral nerve sheath tumor cells.
Authors: Kohli Latika , Carroll Steven L. , Roth Kevin A. 
Published: June 2012

Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell-derived sarcomas. The erbB family of membrane tyrosine kinases has been implicated in stimulating MPNST cell proliferation and invasion rendering it an attractive therapeutic target. However, tyrosine kinase inhibitors (TKIs) used as single agents are ineffective tumoricidal agents. Manipulating the autophagy lysosomal pathway in cells treated with cytostatic agents can promote apoptotic cell death in some settings. The goal of this study was to establish a mechanistic basis for formulating drug combinations to effectively trigger death in MPNST cells. We assessed the effects of the pan erbB inhibitor PD168393 on MPNST cell survival. PD168393 induced a cytostatic but not a cytotoxic response in MPNST cells which was accompanied by suppression of Akt and mTOR activation and increased autophagic activity. The effects of autophagy modulation on MPNST survival were then assessed by pharmacologic and genetic manipulations following the induction of chloroquine (CQ)-induced lysosomal stress. We observed that CQ-induced death is atleast in part apoptotic. In contrast, increased autophagy induction by inhibition of mTOR did not trigger cytotoxicity, possibly due to Akt activation. We thus hypothesized that dual targeting of mTOR and Akt by PD168393 would significantly increase cytotoxicity in cells exposed to lysosomal stress. We found that PD168393 and CQ in combination significantly increased cytotoxicity. We conclude that combinatorial therapies with erbB inhibitors and agents inducing lysosomal dysfunction may be an effective means of treating MPNSTs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A33.
Abstract A47: Circulating tumor cell (CTC) assay development for detection of phosphohistone H3 (pHH3) as a clinical pharmacodynamic (PD) marker for LY2523355, an Eg5 kinesin inhibitor.
Authors: Um Suzane L. , Yan S. Betty , Peek Victoria L. , Yan Lei , Ye Xiang S. , Westin Eric H. 
Published: June 2012

Abstract
Circulating tumor cells have been shown to be prognostic of survival in metastatic breast, colon, and prostate cancers. Additionally, CTCs are of interest because they may be representative of the phenotype/genotype of the primary and metastatic tumors, and may be a useful tool (i.e. patient stratification) for drug development. CTCs, as “liquid biopsies” are potentially useful as a PD marker as it allows easy repeat sampling before and after drug treatment. We describe the development of a CTC assay that measures the induction of pHH3 by LY2523355, a selective small molecule inhibitor of the human Eg5 kinesin. pHH3 is a biomarker of mitosis. In tumor xenograft mouse models, LY2523355 treatment was shown to reduce tumor volume with elevation of pHH3 in tumors. The CTC assay was developed using the FDA cleared Veridex/CellSearch™ instrument and reagents for enumeration of CTCs from blood. CellSearch defines CTCs as EpCam+/DAPI+/CK 8, 18, 19+/CD45−. For assay development, cells from tumor cell lines representing major solid tumor types were chosen, cultured, treated with LY2523355, or with various standard-of-care chemotherapeutics, and spiked into whole blood drawn into CellSave™ (preservative+EDTA). For initial assay development, mouse whole blood was used and results reproduced subsequently with human whole blood from healthy subjects. The spiked tumor cells in blood samples were recovered using the CellSearch Mouse/Rat CTC kit (for mouse blood) or human CXC kit (for human blood), supplemented with the R-PE conjugated anti-pHH3 antibody. pHH3 in the recovered tumor cells was detected in the open/fourth channel on the CellSearch instrument. About 1–4% of all cultured tumor cells were positive for pHH3 without drug treatment. Significant induction of pHH3 (30–50% cells) in sensitive tumor cell lines was observed with 24 hour treatment with only drugs interfering with mitosis (paclitaxel, taxotere, and LY2523355). The magnitude of the induction of pHH3 in the cells after treatment was dose and cell-line dependent. A dose response of pHH3 induction was observed with 0.5nM-25nM of LY2523355 with several cultured tumor cell lines (Colo205, HCT116, H441, SKBR3, MDA-MB-468), spiked into blood, and assayed using CellSearch. The concentrations of the dose response are similar to the drug exposure levels of that of preclinical tumor xenograft studies. LY2523355 is currently in early phase clinical development, and monitoring CTCs with pHH3 expression post-treatment may be a useful PD marker.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A47.
Abstract A58: Epigenetic regulation of CpG promoters by NF-kB pathway in invasive pancreatic cancer cells.
Authors: Sun Lei , Mathews Lesley , Cabarcas Stephanie , Zhang Xiaohu , Farrar William 
Published: June 2012

Abstract
Pancreatic cancer is one of the most common causes of cancer death internationally. The diagnosis of early-stage pancreatic cancer often has a poor prognosis and the survival rate is quite low once it becomes advanced or metastatic. Epigenetic modifications such as DNA methylation play a significant role during both normal human development and cancer progression. We sought to investigate which genes are epigenetically regulated in the invasive population of pancreatic cancer cells. We conducted epigenetic arrays in both PANC1 and HPAC pancreatic cancer cell lines and compared the global DNA methylation status of CpG promoters in invasive cells to their non-invasive counterparts. The differentially methylated genes were applied into Ingenuity pathway analysis and our results showed that the NF-kB pathway is one of the top activated pathways in invasive cells. In line with this, we determined that upon treatment with NF-kB pathway inhibitors, the invasive and migratory ability of total cells are significantly disrupted. Moreover, the SRY-box transcription factor SOX9, which is demethylated in invasive cells, is shown to play a crucial role in invasion of both cell lines. In addition, we found a potential NF-kB binding site located in the SOX9 promoter in Genomatix database. Interestingly, the NF-kB subunit p65 positively regulates SOX9 expression by binding to its promoter directly, which is enhanced by treatment of demethylation agents. Thus, our work establishes a link between the classical NF-kB signaling transduction pathway and pancreatic cancer cell invasion. We believe our data can result in the identification of novel signals and molecules at an epigenetic level that can potentially be targeted in pharmaceutical investigations and clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A58.
Abstract A64: Adenovirus-mediated NK4 gene therapy for malignant mesothelioma.
Authors: Deng Xu-Bin , Xiao Li , Jin Fang , Testa Joseph , Xiao Guang-Hui 
Published: June 2012

Abstract
Malignant mesothelioma (MM) is a highly invasive and chemoresistant malignancy induced by asbestos fibers. Hepatocyte growth factor (HGF) and its receptor Met play a critical role in the pathogenesis of MM, and targeting HGF/Met signaling could be therapeutically important. NK4, a HGF antagonist and angiogenesis inhibitor, consists of the N-terminal hairpin domain and four kringle domains of the -chain of HGF. The therapeutic potential of NK4 has been demonstrated in several types of tumors. However the mechanisms by which NK4 inhibits tumor growth have not been well elucidated. In this study, we show that the NK4 adenovirus potently inhibits cell viability, invasiveness, migration, and spreading of human MM cells in vitro. Significantly, we demonstrated for the first time that NK4 reduced expression levels of stem cell markers as assessed by western blot analysis and inhibited self-renewal of MM stem cells as measured by spheroid formation assay. Furthermore, NK4 adenovirus had strong antitumor and anti-angiogenesis effects in two different mouse models of MM. These findings suggest that NK4 holds promise as a therapeutic agent for patients with MM.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A64.
Abstract A71: Cdk2, Mad2, and the tetraploidy checkpoint in paclitaxel-induced endoreduplication.
Authors: Jahn Stephan , Corsino Patrick , Law Mary , Davis Brad , Law Brian 
Published: June 2012

Abstract
The classic chemotherapeutic, paclitaxel, causes endoreduplication in cells, but the mechanism and cellular characteristics that promote this genome doubling are poorly understood. In studying the chromosomal instability of tumor cell lines from mice with mammary expression of a constitutively active Cyclin D1-Cdk2 fusion protein, we noticed an increased rate of this paclitaxel induced endoreduplication. Further studies have shown that this effect is specifically due to the kinase activity of Cdk2 and that increased Cdk2 activity causes of upregulation of the mitotic checkpoint protein, Mad2. While increased Mad2 expression alone has previously been shown to cause mitotic defects and genome doubling, it does not appear to be the culprit in this situation. We instead found that normalization of Mad2 levels through short hairpin RNA-mediated knockdown further increased the rate of endoreduplication in the presence of paclitaxel. It was seen that while exposure to the spindle poison further elevated Mad2 levels, long-term treatment led to an overall decrease in protein expression. This presumably allows cells to escape mitotic arrest and enter G1 phase, potentially triggering the somewhat controversial p53-mediated tetraploidy checkpoint. Indeed, stable knock-down of p53 cooperates with increased Cdk2 activity to create a very high rate of endoreduplication. These findings raise intriguing questions about the consequences of using one of the world's most widely used chemotherapeutic agents in patients with increased Cdk2 activity. Future studies will investigate whether this increased rate of endoreduplication worsens treatment outcome by eliciting chromosomal instability or improves it by generating cells that are unviable in the long-term.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A71.
Abstract A84: Lack of efficacy of the anti-diabetic drug metformin in the ER+ methylnitrosourea (MNU)-induced and the ER− MMTV-Neu/p53KO models of mammary cancer.
Authors: Grubbs Clinton J. , Clapper Margie , Bode Ann , Steele Vernon , Lubet Ronald 
Published: June 2012

Abstract
Metformin, an anti-diabetic drug, activates AMP-activated protein kinase (AMPK), and has generated a great deal of interest as a potential preventive agent for a variety of cancers, including breast. This interest is based both on epidemiologic studies showing that diabetics treated with metformin have a lower incidence of a variety of cancers, and on mechanistic considerations arguing that activation of AMPK is likely to be relevant to cancer treatment and prevention. We examined the preventive efficacy of metformin in ER+ and ER− rodent mammary cancer models. Treatment of Sprague-Dawley female rats at 50 days of age with a single dose of MNU (75 mg/kg BW) resulted in the development of multiple ER+ mammary cancers beginning approximately 7 weeks after MNU treatment. This model has been highly responsive to a wide variety of agents that affect ER+ tumors in humans (SERMs, aromatase inhibitors, pregnancy, ovariectomy). Metformin was administered by gavage (7×/week) at either 150 or 50 mg/kg BW/day beginning 7 days after MNU dosing, and continuing for the duration of the study. Metformin failed to decrease mammary tumor incidence and, in fact, increased tumor multiplicity in this model by approximately 35%. In addition, we are evaluating the ability of metformin to inhibit mammary cancer in MMTV-Neu/p53KO mice (which spontaneously develop ER− cancers). In this study, metformin was administered in the diet at a dose level of 1500 mg/kg diet. Initial supplementation of the diet with this agent began when the mice were 60 days of age, and will continue for 10 months. This study similarly has shown no preventive efficacy of metformin (av. tumors/mice: controls, 2.1; metformin, 2.5). Thus, these initial studies fail to observe any chemopreventive efficacy of metformin in two commonly employed models of ER+ and ER− mammary cancers in rodents.
Supported by NCI contract number HHSN261200433001C.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A84.
Abstract A92: A phase 1 safety and pharmacokinetic study of navitoclax in combination with docetaxel in patients with solid tumors.
Authors: Eskens Ferry ALM , Gutierrez Martin , Cosgrove David , Puglisi Martina , van Doorn Leni , Blanco Montserrat , de Jonge Maja JA , Moran Kirsty , Walther Axel , Yang Jianning , Busman Todd A. , Franklin Catherine A. , Mabry Mack H. , Humerickhouse Rod A. , Molife Lulama Rhoda 
Published: June 2012

Abstract
Background: Navitoclax (N; ABT-263) is a first-in-class orally available Bcl-2 protein inhibitor that in vitro and in vivo potentiates docetaxel (D) activity across a variety of solid tumor types. This ongoing phase I study evaluates the maximum tolerated dose (MTD) and safety and pharmacokinetic (PK) profile of N plus D.
Methods: Patients (pts) with advanced solid tumors, adequate organ function and ECOG PS ≤1 were eligible. Pts were treated with (a) N 150 mg or 200 mg PO, QD on days (d) 1–3 or d1–5 q21 plus D 75 mg/m2 IV on d1 q21; or (b) N 150 mg PO, QD on d1–3, d8–10, and d15–17 q28 plus D 30 mg/m2 IV given on d1, 8, and 15 q28. To compare the PK of either agent alone, N was given on d3–5 or d3–7 only in cycle 2 of q21. PK samples were collected for N and D in cycles 1 and 2. Treatment-emergent adverse events (TAEs) were graded by NCI CTCAE V3.0.
Results: Of 37 pts (M/F, 24/13) enrolled, data on 31 pts are available for safety, 33 pts for tumor response, and 13 pts for PK analysis. Pts (median age, 59 y; range, 30–83 y) were treated at 3 dose levels of N: 150 mg and 200 mg on d1–5 q21; 200 mg on d1–3 q21; and 150 mg on d1–3, d8–10, and d15–17 q28. Dose-limiting toxicities (DLTs) were grade (gr) 3 febrile neutropenia, and gr 4 thrombocytopenia (TCP) at N 200 mg d1–5 plus D 75 mg/m2 q21; gr 3/4 febrile neutropenia, gr 4 neutropenia, and gr 3 fatigue at N 200 mg d1–3 plus D 75 mg/m2 q21; gr 3 febrile neutropenia, gr 4 TCP, and death at N 150 mg d1–5 plus D 75 mg/m2 q21. The MTD of N with D at 75 mg/m2 q21 was 150 mg on d1–5. Other gr 3/4 TAEs (≥20%) were neutropenia (55%), leukopenia (32%), febrile neutropenia (29%), TCP (29%), and fatigue (13%); frequently occurring TAEs (≥20%) were fatigue (55%), TCP (45%), alopecia (42%), nausea (42%), anemia (36%), constipation (32%), decreased appetite (32%), diarrhea (32%), vomiting (32%), and dyspnoea (26%). Best tumor responses were 3 confirmed partial responses (PR), 2 currently unconfirmed PR, 8 stable disease (SD), 13 progressive disease, and 7 pts had incomplete data. Based on limited data, there was no significant PK interaction between N and D (Table).
Conclusions: Navitoclax may be administered safely with D in 2 schedules; 150 mg with D 75 mg/m2 q21 and with D 30 mg/m2 q28. Both combinations were tolerable with no significant PK interactions in the D 75 mg/m2 q21 schedule. Antitumor activity was observed. Exploration of N 200 mg with weekly D is ongoing.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A92.