bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5456: The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer.
Authors: Qi Jianfei , Tripathi Manisha , Sahgal Natasha , Fazil Ladan , Ettinger Susan , Placzek William J. , Claps Giuseppina , Chung Leland W.K. , Bowtell David , Gleave Martin , Bhowmick Neil , Ronai Ze'ev
Published: August 2014

The androgen receptor (AR) plays a central role in the development of castration-resistant prostate cancer (CRPC), which is a major challenge for hormone therapy of advanced/metastatic prostate cancer (PCa). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination-dependent degradation, and this promotes the subsequent recruitment of p300-bound, transcriptionally active AR to a select group of AR target gene promoters/enhancers. Consequently, Siah2 promotes the expression of ∼13% of androgen-responsive genes involved in lipid metabolism, cell motility and proliferation. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under the androgen-deprivation condition in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity.

Citation Format: Jianfei Qi, Manisha Tripathi, Natasha Sahgal, Ladan Fazil, Susan Ettinger, William J. Placzek, Giuseppina Claps, Leland W.K. Chung, David Bowtell, Martin Gleave, Neil Bhowmick, Ze'ev Ronai. The E3 ubiquitin ligase Siah2 regulates the androgen receptor activity and contributes to castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2013-5456

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5468: Interaction between cetuximab and chemotherapy in colon cancer.
Authors: Santoro Valeria , Hartley John A. , Hochhauser Daniel
Published: August 2014

The epidermal growth factor receptor (EGFR) is overexpressed in many tumours and is a target for cancer therapy. Cetuximab is a monoclonal antibody targeting EGFR. It is used for the treatment of metastatic colorectal cancer (mCRC) as monotherapy and in combination with oxaliplatin or irinotecan-based chemotherapy. Several clinical studies have shown no benefit when cetuximab is combined with oxaliplatin as opposed to the positive effects observed with irinotecan. The aim of this study is to investigate these interactions in cellular models of colon cancer.

The antitumour effects of cetuximab in vitro in combination with oxaliplatin or irinotecan were determined in the SW 48 colon cancer cell line and the isogenic KRAS mutant G12A cell line. Combination indices (CI) describing the interaction of a fixed concentration of cetuximab and a range of concentrations of oxaliplatin or irinotecan were determined. Combination of cetuximab (100μg/ml) with oxaliplatin (1μM) indicated antagonism in both cell lines tested (CI=4.7 in the KRAS wild type cell line and CI=19.9 in the KRAS G12A cell line). In contrast, the combination of cetuximab (100μg/ml) with irinotecan (0.1μM) showed synergistic effects (CI=0.28 in the KRAS wild type cell line and CI=0.14 in the KRAS G12A cell line). Preclinical studies have suggested that the cytotoxic efficacy of oxaliplatin may depend partially on the production of Reactive Oxygen Species (ROS). The combination of cetuximab with oxaliplatin resulted in a reduction of ROS levels by 30% ± 2.9 in the KRAS WT and by 40% ± 10 in the KRAS G12A cell line compared to those produced by oxaliplatin alone. Additionally, levels of oxaliplatin-induced apoptosis measured by caspase 3/7 cleavage, were reduced by 70% ± 5.4 in the KRAS WT and by 50% ± 2.7 in the KRAS G12A cell line with the antioxidant N-acetyl-cysteine (NAC), suggesting that oxaliplatin induces apoptosis through the production of ROS. To elucidate the mechanism of the modulation of ROS by cetuximab and oxaliplatin, RT-PCR arrays analyzing 84 genes involved in oxidative stress response were performed following cetuximab, oxaliplatin and their combination treatment. Experiments to determine the contribution of these genes to the antagonism between oxaliplatin and cetuximab are under investigation.

Our results show that alteration of ROS levels by cetuximab affects efficacy of oxaliplatin and suggests a key role for ROS in the observed antagonism between the two drugs.

Citation Format: Valeria Santoro, John A. Hartley, Daniel Hochhauser. Interaction between cetuximab and chemotherapy in colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5468. doi:10.1158/1538-7445.AM2013-5468
Abstract 5470: Pre-clinical characterization of ARGX-110: A neutralizing, humanized monoclonal antibody to the human CD70 antigen with enhanced ADCC properties.
Authors: Silence Karen , De Haard Hans , Dreier Torston , Ulrichts Peter , Moshir Mahan , Gabriels Sofie , Thibault Alain
Published: August 2014

The expression of CD70 is normally restricted to activated B- and T- cells, as well as mature dendritic cells. Overexpression has been documented in a variety of solid and hematological tumors, where it is thought to play a role in evasion of immune surveillance. ARGX-110 is a defucosylated, humanized IgG1 monoclonal antibody that selectively targets and neutralizes CD70, a ligand of CD27. A detailed biological and functional characterization of ARGX-110 was carried out to support its clinical development for the treatment of cancers dependent on signaling through the CD70/CD27 axis. In competitive equilibrium binding experiments, ARGX-110 bound to human and cynomolgus monkey CD70 with affinities of approximately 0.4 nmol/L and 0.6 nmol/L, respectively. ARGX-110 inhibited in a dose-dependent fashion CD70/CD27-induced IL-8 release in Raji cells with IC50 values of 0.1 nmol/L. CD70 is minimally internalized (<40%) by most hematological cell lines, thus providing a plausible rationale to develop a therapeutic mAb designed to enhance ADCC. In cell depletion studies, ARGX-110 was associated with comparable to better cell lysis compared to Rituximab. Cell lysis by ARGX-110 was not dependent on the internalization rate of the ARGX-110/CD70 complex in hematological cell lines. Independence from CD70 copy numbers at the cell surface was also demonstrated. In a Burkitt lymphoma (CD70+ Raji cells) SCID mouse model, ARGX-110 administered intraperitoneally twice weekly at doses ranging from 0.001 to 10 mg/kg starting one day after inoculation resulted in a dose-response effect on animal survival. In cynomolgus monkeys, ARGX-110 did not demonstrate any toxicity upon repeated administration of high doses of 30 mg/kg. B, T and NK cell numbers remained unaltered. ARGX-110 is currently in phase I clinical trial for patients with CD70+ malignancies.

Citation Format: Karen Silence, Hans De Haard, Torston Dreier, Peter Ulrichts, Mahan Moshir, Sofie Gabriels, Alain Thibault. Pre-clinical characterization of ARGX-110: A neutralizing, humanized monoclonal antibody to the human CD70 antigen with enhanced ADCC properties. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5470. doi:10.1158/1538-7445.AM2013-5470

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5517: MD-164 strongly inhibited various tumor cells and also metastasis of pancreatic tumor cells via modulation of Arp2/3 complexes.
Authors: Kwon Byoung-Mog , Han Young Min
Published: August 2014

Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology in Korea Daejon 305-806, Republic of Korea

The most difficult problem in the treatment of cancer patients is a metastatic recurrence. We focused to find novel anti-metastatic chemicals without cytotoxicity. In preliminary results, more than 800 commercially available pharmaceuticals and pre-clinical drugs were screened to identify inhibitors of tumor cell migration that are intimately tied to the steps of metastasis. The ARP2/3 complex which induces actin-polymerization and Y-branching is an essential element for lamellipodia, invadopodia and filopodia at the early stages of the metastasis in cells. Two classes of small molecule inhibitors of Arp2/3 were reported. However, inhibitors of ARPC1∼5 subunit have not yet been reported. Regulating the ARPC1∼5 subunits for inhibition of actin polymerization by utilizing small molecules will benefit actin based cell migration research. Furthermore, Inhibitors of specific ARPC1∼5 subunit are highly advantageous for developing anti-metastasis drug without toxicity and side effects. As a result of the screening, MD-164 was found to effectively reduce migration and invasion in various cancer cell lines by targeting an ARP2/3 complex subunit2, a component of actin related protein complex 2/3 (ARP 2/3). When AsPc-1 cells stably expressing luciferase were injected into the tail vein of the mice and the mice were treated with MD164, MD164 inhibited lung metastases about 70%.

Citation Format: Byoung-Mog Kwon, Young Min Han. MD-164 strongly inhibited various tumor cells and also metastasis of pancreatic tumor cells via modulation of Arp2/3 complexes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2013-5517

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 552: The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer.
Authors: Sedletcaia Anya , Unger Helen A. , Snyder Rose B. , Holz Marina K.
Published: August 2014

The mammalian target of rapamycin complex 1 (mTORC1) is a central signaling node in mediating cellular responses to mitogens, hormones and nutrients. The 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt, RSK and many others. S6K1 is the principal kinase effector downstream mTORC1. S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels, and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis, and cell migration and invasion.

Growing evidence indicates that there exists a close interaction between the mTORC1/S6K1 pathway and estrogen receptor (ER) signaling. Notably, endocrine resistance is often associated with ligand-independent activation of ERα signaling due to hyperactivation of the mTORC1 signaling pathway, and can be reversed by the mTORC1 inhibitor everolimus in vitro.

Several lines of evidence suggest an important role for S6K1 in ER-positive breast cancer. We demonstrated that S6K1 directly phosphorylates ERα on Ser167, leading to activation of its transcriptional activity. While the MAPK-regulated p90 RSK also contributes to phosphorylation of this site, its contribution is early and transient, while the phosphorylation of Ser167 by S6K1 is prolonged and sustained. Intriguingly, we also found that S6K1 expression is estrogenically regulated by a mechanism that involves the transcription factor GATA-3. Thus it appears that S6K1 expression is maintained in two modes: a basal level of expression, typical of normal cells, and an estrogen/ERα-dependent specific upregulation. Therefore, there exists a feed-forward regulatory loop whereby S6K1 activates ERα transcriptional activity, leading to increased expression of S6K1. Our current work aims to uncover the mechanistic details of the transcriptional regulation of S6K1 expression, to delineate signaling cross-talk between mTORC1, S6K1 and ERα, and to asses whether inhibition of S6K1 overexpression and activation affects the development and progression of breast cancer.

Citation Format: Anya Sedletcaia, Helen A. Unger, Rose B. Snyder, Marina K. Holz. The role of the mTORC1/S6K1 signaling pathway in ER-positive breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 552. doi:10.1158/1538-7445.AM2013-552
Abstract 5526: Mass-action law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development.
Authors: Chou Ting-Chao
Published: August 2014

Physico-chemical principle of the mass-action law algorithm (MALA) is the basis for systematic pharmacodynamics (PD) that leads to general median-effect equation (MEE) for single entity effect and the combination index equation (CIE) for multiple entity interactions (Chou TC, Pharmacol. Rev. 58: 621-681, 2006; Free web access: http://pharmrev.aspetjournals.org/content/58/3/621). “Median” is the common-link and universal reference point for single and multiple entities and for 1st-order and higher-order dynamics. Median is also the harmonic mean of kinetic constants where the harmony is the state of pure non-competitiveness [Chou, Nature Precedings (npre.2008.2064-2). Available free at http://precedings.nature.com/documents/2064/version/2]. Based on MEE, all dose-effect curves whether hyperbolic or sigmoidal, weak or strong, 1st-order or higher-order, in vitro or in vivo, can be linearlized by the median-effect plot with small number of data points in small size experiments (Chou, J. Theor. Biol. 59: 253-276, 1976; Pharmacol. Rev. .ibid). Based on CIE, CI<1, =1, and >1 quantitatively indicates synergism, additive effect, and antagonism, respectively (Chou & Talalay, Adv. Enz. Regul. 22: 27-55, 1984; Cancer Res. 70: 440-446, 2011). Thus. MEE is the common denominator for simple and complex bio-systems in vitro, in animal and in clinics. Computerized simulation of MEE or CIE can take <1 second, and the graphics can be drawn automatically (CompuSyn, www.combosyn.com, Free download). Applying this theory in this author's laboratory (personnel < 5 for decades) has published 253 articles that have been cited 13,749 times in over 523 different biomedical journals with h-index of 55 (Thomson Reuters Web of Science, www.researcherid.com/rid/B-4111-2009) along with 30 US patents. Thus, MALA-PD theory is the common denominator for integrating complex bio-systems and its computerized simulation have proven to lead to efficient, quantitative and econo-green bio-research and new drug discovery and development as illustrated in Chou, Integr. Biol. 3: 548-559, 2011; DOI: 10.1039/c0ib00130a and in Am. J. Cancer Res. 1(7): 925-954, 2011, Free web access: www.ajcr.us.

Citation Format: Ting-Chao Chou. Mass-action law algorithm-based computer simulation for efficient and econo-green cancer drug discovery and development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5526. doi:10.1158/1538-7445.AM2013-5526

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 5560: Characterization of a new non-steroidal small molecule inhibitor of CYP17 for castration-resistant prostate cancer.
Authors: Oehlen Bert , McCormack Siobhan , Ma Gaifeng , Lim Dong Sung , Panicker Bijoy , Goldberg Itzhak D.
Published: August 2014

Prostate cancer affects 1 in 6 men and is the second most common cause of cancer-related death. Since the majority of prostate cancers critically depend on androgens for growth, androgen deprivation therapy is a frontline treatment for advanced prostate cancer. The majority of prostate tumors initially respond to androgen deprivation therapy, but eventually the disease often progresses to castration-resistant prostate cancer. However, the current therapies that only reduce androgen produced in the testis do not affect androgen produced by adrenal glands can also produce androgens. This extra-testicular androgen production is thought to be a key factor in the development of castration resistant prostate cancer. CYP17 is a P450 enzyme that catalyzes the last step of androgen biosynthesis in both the testis and the adrenals. Inhibition of CYP17 therefore completely blocks androgen production and it is thus thought to be more effective to prevent prostate cancer progression than current therapies.

Angion Biomedica has identified a promising series of proprietary non-steroidal CYP17 inhibitors. Our lead compound is potent, orally bioavailable, and significantly reduces serum testosterone levels in mice. Treatment of rats and mice with our lead CYP17 inhibitor significantly reduces the weights of androgen dependent organs. In two mouse xenograft models of androgen-dependent tumor growth our lead CYP17 inhibitor markedly reduces primary tumor growth, serum testosterone and PSA levels. Angion is currently further evaluating the therapeutic potential of this series of compounds as a possible therapy for castration resistant prostate cancer.

Citation Format: Bert Oehlen, Siobhan McCormack, Gaifeng Ma, Dong Sung Lim, Bijoy Panicker, Itzhak D. Goldberg. Characterization of a new non-steroidal small molecule inhibitor of CYP17 for castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5560. doi:10.1158/1538-7445.AM2013-5560
Abstract 5564: Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis.
Authors: Wang Ying , Cheryan Vino T. , Jamal Shazia , Chen Di , Yang Huanjie , Polin Lisa A. , Pass Harvey I. , Dou Q Ping , Sharma Sunita , Rishi Arun K. , Wali Anil
Published: August 2014

Disulfiram (DSF) is a member of the dithiocarbamate family of compounds that bind with copper and function as inhibitor of aldehyde dehydrogenase. DSF is one of the drugs approved by Food and Drug Administration for treatment of alcoholism. Recent studies have indicated anti-tumor and chemosensitizing properties of DSF. However, the molecular mechanisms of DSF action remain unclear. Here we investigated malignant pleural mesothelioma (MPM) suppressive effects of DSF and the molecular mechanisms involved. DSF inhibited growth of the murine as well as patient-derived MPM cells in part by decreasing the chymotryptic activity of the proteasome that resulted in accumulation of ubiquitinated proteins. DSF suppression of MPM growth also involved elevated apoptosis as evidenced by activation of caspase-3, elevated levels of pro-apoptotic Bax protein and cleavage of poly-(ADP-ribose)-polymerase. Our studies including gene-array based analyses further revealed that DSF suppressed a number of cell growth and metastasis-promoting genes including matrix metallopeptidase 3 and 10. DSF treatments also stimulated expression of sulfatase 1, growth arrest-specific (GAS) 6 protein, and CARP-1/CCAR1, a novel transducer of cell growth signaling. Administration of 50mg/kg DSF by daily i.p injections inhibited growth of murine MPM cell-derived tumors in vivo in part by stimulating cell growth arrest and apoptosis. Together our in vitro and in vivo studies suggest that DSF suppresses MPM growth by targeting multiple pathways that include blockage of metastasis signaling and stimulation of apoptosis, and thus holds promise as an anti-MPM agent.

Citation Format: Ying Wang, Vino T. Cheryan, Shazia Jamal, Di Chen, Huanjie Yang, Lisa A. Polin, Harvey I. Pass, Q Ping Dou, Sunita Sharma, Arun K. Rishi, Anil Wali. Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2013-5564
Abstract 5569: Tumor Treating Fields inhibit the growth of pancreatic and ovarian cancer in preclinical models .
Authors: Giladi Moshe , Schneiderman Rosa S. , Porat Yaara , Munster Mijal , Itzhaki Aviran , Mordechovich Daniel , Cahal Shay , Weinberg Uri , Kirson Eilon D. , Palti Yoram
Published: August 2014

Tumor Treating Fields (TTFields) therapy is an established anti-mitotic treatment modality. The Novo TTF-100A system, which delivers TTFields to the brain received FDA approval for the treatment of patients with Recurrent Glioblastoma (GBM) Brain Tumors. The goal of the present study is to test whether TTFields therapy is effective as a treatment in pre-clinical models of pancreatic and ovarian cancer.

TTFields of various frequencies were applied for 72h to cancerous tumor cells using two pairs of perpendicular insulated electrodes. Pancreatic adenocarcinoma and ovarian carcinoma culture growth was significantly reduced compared to controls (65%+10% and 21%+13%, respectively) with a maximal inhibitory effect seen at 150 and 200 kHz (respectively). The surviving cells exhibited increased cell volume (35%+11% and 61%+43% for pancreatic and ovarian cell lines, respectively) and a reduced viability. Fluorescence microscopy and FACS analysis revealed abnormal mitotic figure in the treated cells cultures and an increase in the 4N population, suggesting these cells failed to complete mitosis. Yet, the increase in the 4N cells fraction was too small to explain for the observed increase in cell volume in the entire remaining cell population. Combining TTFields with gemcitabine and paclitaxel commonly used for the treatment of pancreatic and ovarian cancer, enhanced treatment efficacy and led to a further increase in cell volume.

The efficacy of TTFields either alone or in combination with 5FU or gemcitabine was tested in hamsters bearing syngeneic, orthotopic pancreatic tumors. In vivo imaging as well as post mortem analysis demonstrated a significant decrease in tumor weight and volume. Compared to chemotherapy treatment alone, TTF had a sensitizing effect and increased tumor response to chemotherapy.

Based on previous reports, the observed increase in cell volume is expected to shift the peak response to TTFields to a lower frequency, allowing some of the cells to escape the effect of TTFields. While this is the first proposed mechanism of resistance to TTFields it also opens the possibility of overcoming that resistance using serial application of several frequencies.

Citation Format: Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Aviran Itzhaki, Daniel Mordechovich, Shay Cahal, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Tumor Treating Fields inhibit the growth of pancreatic and ovarian cancer in preclinical models . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2013-5569
Abstract 5570: Targeted drug delivery system and magnetic resonance imaging with intrinsic ferromagnetic nano-particle compound.
Authors: Eguchi Haruki , Hirata Kunio , Kurotani Reiko , Fukumura Hidenobu , Singh David J. , Yamamoto Masahiro , Sato Itaru , Umemura Masanori , Yamamoto Masaki , Nagashima Yoji , Ishikawa Yoshihiro
Published: August 2014

First principles calculations based on structures obtained by X-ray crystallography analysis are applied to identifying the intrinsic ferromagnetic nano-particle compound. We have found that this organic based nano-particle compound (EI236) exhibits anti-cancer property and, more important, possesses a magnetic property as it was readily attached to a magnet. EI236 exhibited intrinsic ferromagnetic behaviors from -268 celcius degree to 37 celsius degree and inhibited melanoma expansion in mouse tails when delivered to the melanoma lesion using a commercially available magnet. The local accumulation of the compound, as induced by the magnet, was readily visualized by magnetic resonance imaging (MRI) in mice. (n=4) Thus, EI236 acted as both an anti-cancer drug and an MRI contrast, and had pharmacological effects that could be delivered in a controlled manner. The identification of such compounds can overcome the long-standing problems of controlled drug delivery by magnetic force and may dramatically alter our concept of pharmacotherapy in the future, i.e., drug-targeting using a magnet and drug-dosing using MRI.

Citation Format: Haruki Eguchi, Kunio Hirata, Reiko Kurotani, Hidenobu Fukumura, David J. Singh, Masahiro Yamamoto, Itaru Sato, Masanori Umemura, Masaki Yamamoto, Yoji Nagashima, Yoshihiro Ishikawa. Targeted drug delivery system and magnetic resonance imaging with intrinsic ferromagnetic nano-particle compound. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5570. doi:10.1158/1538-7445.AM2013-5570
Abstract 5579: Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor.
Authors: Miller Anna V. , Hicks Mark A. , Richardson Amanda C. , Windle Jolene J. , Harada Hisashi
Published: August 2014

Breast cancer is a leading cause of death among women. Understanding breast cancer at the molecular level is imperative for finding more effective approaches to successfully treat these patients. Microtubule inhibitors are among the most frequently used agents for breast cancer treatment, with proven efficacy in both localized and metastatic disease. Paclitaxel (Taxol) is a member of the taxane class of anti-neoplastic microtubule damaging agents and exhibits activity against a wide range of human malignancies including breast cancer. Paclitaxel stabilizes microtubules, resulting in G2/M cell cycle arrest, and continuous treatment with paclitaxel ultimately leads to cell death. However, the precise mechanisms of how this mitotic arrest triggers cell death are still unclear.

When cells undergo paclitaxel-induced cell death, the BCL-2 family-dependent mitochondrial apoptotic pathway is activated. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak−/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that cdk activation at mitotic arrest could induce MCL-1 phosphorylation and subsequent degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.

Citation Format: Anna V. Miller, Mark A. Hicks, Amanda C. Richardson, Jolene J. Windle, Hisashi Harada. Paclitaxel-induced apoptosis is BAK-dependent, but BAX and BIM-independent in breast tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5579. doi:10.1158/1538-7445.AM2013-5579
Abstract 558: MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers.
Authors: Rosa Carrasco A. , Wetzel Leslie , Kinner Krista , Chen Hong , Rothstein Raymond , Tice David , Hollingsworth Robert , Steiner Philipp , Xiao Zhan
Published: August 2014

HER3 (ErbB3) is a member of the EGFR/HER family of receptor tyrosine kinases (RTK), consisting of EGFR, HER2, HER3 and HER4. Due to its unique kinase-deficient nature, HER3 needs to form heterodimers with EGFR, HER2 or other RTKs to be functionally active. Dimerization is induced by either HER3 ligand (Heregulin, HRG) binding, or overexpression of partner RTKs in a ligand-independent (LI) manner. In both settings, HER3 acts as a critical scaffold coupling the upstream RTKs to efficient PI3K/AKT pathway induction to drive tumor growth and survival.

We have developed a potent antagonistic human monoclonal antibody against HER3, termed MEDI3379, and tested it in multiple cancer models with either ligand-dependent or ligand-independent HER3 activities. For ligand-dependent models, we have chosen MDA-MB-175VII, a breast cancer cell-line with known γ-HRG expression, and HMCB, a melanoma cell-line with β-HRG expression. Efficient suppression of cell proliferation by MEDI3379 or 2C2, a precursor of MEDI3379, was observed in both models. This anti-tumor effect is directly due to the abrogation of HER3 activation (as determined by pHER3 formation) and its downstream effector pAKT. Her2-amplified breast cancer models such as BT474 are known to display high ligand-independent HER3 activity that is due to constitutive dimerization of HER2 and HER3. Treatment of BT474 with MEDI3379 led to effective suppression of pHER3, pAKT, and cell-proliferation in vitro. We extended this observation in vivo by exploring the antitumor activity of MEDI3379 in several orthotopic HER2-amplified breast cancer xenografts in nude mice. Consistent with in vitro observations, the BT474 xenograft model responded to MEDI3379 treatment with 65% tumor growth inhibition. In contrast, two published HER3 mAbs (Ab #6 and U1-15) failed to display activity in this ligand-independent model. In conclusion, our findings demonstrated that MEDI3379 is a HER3 antagonist that is effective in models of human cancers driven by both ligand-dependent as well as ligand-independent HER3 activities.

Citation Format: Carrasco A. Rosa, Leslie Wetzel, Krista Kinner, Hong Chen, Raymond Rothstein, David Tice, Robert Hollingsworth, Philipp Steiner, Zhan Xiao. MEDI3379, a human monoclonal antibody against HER3, suppresses HER3 activity and cell proliferation in both ligand-dependent and independent cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2013-558
Abstract 5580: Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC).
Authors: Huelsewig Carolin , Bernemann Christof , Ruckert Christian , Kiesel Ludwig , Pusztai Lajos , Liedtke Cornelia
Published: August 2014

Background: Triple negative breast cancer is characterized by an unfavorable prognosis. While patients do not benefit from endocrine or Her2 targeted therapies except chemotherapy, there is an increased response (pCR) to taxane-/anthracycline-containing therapy compared to other breast cancers. However, molecular determinants of chemotherapy specifically in TNBC remain largely unknown. Current research suggests an increased Wnt Pathway activity in TNBC while Wnt pathway activity has been shown to play an important role in breast cancer pathogenesis. Material and Methods: Differentially expressed genes in TN vs. non-TN breast cancers of patients treated with neoadjuvant taxane-/anthracycline-containing chemotherapy were identified and validated in an independent AffymetrixU133A gene chip dataset (Hess et al. 2006). Genes were tested for correlation with relapse-free survival, response to neoadjuvant chemotherapy and Ki67 expression. The effects of siRNA mediated knockdown of SFRP1 and treatment with small molecule XAV939 (specific inhibitor of Wnt signaling) were analyzed in TNBC cell lines MDA-MB 468, MDA-MB 231, HCC 1806 and luminal cell line MCF7 on chemo sensitivity. Results: Our list of over expressed genes in TNBC vs. non-TNBC contains several genes which are already discussed as potential markers for TNBC like αB-crystallin and transcription factor FOXC1. Furthermore, a few Wnt pathway associated genes (i.e. SFRP1, TCF7L1, TCF7L2, SOX10) occur in this list, which was validated in an independent dataset. While SFRP1 expression was not associated with relapse-free survival in TNBC, it was significantly correlated with a pCR. Importantly, no correlation to Ki67 expression could be demonstrated. mRNA knockdown of Wnt pathway inhibitor SFRP1 in two different TNBC cell lines (MDA-MB 468 and HCC 1806) resulted in an increased resistance to paclitaxel, doxorubicin and cisplatin. Treatment with Wnt inhibitor XAV939 resulted in TNBC cell lines MDA-MB 231, MDA-MB 468 and in luminal cell line MCF7 increased chemo sensitivity to paclitaxel and doxorubicin. Conclusion: We suggest Wnt Signaling and/or SFRP1 expression as a novel maker of chemotherapy sensitivity to taxane-, anthracycline and/or platinum-containing chemotherapy in TNBC in vitro that is independent of Ki67 expression.

Citation Format: Carolin Huelsewig, Christof Bernemann, Christian Ruckert, Ludwig Kiesel, Lajos Pusztai, Cornelia Liedtke. Wnt signaling as chemotherapy sensitivity marker of triple negative breast cancer (TNBC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5580. doi:10.1158/1538-7445.AM2013-5580
Abstract 560: Mechanical stress activates a mitotic checkpoint in multicellular tumor spheroids.
Authors: Desmaison Annaïck , Grenier Katia , Frongia Celine , Lorenzo Corinne , Ducommun Bernard , Lobjois Valerie
Published: August 2014

Expanding solid tumors are subjected to mechanical stress that impact on their growth rate and development. However little is known on the mechanisms by which mechanical cues are acting on tumor cell biology.

To address that issue, we used MultiCellular Tumor Spheroid (MCTS), a 3D model recapitulating the microenvironment, the proliferative gradient and cell-cell interactions found in a tumor. To test the impact of mechanical stress on tumor cell proliferation, we first designed, produced and used dedicated polymer microdevices in which MCTS engineered to express fluorescent biomarkers were confined to apply mechanical constraints. We observe that under constraints, MCTS display a high proportion of mitotic cells in low proliferative regions of confined spheroids. We show that these cells are being arrested in mitosis for at least 24 hours (EdU incorporation neg.) and that mitotic arrest is not caused by impairment of rounding.

We next used live SPIM (Selective Plane Illumination Microscopy) 3D imaging to monitor mitosis progression in isotropically constrained MCTS. We show that constraint impairs bipolar spindle assembly and delays progression toward metaphase-anaphase transition.

Our data indicate that in a multicellular structure mechanical constraints are responsible for a defect in cell cycle progression associated with a mitotic arrest.

Citation Format: Annaïck Desmaison, Katia Grenier, Celine Frongia, Corinne Lorenzo, Bernard Ducommun, Valerie Lobjois. Mechanical stress activates a mitotic checkpoint in multicellular tumor spheroids. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 560. doi:10.1158/1538-7445.AM2013-560
Abstract 5601: Efficient tumor therapy by anthrax toxin fusion proteins that contain cytolethal distending toxin B.
Authors: Bachran Christopher , Abdelazim Suzanne , Hasikova Radka , Liu Shihui , Leppla Stephen H.
Published: August 2014

Cytolethal distending toxin (Cdt) is produced by several Gram-negative bacterial species. It is composed of three subunits, CdtA, CdtB, and CdtC, with CdtB being the catalytic subunit. We fused CdtB from Haemophilus ducreyi with the N-terminal 254 amino acids of Bacillus anthracis toxin lethal factor (LFn) to produce a novel, potent anti-tumor drug. CdtB is transported into the cytosol of targeted cells via the efficient delivery mechanism of anthrax toxin. The fusion protein efficiently killed various human tumor cell lines by inducing a complete cell cycle arrest in the G2/M phase and subsequently inducing apoptosis. Despite the described role of CdtB as a DNase, we detected a prominent phosphatase activity of CdtB, similar to phosphatase and tensin homolog (PTEN) activity. Animal studies showed very low toxicity of a systemically-applied tumor-specific treatment and impressive anti-tumor effects, resulting in a 90% cure rate. This study demonstrates the great potential of a combination of efficient drug delivery by a modified anthrax toxin system and the enzymatic activity of CdtB, and argues for the continued development of this novel anti-cancer drug.

Citation Format: Christopher Bachran, Suzanne Abdelazim, Radka Hasikova, Shihui Liu, Stephen H. Leppla. Efficient tumor therapy by anthrax toxin fusion proteins that contain cytolethal distending toxin B. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5601. doi:10.1158/1538-7445.AM2013-5601
Abstract 5639: hsa-miR-200a regulates VEGF-C to induce epithelial-mesenchymal transition in sorafenib resistance hepatocellular carcinoma cells.
Authors: Chiou Jean , Su Jen-Liang , Hsiao Michael
Published: August 2014

Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Although treatment and perioperative management have evolved in recent years with dramatic advances in diagnostic techniques, operative methods, and combined chemoradiotherapy, the prognosis of patients with liver cancer remains dissolve. Sorafenib, a multikinase inhibitor targeting angiogenesis of hepatocellular carcinoma (HCC), demonstrated survival benefits in recent clinical trials. However, disease stabilization with sorafenib lasts a few months, possibly due to the development of resistance. It has been reported that Vascular endothelial growth factor (VEGF)-C signaling through VEGFR-3 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. In this study, we will elucidated the molecular mechanisms of VEGF-C with sorafenib-resistance in hepatocellular carcinoma. Our results showed that recombinant VEGF-C protein protected Huh-7/WT cell from sorafenib treatment. Knockdown of VEGF-C in Huh7/SR (sorafenib-resistance) cells decreased the cell survival in sorafenib treatment. The sorafenib-resistant cells changed their appearance from epithelial type to mesenchymal type compared to control. In Affymetrix microarray and microRNA microarray assays, we also found significant differences between Huh7/WT and Huh7/SR cell lines. hsa-miR-200a was found down-regulated in Huh7/SR cells which was found to be associated with epithelial-mesenchymal transition (EMT). Overexpression of hsa-miR-200a was found to regulate VEGF-C to alter EMT status in Sorafenib-resistance HCC. In conclusion, EMT may induce VEGF-C and downstream signaling pathways which resulted in sorafenib-resistance in HCC and hsa-miR-200a was found to be playing an important role in this process.

Citation Format: Jean Chiou, Jen-Liang Su, Michael Hsiao. hsa-miR-200a regulates VEGF-C to induce epithelial-mesenchymal transition in sorafenib resistance hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5639. doi:10.1158/1538-7445.AM2013-5639
Abstract 5641: Sunitinib inhibits AXL phosphorylation in tumor cells.
Authors: Van der Mijn Johannes C. , Gotink Kristy J. , de Haas Richard R. , Dekker Henk , Jimenez Connie R. , Broxterman Henk J. , Verheul Henk M.w.
Published: August 2014

Background Sunitinib is a multi-targeted tyrosine kinase inhibitor (TKI), that is used for treatment of patients with advanced renal cell cancer (RCC) Drug resistance to sunitinib is a major clinical problem. We recently reported that continuous exposure to sunitinib causes acquired resistance of tumor cells. The receptor tyrosine kinase Axl has been implicated in acquired resistance to multiple TKIs, including erlotinib and lapatinib. In addition, sunitinib was previously reported to be a potential inhibitor of Axl catalytic activity. We therefore investigated the potential role of Axl in sunitinib resistance. Methods 786-O cells resistant to sunitinib were obtained by continuous exposure to the drug as previously published (Gotink et al. Clin Cancer Res 2011). AXL expression was studied in 786-O cell lines and EC-RF24 endothelial cells by RT-PCR and Western blot. Sunitinib and AXL inhibitor R428 sensitivity of cells transfected with siRNAs against AXL or scrambled siRNAs was determined by MTT cell viability assays. For kinase activity experiments recombinant AXL and tyrosine peptide arrays (PamGene, ‘s Hertogenbosch, the Netherlands) were used. Phospho-AXL and total AXL in cell lysates were measured by ELISA. Results Axl phosphorylation in vitro in both 786-O and EC-RF24 cells was dose-dependently inhibited by sunitinib, with a 50% inhibitory concentration of 5 μM. Activity of recombinant Axl kinase was measured on tyrosine containing peptide arrays in presence of 0, 1 or 4 μM sunitinib or 2 μM R428. Sunitinib induced dose-dependent inhibition of Axl activity, where 2 μM R428 blocked all peptide phosphorylations. In addition, 786-O sunitinib resistant cells (786-O SUN) showed a 4-fold overexpression of Axl protein compared to 786-O parental cells. However, gene silencing of AXL in 786-O SUN cells by RNA interference did not sensitize the cells to sunitinib. Sunitinib resistant cells were shown to be cross-resistant to the Axl inhibitor R428 with respective IC50 values of 0.9 μM (±0.1 μM) and 1.8 μM (±0.1 μM). Conclusion Phosphorylation of Axl is inhibited by sunitinib in both 786-O RCC and EC-RF24 endothelial cells. Despite its overexpression in sunitinib resistant cells, gene silencing of AXL did not sensitize 786-O resistant cells to sunitinib, indicating that sunitinib resistance is not mediated by AXL.

Citation Format: Johannes C. Van der Mijn, Kristy J. Gotink, Richard R. de Haas, Henk Dekker, Connie R. Jimenez, Henk J. Broxterman, Henk M.w. Verheul. Sunitinib inhibits AXL phosphorylation in tumor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5641. doi:10.1158/1538-7445.AM2013-5641
Abstract 5664: The antiangiogenic effect of two drugs loaded nanocarriers and its potential application for cancer metronomic treatment.
Authors: Alani Adam G. , Mishra Gyan
Published: August 2014

Purpose: To synthesize and evaluate the antiangiogenic effect of individual and mixed paclitaxel (PTX) and rapamycin (RAP) conjugated micelles

Methods: RAP or PTX were conjugated to poly(ethyleneglycol)-block-poly(aspartate-hydrazide) utilizing a pH-sensitive linker based on hydrazone prodrug strategy. The synthesized drug-polymer conjugates were characterized using NMR and gel permeation chromatography (GPC). RAP and PTX polymer conjugates, PEG-RAP and PEG-PTX respectively were assembled into individual and mixed micelles. The size of these micelles was determined using dynamic light scattering. The micelle drug content was quantified by RP-HPLC. The antiangiogenic effect of individual and mixed micelles was evaluated in in vitro Human Umbilical Vein Endothelial Cells (HUVEC) model through proliferation, tube formation and migration assays. The HUVEC cell proliferation was evaluated by the CellTiter-Blue® Cell Viability Assay, the tube formation was evaluated by measuring the total area covered by the HUVEC capiliary formation while the HUVEC cell migration was determined by xCELLigence System.

Results: PEG-RAP and PEG-PTX were successfully synthesized and the molecular weight of the polymers was determined by GPC and NMR. The number of drug molecules attached to the polymer for RAP and PTX were 22 and 25 respectively. PEG-RAP and PEG-PTX were assembled into individual and mixed micelles as mono dispersed populations in the range of 40-100nm. The IC50 of PEG-RAP and PEG-PTX individual micelles were 12μM and 2nM respectively. The mixed micelles showed synergistic effect in inhibiting the HUVEC cell proliferation. Individual and mixed micelles inhibited HUVEC tube formation and migration with the mixed micelles showing a synergistic effect.

Conclusions: We were successful in synthesizing new conjugates of RAP and PTX with a pH-sensitive linker. These polymers were formulated into individual and mixed micelles. Antiangiogenic effect was observed with individual and mixed micelles. The antiangiogenic effect was synergistically enhanced with the use of mixed micelles.

Citation Format: Adam G. Alani, Gyan Mishra. The antiangiogenic effect of two drugs loaded nanocarriers and its potential application for cancer metronomic treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5664. doi:10.1158/1538-7445.AM2013-5664