bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3680: (R,R')-4′-methoxy-1-naphtylfenoterol inhibits pro-survival signaling, proliferation and motility of select human melanoma cell lines
Authors: Wnorowski Artur , Paul Rajib K. , Jimenez Lucita , Toll Lawrence , Kotb Abdelmohsen , Bernier Michel , Wainer Irving W. 
Published: May 2015

Abstract
(R,R')-4′-methoxy-1-naphtylfenoterol (MNF) inhibits proliferation of 1321N1 astrocytoma cell line in a β2-adrenergic receptor (β2AR)-dependent manner, while reducing rat C6 glioma growth in a xenograft mouse model. MNF interferes also with pro-oncogenic signaling induced by the orphan G-protein-linked receptor, GPR55, in human HepG2 hepatocarcinoma and PANC-1 pancreatic carcinoma cells. Here, we utilized a number of cellular and biochemical techniques to investigate the anti-tumorigenic potential of MNF in a panel of human melanoma cell lines. Cell migration, which was performed using scratch wound healing assay, demonstrated the ability of MNF to dose-dependently reduce the motility of EGFR-expressing UACC-647 and M93-047 cell lines in a biphasic (IC50 = 0.32 nM and 1.48 µM) and sigmoidal (IC50 = 7.14 nM) fashion, respectively. In contrast, EGFR-negative UACC-903 cells were unresponsive to MNF. The proliferation rate of UACC-647 cells was diminished by 38 ± 3.7% in the presence of MNF, with an IC50 of 136 nM. Pharmacological inhibition of β2AR with the selective antagonist ICI-118,551 (50 nM) did not confer protection against the actions of MNF on cell motility and proliferation. U-shaped dose-response curves, with a nadir at 1 nM, were observed when the levels of phosphorylated MEK and ERK were determined in MNF-treated UACC-647 cells. A similar dose-response relationship was observed with the β2AR agonists, epinephrine and (R,R')-fenoterol, and cell pretreatment with 50 nM ICI-118,551 abolished MNF-evoked drop in phospho-ERK levels. However, MNF markedly increased inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) on Thr56, which was accompanied by global defect in protein biosynthesis as revealed by pulse-labeling experiments with [35S]-methionine. We conclude that the anti-tumorigenic functions of MNF most likely reflect dual effects of MNF through interaction with different receptors in melanoma. This work was supported entirely by the Intramural Research Program of the National Institute on Aging/NIH and NIA/NIH contract N01-AG31009, and the Foundation for Polish Science (TEAM 2009-4/5 programme).
Citation Format: Artur Wnorowski, Rajib K. Paul, Lucita Jimenez, Lawrence Toll, Abdelmohsen Kotb, Michel Bernier, Irving W. Wainer. (R,R')-4′-methoxy-1-naphtylfenoterol inhibits pro-survival signaling, proliferation and motility of select human melanoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3680. doi:10.1158/1538-7445.AM2014-3680
Abstract 3687: Analgesic effects of capsazepine on a mouse model of bone cancer pain
Authors: Balenko Matthew D. , Seidlitz Eric , Singh Gurmit 
Published: May 2015

Abstract
Breast cancer has the highest incidence rate in women, accounting for more than 22% of all cancers and possessing a strong disposition to metastasize to bone. Discovered in 70% of advanced breast cancer patients and over 90% prevalence in patients who die from breast cancer, the affinity of this disease to metastasize bone has become overwhelming. These skeletal metastases become a significant cause of morbidity and mortality in patients with the primary symptom being pain. Pain is a major concern in determining a patient's quality of life and there have been many attempts to understand and control bone pain with little success.
Capsazepine was identified during a high throughput screen to be a potent inhibitor of breast cancer cell-mediated glutamate release, a neurotransmitter with known associations in both neural communication and pain. This drug also has antagonistic effects on transient receptor potential vanilloid type 1 (TRPV-1) receptors which act as key players in both heat and vanilloid-induced nociception. Studies have shown that glutamate plays a role in bone cancer pain, with an excess in free glutamate able to cause pain either directly through excitotoxic pathways or indirectly though the dysregulation of osteoclasts and osteoblasts, causing bone dysregulation. TRPV-1 receptors have also has been implicated in the mechanisms of bone cancer pain, as osteoclasts release protons during bone remodeling which can elicit a TRPV-1-related nociceptive response from neurons in the surrounding periosteum. These findings suggest that Capsazepine may provide a powerful multi-pronged approach to treating cancer pain.
A model of breast cancer-induced bone pain has been established using human MDA-MB-231 breast adenocarcinoma cells injected into the femurs of BALB/c nude mice. Behavioural tests are then preformed using the dynamic plantar aesthesiometer (DPA) and the dynamic weight bearing (DWB) devices on the affected limb for both movement-evoked and spontaneous pain-related behaviours.
Using Capsazepine, delivered intraperitoneally via mini-osmotic drug pumps (5kg/mg and 10kg/mg), we demonstrate a dose-dependent attenuation of pain behaviours in vivo. While confirming tumour presence using immunohistochemistry (IHC) we show that TRPV-1 and glutamate play an important role in the onset and severity of bone cancer pain. The use of Capsazepine was able to attenuate these pain-related behaviours without the side effects of common analgesics.
(This work is supported by the Canadian Institutes of Health Research (CIHR))
Citation Format: Matthew D. Balenko, Eric Seidlitz, Gurmit Singh. Analgesic effects of capsazepine on a mouse model of bone cancer pain. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3687. doi:10.1158/1538-7445.AM2014-3687
Abstract 3688: Arctigenin induced immunogenic cell death through a reactive oxygen species/endoplasmic reticulum stress pathway in lung cancer
Authors: Kuo Chih-Hsin , Hsu Ya-Ling , Huang Ming-Shyan 
Published: May 2015

Abstract
Induction of immunogenic cell death (ICD) is characterized by surface exposure of damage-associated molecular pattern molecules, which can induce a tumor-specific immune response. ICD are promising treatments for cancer by restoring efficient anti-tumor immunity. Here we reported that the arctigenin, an anti-inflammation and anti-cancer agent, elicits a potent anticancer immunity effect by inducing the translocation of calreticulin (CRT) to cell membrane and the release of high-mobility group protein 1 (HMGB1) in lung cancer. Treatment of A549 cells with arctigenin increased the production of ROS generation, which in turn triggered an endoplasmic reticulum (ER) stress response, including the phosphorylation of PERK (PKR-like endoplasmic reticulum kinase and IRE1 (inositol-requiring 1). The antioxidant, EUK8, significantly decreased CRT translocation and HMGB release by inhibiting the ER stress (PERK phosphorylation). Taken together, the production of ROS induced CRT translocation and HMGB1 release, mediating arctigenin-induced enhancement of tumor immunity. This indicated that arctigenin is a potential immunetherapeutic agent against lung tumor.
Citation Format: Chih-Hsin Kuo, Ya-Ling Hsu, Ming-Shyan Huang. Arctigenin induced immunogenic cell death through a reactive oxygen species/endoplasmic reticulum stress pathway in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3688. doi:10.1158/1538-7445.AM2014-3688
Abstract 3691: Met target inhibition-guided efficacy in preclinical models
Authors: Srivastava Apurva K. , Hollingshead Melinda G. , Govindharajulu Jeevan P. , Covey Joseph M. , Liston Dane , Peggins James , Bottaro Donald P. , Wright John J. , Kinders Robert J. , Tomaszewski Joseph E. , Doroshow James H. , Parchment Ralph E. 
Published: May 2015

Abstract
Background: A direct comparison of drug efficacy for the multiple agents currently in clinical development targeting MET-driven cancers would be useful for the selection of optimal treatment options. Previously, we utilized validated MET pharmacodynamic (PD) assays to compare the time course of phosphorylated-MET (pMET) suppression for five MET inhibitors (ASCO 2013). In the current study, we selected three candidates that demonstrated potent MET inhibition to compare anti-tumor efficacy.
Methods: PD time course and tumor PK data were utilized to simulate a dosing schedule anticipated to produce &gt;90% pMET suppression in a SNU5 gastric cancer xenograft model. From these data, dosing schedules of 44 mg/kg (Q12H) cabozantinib, 12.5 mg/kg (Q12H) EMD1214063, and 16.5 mg/kg (QD) foretinib were chosen to achieve necessary tumor exposure to suppress pMET. Once tumors reached a 150±50 mm3 size, drugs were administered continuously for 21 days and tumor volumes were measured intermittently for 62 days. To measure pMET suppression, tumor quadrants were collected at 4, 12, and 24 hrs from all treatment groups after dose 1 (day 1) and on day 8 (after dose 8 of foretinib or dose 14 of cabozantinib and EMD1214063).
Results: Intact MET levels (pM/μg protein) were approximately 70% lower than vehicle controls at all day 8 collection points for all three drugs. The pY1234/35MET/MET ratios were 89%-99% (p&lt;0.001) lower than vehicle controls on day 8 at 4 and 12 hrs post-dose for all three drugs. Compared to pretreatment levels, tumor volumes were reduced by 80-90% for all three drugs within 10-15 days post therapy and remained regressed until 13-20 days after treatment was stopped. Tumors then slowly regrew, but remained approximately 80% smaller than the vehicle group on day 62 (end of study).
Conclusions: These studies demonstrate that PD response-guided regimens delivered drug doses that were lower than efficacious doses described previously (except cabozantinib), but effectively reduced tumor volume in SNU5 xenografts. The three MET inhibitors showed comparable anti-tumor efficacy when accompanied by equivalent pMET inhibition. Our data also affirms the utility of the MET PD assays to guide dose ranging studies. Funded by NCI Contract No HHSN261200800001E.
Citation Format: Apurva K. Srivastava, Melinda G. Hollingshead, Jeevan P. Govindharajulu, Joseph M. Covey, Dane Liston, James Peggins, Donald P. Bottaro, John J. Wright, Robert J. Kinders, Joseph E. Tomaszewski, James H. Doroshow, Ralph E. Parchment. Met target inhibition-guided efficacy in preclinical models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3691. doi:10.1158/1538-7445.AM2014-3691
Abstract 3694: Relationship between in vivo antitumor activity of ADC and payload release in preclinical models
Authors: Li Fu , Zhang Xinqun , Emmerton Kim , Jonas Mechthild , Setter Jocelyn , Arthur Bill , Okeley Nicole , Lyon Robert , Benjamin Dennis , Law Che-Leung 
Published: May 2015

Abstract
Antibody-drug conjugates (ADC) deliver cytotoxic payloads to target cells via receptor-mediated internalization. We have demonstrated that SGN-35 (cAC10-vcMMAE) binds to CD30 on target cells and releases intracellular monomethyl auristatin E (MMAE) in vitro, contributing to potent killing of CD30+ cells. Using a set of auristatin-based ADCs, we evaluated whether the intratumoral concentration of the released payload is a predictive indicator of antitumor activity in preclinical models.
We first treated CD30+, anaplastic large cell lymphoma (ALCL) Karpas 299 tumors with SGN-35 or a non-binding control ADC (IgG-vcMMAE). The plasma ADC and MMAE PK measurements were similar in SGN-35 and IgG-vcMMAE treated tumor-bearing animals. In contrast, SGN-35 generated 5-fold greater intratumoral MMAE exposure than IgG-vcMMAE, which correlated with tumor regression observed in the SGN-35- treated group.
We then examined the relationship between released MMAE and in vitro cytotoxicity by targeting different receptors expressed on the same cells. The lymphoma cell line L82 expresses CD30, CD70, and CD71 receptors. Although auristatin-based ADCs targeting each of these targets has a different IC50, the intracellular MMAE was similar when 50% growth inhibition was achieved (approximately 200 nM). In vivo, CD30, CD70, or CD71-directed ADCs demonstrated similar antitumor activity for a given dose level (0.5, 1, or 3 mg/kg). Concordantly, equal intratumoral MMAE concentrations were observed for a given dose level, regardless of the antigen target.
The cell permeable MMAE has been shown to mediate bystander killing in vitro. To evaluate whether intratumoral MMAE mediates bystander killing in vivo, an admixed tumor model consisting CD30+ and CD30- Karpas 299 cells was treated with SGN-35. As predicted, both CD30+ and CD30- tumor cells were killed, presumably due to intratumoral diffusion of MMAE across cell membranes. In contrast, a conjugate with a highly polar form of auristatin (MMAF) was unable to kill the CD30-negative cell population of the admixed tumors.
These preclinical results provide evidence that the concentration of released MMAE within the tumor correlates with the ADC antitumor activity in vitro and in vivo. Moreover, the in vivo bystander activity of MMAE may improve utility of this chemotype in tumors with heterogeneous antigen expression.
Citation Format: Fu Li, Xinqun Zhang, Kim Emmerton, Mechthild Jonas, Jocelyn Setter, Bill Arthur, Nicole Okeley, Robert Lyon, Dennis Benjamin, Che-Leung Law. Relationship between in vivo antitumor activity of ADC and payload release in preclinical models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3694. doi:10.1158/1538-7445.AM2014-3694
Abstract 3696: Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations
Authors: Hu Shuiying , Bruijn Peter D. , Mathijssen Ron H.j. , Baker Sharyn D. , Sparreboom Alex 
Published: May 2015

Abstract
Background: Several tyrosine kinase inhibitors (TKIs) evaluated in combination regimens with docetaxel, including axitinib, pazopanib, and sorafenib, can increase the systemic exposure to taxane in cancer patients by an unknown mechanism. We previously reported that differential expression of organic anion transporting polypeptides of the OATP1B-family in the human liver regulate the initial, rate-limiting step in the elimination of docetaxel, in advance of metabolism. In the current study, we tested the hypothesis that these interactions are mediated by the hepatic uptake transporter OATP1B1 using in vitro and in vivo models.
Materials and Methods: The influence of 16 approved TKIs on transport was studied in vitro using HEK293 cells expressing OATP1B1 or its mouse equivalent OATP1B2, determined by assessing the effect of TKIs on the intracellular accumulation of estradiol-17β-D-glucuronide, or docetaxel. Contribution of this process to an interaction with docetaxel in vivo was determined by pharmacokinetic studies using mice that are knock-out for OATP1B2 or knock-in for OATP1B1.
Results: Axitinib, nilotinib, pazopanib, and sorafenib were identified as potent inhibitors of OATP1B1 (&gt;90% inhibition) when using estradiol-17β-D-glucuronide as a prototypical model substrate. As a representative of this class of TKIs, sorafenib was further evaluated and found to also potently inhibit OATP1B1-mediated transport of docetaxel with a half-inhibitory maximum concentration (IC50) of 6.96 nM, and almost completely inhibited the function of OATP1B1 and OATP1B2 at a concentration readily achievable in humans and mice. While OATP1B2-deficiency was associated with significantly increased exposure to docetaxel, as measured by peak plasma concentration (Cmax, P&lt;0.05) and area under the curve (AUC, P&lt;0.001), co-administration of a single or multiple oral dose of sorafenib did not result in statistically significantly altered exposure to docetaxel in either wildtype or OATP1B2 (-/-) mice.
Conclusion: These findings support a direct contribution of OATP1B1 in previously recorded pharmacokinetic interactions between TKIs and docetaxel, which can be predicted from a simple in vitro experiment. Our failure to reproduce this interaction in mice suggests that caution is warranted when attempting to extrapolate in vivo findings to a clinical scenario.
Citation Format: Shuiying Hu, Peter De Bruijn, Ron H.j. Mathijssen, Sharyn D. Baker, Alex Sparreboom. Inhibition of OATP1B1 by tyrosine kinase inhibitors: in vitro-in vivo correlations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3696. doi:10.1158/1538-7445.AM2014-3696
Abstract 3697: SIRT2 is a modulator of response to targeted therapies through regulation of MEK kinase activity
Authors: Bajpe Prashanth K. , Prahallad Anirudh , Horlings Hugo , Nagtegaal Iris , Beijersbergen Roderick , Bernards Rene 
Published: May 2015

Abstract
Resistance to targeted therapies is a major problem in cancer treatment. The Epidermal Growth Factor Receptor (EGFR) antibody drugs are effective in a subset of colorectal cancers, but the molecular mechanisms of resistance are understood poorly. Genes involved in epigenetic regulation are frequently deregulated in cancer, raising the possibility that such genes also contribute to drug resistance. To address this question, we compiled an shRNA library for chromatin modifying enzymes, chromatin remodelers, and many other factors associated with chromatin regulation. Using this library, we performed a loss of function genetic screen in colon cancer cell lines sensitive to EGFR inhibitors. We identified SIRT2, a NAD+ dependent deacetylase, as a modulator of the response to EGFR inhibitors in colon and lung cancer. Mechanistically, loss of SIRT2 expression enhanced MEK acetylation, resulting in increased ERK activity. Conversely, overexpression of SIRT2 led to reduced phospho ERK and inhibition of growth. SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. These results warrant a further investigation into a potential role of SIRT2 in resistance to drugs that act in the Receptor Tyrosine Kinase-RAS-RAF-MEK-ERK signaling pathway.
Citation Format: Prashanth K. Bajpe, Anirudh Prahallad, Hugo Horlings, Iris Nagtegaal, Roderick Beijersbergen, Rene Bernards. SIRT2 is a modulator of response to targeted therapies through regulation of MEK kinase activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3697. doi:10.1158/1538-7445.AM2014-3697
Abstract 37: Bone metastases in renal cell carcinoma are predicted by characteristics of the primary tumor
Authors: Schneider Elke , Haber Tobias , Roos Frederick C. , Hampel Christian , Junker Kerstin , Thüroff Joachim W. , Brenner Walburgis 
Published: May 2015

Abstract
Introduction: The poor prognosis of renal cell carcinoma (RCC) is caused by a high risk of metastasis. 30 % of all RCC patients develop bone metastases during course of disease. The outcome of RCC patients with bone metastases is poor so that a prediction would be of advantage. The aim of this study was to elucidate the mechanisms that lead to an organ specific metastasis of RCC in bones and probably predict bone metastasis.
Methods: In 30 RCC tissue specimens and 9 RCC primary cell lines collected from patients who had developed no metastases, lung or bone metastases within 5 years after nephrectomy (each 10 RCC tissue specimens, each 3 RCC cell lines) expression and/or activity of 46 cellular signalling molecules were quantified by a phospho kinase array and Western blot analyses. As steps of metastasis, migration of the primary RCC cells was analysed in a Boyden chamber with 10 µg/ml fibronectin as chemotaxin, adhesion to extracellular matrix compounds fibronectin, collagen I and IV was determined after cell staining with crystal violet.
Results: In RCC tissue specimens and primary cells from patients who developed bone metastases a higher expression of alpha5 integrins, higher activity of Akt and FAK as well as a lower expression of PTEN was detected, compared to those from patients without or with lung metastases. According to these results we observed an enhanced chemotactic migration (13-fold) of bone metastatic RCC cells and adhesion to fibronectin (6-fold) or collagen type I (8-fold) - both components of the bone matrix.
Conclusion: These results show that specific characteristics like the expression and activity of cell signalling mediators and the cellular behaviour of the primary tumor determine the location of the subsequent metastasis in RCC and could be used as prognostic marker for bone metastasis. This should be considered during follow-up care.
Funded by the Wilhelm Sander Foundation
Citation Format: Elke Schneider, Tobias Haber, Frederick C. Roos, Christian Hampel, Kerstin Junker, Joachim W. Thüroff, Walburgis Brenner. Bone metastases in renal cell carcinoma are predicted by characteristics of the primary tumor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 37. doi:10.1158/1538-7445.AM2014-37