bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5498: Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139
Authors: Balhorn Monique Cosman , Hok Saphon , Balhorn Rod 
Published: August 2015

Abstract
The tridentate selective high affinity ligand (SHAL) SH7139 is selectively cytotoxic at sub-nanomolar concentrations to lymphoma cells over-expressing HLA-DR10. Recent studies suggest SH7139 is unusual in that multiple mechanisms may contribute to its killing of targeted tumor cells. Electron microscopy data suggest one mechanism involves the triggering of a cell-signaling event that leads to the induction of apoptosis when SH7139 binds to a unique site on HLA-DR10 (the same region/epitope recognized by the Lym-1 antibody). A second mechanism appears to involve the internalization of SH7139 by tumor cells and the subsequent release of it's three individual recognition elements/ligands by metabolic cleavage of the amide bonds that link them to a scaffold (a unique feature of SHALs). Analogous to the process of toxin delivery by antibody-drug conjugates, once these ligands are released inside the cell, they can each inhibit a different key pathway required for tumor cell survival. Additional metabolic conversions of these ligands by the tumor cells to toxic metabolites may also contribute to cell killing through the inhibition of a number of other critical cellular functions. The third proposed mechanism is based on the fact that the target receptor HLA-DR10 participates in the activation of T-cells. The binding of SH7139 to the antigen binding pocket of HLA-DR10 may trigger an immune response that targets the cancer cells with bound drug. All three proposed mechanisms are currently under study. If multiple diverse mechanisms of action contribute to SH7139's cytotoxicity, it will be extremely difficult for lymphoma cells to develop a resistance to the drug. This research was supported by the National Cancer Institute Phase II SBIR Award R44CA159843-02 to SHAL Technologies Inc. Part of this work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.
Citation Format: Monique Cosman Balhorn, Saphon Hok, Rod Balhorn. Multiple mechanisms of action may contribute to the lymphoma cell-killing activity of SH7139. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5498. doi:10.1158/1538-7445.AM2015-5498
Abstract 5503: Panaxynol, a potential treatment for colitis, selectively targets pro-inflammatory macrophages for DNA damage and apoptosis
Authors: Chaparala Anusha , Poudyal Deepak , Cui Xiangli , Li Bin , Witalison Erin E. , Cui Taixing , Hofseth Lorne J. 
Published: August 2015

Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that has been associated with a high risk for colorectal cancer. Since available conventional treatments provide mostly modest relief and are paired with a high risk of side effects, complementary and alternative medicines (CAMs) can offer a safe and effective option for the treatment of IBD. Earlier studies in our lab have shown that American Ginseng can suppress colitis and also prevent colitis-associated colon cancer in mice. During the process of isolating active ingredients from this plant, Panaxynol was identified as a key component. Panaxynol has been shown to have anti-cancer and anti-inflammatory properties, but it has not been studied in macrophage-driven autoimmunity models. Here, we study the effects of Panaxynol on macrophages and other cell lines in an attempt to understand its mechanism of action. We show that Panaxynol induces DNA damage and apoptosis in macrophages in a dose-dependent manner using phosphorylated γ-H2AX detection and TUNEL assays, respectively. Importantly, DNA damage and apoptosis were induced in other cell types (e.g. epithelial cells and fibroblasts) only when using higher doses of Panaxynol (&gt;50μM). Co-culture experiments confirm that Panaxynol selectively targets macrophages in the presence of colon cancer cells. To explore mechanisms, we asked whether Panaxynol inhibits the STAT1 pathway. Results showing an inhibition of STAT1 phosphorylation are consistent with the hypothesis. We plan to extend these studies to an in vivo mouse model of DSS-induced colitis in order to understand the anti-inflammatory mechanisms of Panaxynol. Positive outcomes from this study can potentially serve as a model for the treatment of colitis and other autoimmune diseases (at least partly) associated with macrophage dysfunction.
Citation Format: Anusha Chaparala, Deepak Poudyal, Xiangli Cui, Bin Li, Erin E. Witalison, Taixing Cui, Lorne J. Hofseth. Panaxynol, a potential treatment for colitis, selectively targets pro-inflammatory macrophages for DNA damage and apoptosis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5503. doi:10.1158/1538-7445.AM2015-5503
Abstract 5505: MyD88-dependent signaling decreases the anti-tumor efficacy of epidermal growth factor receptor inhibition in head and neck cancer cells
Authors: Simons-Burnett Andrean L. , Koch Adam T. , Love-Homan Laurie , Stanam Aditya 
Published: August 2015

Abstract
Epidermal growth factor receptor (EGFR) is upregulated in the majority of head and neck squamous cell carcinomas (HNSCC). However many HNSCC patients respond poorly to EGFR inhibitors (EGFRIs) despite tumor expression of EGFR. Gene expression analysis of erlotinib-treated HNSCC cell lines revealed an upregulation of genes involved in MyD88-dependent interleukin-6 (IL-6) expression compared to their respective vehicle treated cell lines. We therefore proposed that MyD88-dependent signaling may reduce the anti-tumor efficacy of the EGFR inhibitor erlotinib in HNSCC. Erlotinib significantly upregulated IL-6 secretion which we have previously reported to result in reduced drug efficacy and drug resistance (Fletcher et al, 2013). Suppression of MyD88 expression significantly blocked erlotinib-induced IL-6 secretion in vitro and increased the anti-tumor activity of erlotinib in vivo. There was little to no evidence of toll-like receptor (TLR) or interleukin-18 receptor (IL-18R) involvement in erlotinib-induced IL-6 secretion. However, suppression of the interleukin-1 receptor (IL-1R) signaling through pharmacologic and genetic methods significantly reduced erlotinib-induced IL-6 production and increased HNSCC cell sensitivity to erlotinib in vitro. A time-dependent increase of IL-1 alpha (IL-1α) but not IL-1 beta (IL-1β) was observed in response to erlotinib treatment and IL-1α blockade significantly increased the anti-tumor activity of erlotinib and the EGFR antibody inhibitor cetuximab in vivo. Pre-treatment with a pan-caspase inhibitor but not a caspase-1 inhibitor reduced erlotinib-induced IL-1α secretion suggesting that IL-1α was released due to cell death. Human HNSCC tumors showed higher IL-1α mRNA levels compared to matched normal tissue, and IL-1α was found to be negatively correlated with survival in HNSCC patients. Overall, the IL-1α/IL-1R/MYD88/IL-6 pathway may be responsible for the reduced anti-tumor efficacy of erlotinib and other EGFRIs; and blockade of the MyD88-dependent signaling may improve the efficacy of EGFRIs in the treatment of HNSCC.
Citation Format: Andrean L. Simons-Burnett, Adam T. Koch, Laurie Love-Homan, Aditya Stanam. MyD88-dependent signaling decreases the anti-tumor efficacy of epidermal growth factor receptor inhibition in head and neck cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5505. doi:10.1158/1538-7445.AM2015-5505
Abstract 5508: Fucoidan from Turbinaria conoides attenuates pancreatic cancer progession by regulating p53 - NFκB crosstalk
Authors: Delma Caroline R. , Srinivasan Guru Prasad , Raviprakash Nune , Manna Sunil K. , Somasundaram Somasundaram T. , Aravindan Natarajan 
Published: August 2015

Abstract
Poor prognosis of pancreatic cancer (PC) has been attributed to its resistance to apoptosis and propensity for early systemic dissemination. Existing therapeutic strategies are often circumvented by the molecular crosstalk between cell signaling pathways. The fact that p53 is mutated in more than 50% of PC tissues and NFκB is constitutively activated in therapy resistant residual PC accounts for the evaded cell death and dissemination. In this study, we examined the benefit of fucoidan from a marine brown alga, Turbinaria conoides against PC progression. Five fractions of fucoidan isolated and fractionated using ion exchange chromatography were tested for their potential in this setting using two (MiaPaCa-2, Panc-1) genetically diverse human PC cell-lines. All fractions investigated exerted significant dose dependent and time dependent regulation of cell survival. Coherently, fucoidans induced apoptosis and activated caspase -3, -8 and -9 and cleaved PARP. Pathway-specific transcriptional analysis (QPCR profiling) recognized inhibition of 57 and 38 NFκB pathway molecules with fucoidan-F5 in MiaPaCa-2 and Panc-1 cells, respectively. In addition, fucoidan-F5 was also found to inhibit both the constitutive and TNFα mediated NFκB DNA-binding activity (EMSA) in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB dependent luciferase activity further substantiate inhibitory potential of seaweed fucoidans on NF-κB. Moreover, fucoidan(s) treatment increases cellular p53 in PC cells. Together, the results suggests that fucoidan regulates PC progression and further imply that fucoidans may selectively target p53-NFκB crosstalk and dictate apoptosis in PC cells.
Citation Format: Caroline R. Delma, Guru Prasad Srinivasan, Nune Raviprakash, Sunil K. Manna, Somasundaram T. Somasundaram, Natarajan Aravindan. Fucoidan from Turbinaria conoides attenuates pancreatic cancer progession by regulating p53 - NFκB crosstalk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5508. doi:10.1158/1538-7445.AM2015-5508
Abstract 5509: A drug-screening model to identify compounds active in cells under metabolic stress
Authors: Pellegrini Paola , Haraldsson Martin , Jenmalm Jensen Annika , Lundbäck Thomas , De Milito Angelo 
Published: August 2015

Abstract
Background and aim: Promising anticancer compounds often fail in vivo due to lack of efficacy. Drug screenings to identify anticancer agents are usually performed in culture conditions that very poorly represent the complex metabolic tumor environment. Tumor tissues are characterised by low oxygen (hypoxia) and acidic extracellular pH (acidosis). A screen of a drug-library for compounds able to induce cell death in acidic/hypoxic conditions may lead to discover effective drugs targeting quiescent/hypoxic cells, normally considered responsible for tumor relapses after therapy. Methods: The colon carcinoma cell line HCT-116 has been adapted to grow in low pH conditions (pH 6.8). The Prestwick compound library (1200 FDA-approved compounds) was used to validate the assay. Cell viability was measured using the acid phosphatase assay after 48 hours exposure to test compounds. The assay was validated in HCT-116 cells cultured in normoxic and hypoxic conditions. Multicellular spheroids (MCS) were used to evaluate the sensitivity to hit compounds confirmed at least three times in 2D culture conditions. Results: The assay was optimized to perform the screening at pH 6.8 in normoxic and hypoxic conditions. Experiments have demonstrated the ability of cells to survive and grow in hypoxic conditions (1% oxygen) for at least 4 days. The test was optimized in terms of number of plated cells and serum concentration. Hit compounds were identified based on the mean values for quality control plus 3 standard deviations of untreated samples. The screen led to identify 20 hits for both conditions and 11 hits were further confirmed for hypoxic/acidic conditions. Auranofin and Verteporfin showed to better induce cell death in cells adapted or acutely exposed to low pH compared to parental cells and immortalized epithelial cells (RPE1). Both drugs showed cytotoxic effects on cells grown as MCS, suggesting a potential good efficacy of the therapeutic agent in vivo. In addition, the screening of about 10000 compounds of the LCBKI library is ongoing and about 100 hits have been identified. Conclusions: The screening validation on the Prestwick library will hopefully lead to identify potential “off-label” effects of already approved drugs. The screening of larger drug-libraries will hopefully lead to find and characterize more compounds able to target slow proliferating and therapy resistant cells.
Citation Format: Paola Pellegrini, Martin Haraldsson, Annika Jenmalm Jensen, Thomas Lundbäck, Angelo De Milito. A drug-screening model to identify compounds active in cells under metabolic stress. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5509. doi:10.1158/1538-7445.AM2015-5509
Abstract 5510: Tamoxifen induces estrogen receptor-independent bioenergetic stress: A synthetic lethality approach to target tumor metabolism
Authors: Daurio Natalie A. , Tuttle Stephen , Koumenis Constantinos 
Published: August 2015

Abstract
Tamoxifen, a selective estrogen receptor modulator (SERM) is clinically used for adjuvant treatment of estrogen receptor (ER) positive breast cancer. Recent data from our lab has shown that tamoxifen inhibits oxygen consumption at high, yet clinically relevant, doses. We hypothesize that this occurs through a non-ER dependent, direct effect on the mitochondria, and causes metabolic and signaling changes that can be exploited for therapeutic benefit. ER+, MCF7 breast cancer cells have a higher basal respiratory rate and lower glycolytic rate than ER, MDA231, cells. However, tamoxifen inhibited oxygen consumption to a similar degree in both cell lines Pharmacological inhibition of ERα expression or CRISPR-Cas9 mediated knock out of the ERα did not affect the ability of tamoxifen to decrease oxygen consumption. In response to tamoxifen inhibition of oxygen consumption, tumor cells increased dependence on glycolysis. Glucose deprivation or treatment with glycolytic inhibitors, 2-deoxy glucose (2DG) or 3-bromo-pyruvate significantly sensitized breast cancer cells to tamoxifen treatment. Tamoxifen combined with glucose deprivation or treatment with 2-DG led to robust activation of the AMPK signaling pathway. Knockout of AMPKα1 in breast cancer cells ameliorated cytotoxicity. Based on these data we’ve also demonstrated clinical usefulness of tamoxifen in a non-breast cancer model. BRAF inhibitor resistant melanoma exhibits a higher rate of oxidative phosphorylation over to the BRAF inhibitor sensitive melanoma cells. Tamoxifen-induced inhibition of oxygen consumption increased cytotoxicity in the OxPhos-addicted, BRAF inhibitor-resistant, population compared to the BRAF inhibitor sensitive cells. Our results indicate a new and unanticipated mechanism of action for tamoxifen in ER+ and ER-breast cancers. Moreover, since this effect is not ER dependent, tamoxifen may have clinical use in a wider spectrum of cancers especially when combined with inhibitors of glycolysis.
Citation Format: Natalie A. Daurio, Stephen Tuttle, Constantinos Koumenis. Tamoxifen induces estrogen receptor-independent bioenergetic stress: A synthetic lethality approach to target tumor metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5510. doi:10.1158/1538-7445.AM2015-5510
Abstract 5513: Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform
Authors: Alharbi Hanan M. , Campbell Robert B. 
Published: August 2015

Abstract
Breast cancer is a major cause of cancer death in women worldwide. Breast cancer is a heterogeneous disease characterized by variant pathological features, disparate responses to therapeutics, and substantial differences in patient's long-term survival. The use of drug delivery systems such as liposomes can favorably alter the pharmacokinetic and biodistribution profile of commonly used drugs used to treat breast cancer disease.
An important feature of a drug delivery system is its ability to recognize and selectively target tumor cells with relatively high affinity when compared to healthy tissues. For this reason, the goal of this study was to develop a novel nanoliposome system that would target tumor cells to a significantly greater extent when compared to more conventional liposome systems. In this study, natural lipids extracted directly from breast cancer cells were used to prepare cellular lipid-extracted nanoliposomes (CLENs). The rationale is that an array of different lipids with a unique composition profile would represent a more relevant source of lipid material when compared to more traditional methods of liposome preparation. We therefore investigated whether the inclusion of extracted lipids derived from breast cancer cells would improve the selective uptake of liposomes by breast cancer cells, and related formulation features. To achieve these goals, three breast cancer cell lines were used (4T1, BT-20, and SK-BR-3), a normal breast fibroblast (CRL-2089), and an ovarian cancer cell line (SK-OV-3- used as a negative control).
The size of CLENs fell within the size range of 120- 203 nm and possessed a negatively-charged liposome surface charge potential (ranging between -10.97 and -20.97 mV). The nanoliposomes were also non-toxic to cells within the concentration range evaluated (up to 1μmol). Furthermore, without exception, the cellular uptake of CLENs was greatest when the extracted material used to prepare CLENs was the same as the target cell from which the lipids were extracted. In addition, when the breast cancer cell lines (4T1, SK-BR-3 and BT-20) were used to prepare CLENs, SK-OV-3 and CRL-2089 cell lines took up CLENs to a lesser extent, suggesting a more selective and differential cellular uptake.
In conclusion, the novel nanoliposome platform represents a promising drug delivery alternative to more conventional nano drug delivery systems. Additional formulation studies are currently underway.
Citation Format: Hanan M. Alharbi, Robert B. Campbell. Employing a unique panel of breast cancer cellular lipids extracts in the development of a novel nanoliposome drug platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5513. doi:10.1158/1538-7445.AM2015-5513
Abstract 5521: Interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in colorectal cancer
Authors: Yang Chih-Yung , Lin Chi-Hong , Jiang Jeng-Kai 
Published: August 2015

Abstract
Previously and our studies have observed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We use human atherosclerotic plaque-specific peptide-1 (AP1) that specifically target to IL-4Rα. This study investigated the in vitro binding and internalization of AP1, specific targeting to IL-4Rα, therapeutic efficacy and systemic toxicity in vivo of AP1-conjuagted liposomal doxorubicin. In vitro, The AP1 strongly bound to and was efficiently internalized into IL-4Rα-overexpressed CT26 cells than CT26 control cells, while little binding and internalizing of a control peptide was seen. Selective cytotoxicity experiment revealed AP1-conjugated liposomal doxorubicin preferentially killed the IL-4Rα-overexpressed CT26 cells compared to control CT26 cells. In addition, AP1-conjugated liposomal doxorubicin administered intravenously significantly inhibited tumor growth and decreased cardiotoxicity of doxorubicin in subcutaneously tumor-bearing mouse model. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressed colorectal cancers.
Citation Format: Chih-Yung Yang, Chi-Hong Lin, Jeng-Kai Jiang. Interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5521. doi:10.1158/1538-7445.AM2015-5521
Abstract 5537: Nanoparticle delivery of an SN38 conjugate is more effective than Irinotecan in a mouse model of Neuroblastoma
Authors: Iyer Radhika , Croucher Jamie L. , Chorny Michael , Mangino Jennifer L. , Alferiev Ivan S. , Levy Robert J. , Kolla Venkatadri , Brodeur Garrett M. 
Published: August 2015

Abstract
Purpose: Neuroblastoma (NB) is the most common and deadly solid tumor in childhood. The majority of NB patients have advanced stage disease and a poor prognosis, so more effective, less toxic therapy is needed. We wanted to determine if more targeted delivery of chemotherapeutic agents would improve efficacy and reduce systemic toxicity. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan.
Experimental Design: We formulated ultrasmall-sized (&lt;100 nm) biodegradable poly(lactide)-poly(ethylene glycol) based nanoparticles (NPs) containing SN38 conjugated to tocopherol succinate (SN38-TS). We assessed alternative dosing schedules of SN38-TS NPs compared to irinotecan. An equivalent dose of SN38-TS NPs given 1x/2wk x 4 weeks (2 doses) had identical efficacy to irinotecan given 5x/wk x 4 weeks (20 doses), but none were cured. We then compared irinotecan 5x/wk x 8 weeks (40 doses) to SN38-TS NPs given 2x/wk x 4 weeks, 1x/wk x 8 weeks, and 2x/wk x 8 weeks (8, 8, and 16 doses, respectively).
Results: All SN38-TS NP regimens were far superior to irinotecan, and “cures” were obtained in all NP arms (no cures with irinotecan). SN38-TS NP delivery resulted in 200x the amount of SN38 in NB tumors at 4 hr post-treatment, and 25% of the 4-hr SN38 level remained at 72 hr post-treatment, compared to no SN38 detected at 24 hr post-treatment for the irinotecan arm; no toxicity was seen with NPs.
Conclusions: We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity.
Citation Format: Radhika Iyer, Jamie L. Croucher, Michael Chorny, Jennifer L. Mangino, Ivan S. Alferiev, Robert J. Levy, Venkatadri Kolla, Garrett M. Brodeur. Nanoparticle delivery of an SN38 conjugate is more effective than Irinotecan in a mouse model of Neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5537. doi:10.1158/1538-7445.AM2015-5537