bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2731: Cetuximab resistance is associated with increased dependence on lipogenesis
Authors: Lu Yang , Lu Haiquan , Li Xinqun , Fan Zhen 
Published: August 2012

Abstract
Sterol regulatory element binding proteins (SREBPs) are key transcriptional regulators of cellular lipid homeostasis. By regulating the maturation of SREBPs through the PI3K/Akt and MEK/Erk signaling pathways, the epidermal growth factor receptor (EGFR) regulates de novo lipogenesis, which is essential for the structural needs of proliferation of cancer cells. The objective of current study is to determine the role of inhibition of lipogenesis by cetuximab, an FDA-approved EGFR-blocking antibody, in cetuximab-induced antiproliferative/antisurvival effects in cancer cells and to identify new combinations of cetuximab with approaches interfering with lipid metabolism for improved therapy. We found that addition of cetuximab into culture medium inhibited the activation of SREBP-1 (appearance of a nuclear form through cleavage of SREBP-1 precursor) in HN5 head and neck cancer cells but not in a cetuximab-resistant subline of HN5 cells (HN5R). Compared with parental HN5 cells, HN5R cells exhibit remarkably increased sensitivity to treatment with two pharmacological lipogenesis inhibitors, C75 (a fatty acid synthase inhibitor) and TOFA (an acetyl-CoA carboxylase inhibitor), suggesting that the cetuximab-resistant cells are more dependent on de novo fatty acid synthesis for survival, and combination of cetuximab with lipogenesis inhibitors may be a novel combination therapy. On the other hand, the increased dependence of cancer cells on lipogenesis suggests that cetuximab-resistant cells might also be sensitive to agents that promote fatty acid α-oxidation. We found treatment of HN5R cells with fenofibrate, an agonist of peroxisome proliferator-activated receptor alpha that transcriptionally activates the genes for inducing fatty acid α-oxidation, disrupted the redox balance in the cetuximab-resistant cells, leading to increased production of ROS and depolarization of the mitochondrial membrane potential that resulted in apoptosis. In summary, our data indicate that the antiproliferative/antisurvival effects of cetuximab in cancer cells depend on effective inhibition of lipogenesis. Pharmacological approaches that forcibly switch cancer cell metabolism from aerobic glycolysis to fatty acid α-oxidation may overcome cetuximab resistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2731. doi:1538-7445.AM2012-2731
Abstract 2734: c-Met antibody LY2875358 (LA480) shows differential antitumor effects in non-small cell lung cancer
Authors: Zeng Wei , Yan Lei , Peek Victoria , Wortinger Mark , Tetreault Jonathan , Xia Jinqi , Chow Chi-Kin , Manro Jason R. , Stephens Jennifer R. , Weir Spring N. , Tang Ying , Vaillancourt Peter , Lu Jirong , Yan Betty S. , Liu Ling 
Published: August 2012

Abstract
c-Met is a member of the receptor tyrosine kinase family and is the receptor for hepatocyte growth factor (HGF). c-Met is involved in many mechanisms of cancer proliferation and metastasis. Inappropriate activation of c-Met can be induced by ligand-independent mechanisms such as gene amplification, specific genetic mutations, and transcriptional up-regulation, or by ligand-dependent autocrine or paracrine mechanisms. Lung cancer is the leading cause of cancer death worldwide. Despite the successful development of EGFR- or EML4-ALK-targetd therapies, treatment options remain limited for patients with advanced lung cancer, making the identification of new therapeutic targets essential. c-Met expression was reported in 41-72% non-small cell lung cancer (NSCLC), amplification of c-Met occurs in 5-10 % of patients, and c-Met mutations have been detected in 8-13% of patients. We have developed a bi-valent c-Met antibody LY2875358 (LA480), which blocks ligand-dependent and ligand-independent c-Met activations. It is currently in clinical development. Here, we have demonstrated that LY2875358 alone or in combination with standard-of-care (SOC) affected cell proliferation, migration and signal transduction in NSCLC cells with c-Met gene amplification, mutations and overexpression. In vitro, LY2875358 induces wild type and mutant c-Met internalization and degradation. In vivo, LY2875358 alone shows a marked antitumor activity in Met amplification NSCLC xenograft models. The combination of LY2875358 with SOC chemotherapeutics treatments has better efficacy than either treatment alone, both in vitro and in vivo.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2734. doi:1538-7445.AM2012-2734
Abstract 2743: Triapine sensitizes ovarian cancer cells to platinum drugs and PARP inhibitors
Authors: Lin Z. Ping , Ratner Elena S. , Sartorelli Alan C. 
Published: August 2012

Abstract
Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone) is a ribonucleotide reductase (RNR) inhibitor that is 1000-times more potent than clinically-used hydroxyurea. Consisting primarily of R2 and R1 subunits during the S phase of the cell cycle, RNR catalyzes the rate-limiting step in the production of deoxyribonucleotides (dNTPs) required for DNA synthesis. Triapine chelates iron to form the triapine-Fe complex that quenches the tyrosyl radical at the R2 subunit and leads to enzymatic inactivation. In recent phase I and II trials, treatment of locally advanced cervical cancer with triapine in combination with cisplatin and radiation was well tolerated and produced high durable complete clinical responses in patients. This promising combination therapy may be attributable to the inhibitory effects of triapine on the repair of cisplatin- and radiation-induced DNA damage. However, the exact DNA repair mechanisms modulated by triapine remain poorly understood. In this study, we demonstrate that treatment of ovarian cancer cells with triapine prompts rapid and prolonged depletion of dATP/dNTP pools, which in turn leads to formation of DNA double strand breaks (DSBs) and inhibition of DNA synthesis in S and G2/M phases of the cell cycle. Furthermore, we show that treatment with triapine results in enhanced sensitization of BRCA-proficient (wild-type) ovarian cancer cells to platinum drugs (cisplatin and carboplatin) and the PARP inhibitor olaparib. Both platinum drugs and PARP inhibitors indirectly cause DSBs which require BRCA1- and BRCA2-dependent homologous recombination (HR) to repair. Collectively, these results suggest that triapine acts to abrogate replicative DNA synthesis and post-replication repair, thereby deterring HR repair of DSBs caused by platinum drugs and other DNA damaging modalities. While 70% of ovarian cancer patients initially respond to platinum-based chemotherapy, the majority of these patients will develop recurrent cancer resistant to the platinum drugs. Emergence of platinum-resistant cancer populations may be associated with increasing proficiency of cancer cells to employ HR to repair DNA damage. Given that, our findings provide the rationale for the use of triapine to enhance the efficacy of platinum-based chemotherapy and PARP inhibitors, and potentially eradicate platinum-resistant ovarian cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2743. doi:1538-7445.AM2012-2743
Abstract 2747: Synergistic antileukemic activity of F14512 in combination with AraC
Authors: Vandenberghe-Huez Isabelle , Pillon Arnaud , Créancier Laurent , Gomes Bruno , Annereau Jean-Philippe , Fournier Emmanuel , Brel Viviane , Cartron Valérie , Chansard Nathalie , Pourtau Sandrine , Roy Sabine , Blanchet Jean-Christophe , Verdier Jérôme , Dejean Caroline , Ricome Christel , Offrete Vanessa , Gras Stéphane , André Karine , Guminski Yves , Bailly Christian , Guilbaud Nicolas , Kruczynski Anna 
Published: August 2012

Abstract
New antileukemic agents are urgently needed to achieve improvement of the survival of patients suffering from Acute Myelogenous Leukemia (AML). F14512 combines an epipodophyllotoxin core with a spermine moiety that targets cells with a high demand for polyamines such as cancer cells. F14512 exhibits a high level of in vivo anti-tumor activity in a series of experimental murine and human solid tumor models and has entered into clinical phase one. In this study, we investigated the in vivo antileukemic activity of F14512 against cell line or primary human AML models and evaluated its potential in combination with the reference antileukemic agent, AraC. HL60 cells or AML cells collected from different patients were engrafted onto NSG mice. Using flow cytometry and q-PCR analysis, we demonstrated that multiple administrations of F14512 for 3 weeks resulted in an extensive reduction of AML cell number in the bone marrow and blood of treated mice. We also showed in vitro and in vivo synergistic activity of F14512 in combination with AraC in HL-60 and primary AML models when both compounds were used at suboptimal doses. The mechanisms triggering primary leukemic cell death were investigated and our results indicated that senescence could be involved. Collectively, these results demonstrate that F14512 exhibits a marked in vivo antileukemic activity, supporting the Phase I clinical trials of this novel promising drug candidate.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2747. doi:1538-7445.AM2012-2747
Abstract 275: Enhancing the anticancer activity of pegylated interferon by dual specificity protein phsphatase 1 (DUSP1) silencing in hepatocellular carcinoma based replicon
Authors: Choi Jung Eun , Hur Wonhee , Lyoo KawngSoo , Hong Sung Woo , Kim Sung Woo , Lee Yong Ki , Yoon Seung Kew 
Published: August 2012

Abstract
Chronic hepatitis C infection is one of the important causes of hepatocellular carcinoma (HCC), or primary liver cancer, throughout the world. Worldwide, HCC causes over a million deaths per year (about 10% of all deaths in the adult age range), making it one of the most common malignancies in adults. Although pegylated interferon (PEG-IFN) is a treatment for HCC among patients with HCV, non-responders remains a challenging issue. In this study, we investigated whether anticancer activity of IFN was enhanced after dual specificity protein phosphatase 1 (DUSP1) silencing by regulation of HCV titer. To investigate anticancer activity of IFN by DUSP1, we silenced DUSP1 expression into HCC based replicon. The DUSP1 expression was determined using RT-PCR and western blot analysis. Next, the quantification of viral RNA was measured by real-time PCR. The activity of the proteins belonged to IFN-mediated signaling pathway was detected by Western blot analysis. The number of copies of viral RNA was more decreased in DUSP1 than negative control. Furthermore, the activity of ERK was enhanced through DUSP1 silencing under treatment of IFN. Taken together, these results showed that modulation of DUSP1 activity enhanced the anticancer activity of IFN. Our study suggested that DUSP1 may play an important role in resistance of IFN non-responder patients.This work was supported by Basic Science Research Program through the National Research Foundation of Korea (2011-0026332).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 275. doi:1538-7445.AM2012-275
Abstract 2750: Short-chain lipids catalyse intracellular drug accumulation by a transient molecular gateway that allows plasma membrane traversal
Authors: van Hell Albert J. , Gueth Dayana Martins , Melo Manuel Nuno , Marrink Siewert Jan , Verheij Marcel 
Published: August 2012

Abstract
BACKGROUND: The lipid composition of the plasma membrane provides an effective barrier towards exogenous, potentially cytotoxic molecules. As a consequence, membrane traversal of most therapeutic drugs is sub-optimal and remains a major limitation for clinical efficacy. We previously identified a class of short-chain sphingolipids that facilitate the accumulation of amphiphilic compounds, including the cytostatic drug doxorubicin, within tumor cells, leading to improved therapy response. AIM: In order to elucidate the mechanism of action of short-chain lipids, both in vitro and model membrane studies and in silico molecular dynamics simulation experiments were designed. RESULTS: We demonstrate that short-chain sphingolipids act at the level of the plasma membrane, however, independently of lipid microdomain (raft) formation or membrane proteins. In artificial lipid membranes of well-defined compositions short-chain sphingolipids enhanced doxorubicin-membrane traversal similar to cell membranes; N-octanoyl-glucosylceramide decreased the translocation half-time of doxorubicin over liquid ordered lipid membranes by a factor 1.93 (p &lt; 0.05). In case of liquid disordered membranes, a comparable effect was observed (factor 1.91; p &lt; 0.05); lipid phase separation (raft formation) did not affect enhanced doxorubicin translocation. Molecular dynamics simulations revealed that the short-chain lipids act by assembling a transient molecular gateway for doxorubicin. Accordingly, the free energy barrier for the hydrophilic head group of the drug to dehydrate and translocate to the opposite side of the membrane is reduced by two-fold (p &lt; 0.05). CONCLUSION: Short-chain lipids catalyse the transbilayer movement of amphiphilic cytostatic drugs to achieve higher intratumoral drug accumulation, and their action is explained by the formation of a transient lipid gateway in the plasma membrane of the tumor cell, thus facilitating drug translocation and subsequent intracellular accumulation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2750. doi:1538-7445.AM2012-2750
Abstract 2756: Combination therapy of doxorubicin and the acid-sensitive albumin-binding prodrug of doxorubicin INNO-206 induces complete regressions in a xenograft pancreatic carcinoma model demonstrating excellent tolerability
Authors: Kratz Felix , Azab Samar S E E A , Zeisig Rainer , Fichtner Iduna , Warnecke Andre 
Published: August 2012

Abstract
Combination therapy of macromolecular prodrugs with clinically established low-molecular weight anticancer drugs is a field of research that has been insufficiently explored to date. Recently, we investigated the anticancer effect of a combination of doxorubicin with the clinically assessed albumin-binding prodrug INNO-206, the (6-maleimidocaproyl)hydrazone of doxorubicin, in an ovarian carcinoma xenograft model (A2780). The combination achieved complete remissions as did therapy with INNO-206 alone, but was far better tolerated. Due to these encouraging results, we extended our combination trials to a more chemoresistant tumor indication, i.e. pancreatic cancer. Thus, we compared the following weekly schedules against the MiaPaca-2 xenograft model (i.v. administration): 3 x 6 mg doxorubicin (MTD), 3 x 24 mg/kg INNO-206 (doxorubicin equivalents, MTD), 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg INNO-206, and 3 x 12 mg/kg INNO-206 followed 6 h later by 3 x 3 mg/kg doxorubicin. Whereas therapy with doxorubicin only produced a moderate tumor inhibition, all other therapy arms induced complete long-term remissions until the end of the experiment on day 44. However, there were significant differences in the tolerability as assessed by the body weight changes: whereas therapy at the MTD of INNO-206 (3 x 24 mg/kg) produced a body weight loss of −16 %, therapy with 3 x 12 mg/kg INNO-206 followed 6 h later by 3 x 3 mg/kg doxorubicin produced −7 % body weight loss, but 3 x 3 mg/kg doxorubicin followed 6 h later by 3 x 12 mg/kg INNO-206 produced a body weight gain of + 2 % as a clear indication of minimal systemic toxicity. This animal study is to best of our knowledge the first investigation demonstrating that a combination of an albumin-binding prodrug with its free parent drug not only has clear therapeutic advantages over the free drug but that the time-dependent schedule has a critical influence on the overall tolerability and results in its best case in a 100 % cure rate without causing any body weight loss. The current working hypothesis to explain this surprising effect is that the combination of doxorubicin with an albumin-binding prodrug of doxorubicin with acid-sensitive properties enables a more homogenous distribution of the drugs in the tumor due to different uptake mechanisms in a heterogeneous solid tumor (EPR effect for INNO-206 and free diffusion into the tumor interstitium for doxorubicin).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2756. doi:1538-7445.AM2012-2756
Abstract 2759: Targeting NF2 deficient meningiomas with combinations of small molecule inhibitors and radiation
Authors: Baia Gilson S. , Woodworth Graeme , Ford Eric , Riggins Gregory 
Published: August 2012

Abstract
Meningiomas are common tumors of the central nervous system and are the second most prevalent tumors in Neurofibromatosis type 2 patients. Despite their high frequency, currently there are no chemotherapeutic options for these tumors and treatment is limited to surgery and various forms of radiation therapy either as adjuvant or primary therapy. Some tumors are unresectable due to location and have histhopathologic aggressive features (designated as WHO grade II and III) with higher recurrence rates. When treatment is recommended, these tumors almost uniformly receive some form of radiation therapy. The aim of this study was to find new therapeutic options to couple with radiation, given its common use with non-surgical meningiomas. We are interested in targeting oncogenic pathways in the context of loss of the NF2 gene, which represents the most common genetic alteration in meningiomas, present is 50-70% of sporadic tumors and all of NF2 cases. We used cell-based assays searching for small molecule inhibitors that showed prevalent efficacy against NF2-deficient cells. Cell proliferation and clonogenic assays were employed to investigate the potential synergy effect of drugs and radiation combinations. Three pairs of NF2 isogenic meningioma cells (AC1, SF6717 and KT21MG1) were used to screen libraries of FDA approved compounds. The primary screen was performed using KT21MG1 cells. The top 5% compounds (86 compounds) showing preferential inhibition of NF2-deficient cells were selected for further validation. The secondary screen was used to validate useful targets with AC1 and SF6717 cells. Twelve compounds (∼15%) showed prevalent inhibitory activity on these cells. Small molecules targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor receptor (VEGFR) showed preferential synergistic inhibition of NF2 cells with radiation, compared to either radiation or drug treatment alone. Currently, preclinical testing is in progress to investigate the efficacy of these inhibitors in combination with radiation in a meningioma mouse model.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2759. doi:1538-7445.AM2012-2759
Abstract 2761: Co-administration of the short-chain sphingolipid N-octanoyl-glucosylceramide improves doxorubicin therapy by enhancing intracellular drug accumulation in vivo
Authors: van Hell Albert J. , Koning Gerben , Jonkers Jos , Verheij Marcel 
Published: August 2012

Abstract
BACKGROUND: Plasma membranes are a effective barrier that prevent exogenous therapeutics, including cytostatic drugs, to reach their intracellular targets and become active. Membrane traversal of most drugs is therefore sub-optimal and remains a major limitation for clinical efficacy. We identified a well-defined class of short-chain lipids that modulate the plasma membrane and facilitate the cellular accumulation of amphiphilic drugs, including doxorubicin. RESULTS: A liposomal co-formulation of the short-chain lipid N-octanoylglucosylceramide (GC) and doxorubicin was applied in a genetically engineered mouse (GEM) breast tumor model (Wcre;Cdh1F/F;Trp53F/F). These tumors, which are resistant to a variety of conventional and biological cytostatic therapies, responded to doxorubicin treatment when combined with the membrane modulation strategy. Co-administration of GC generated a sustained anti-tumor response and significantly improved overall survival (30 days versus 11 days for control; p &lt; 0.005). Using a nuclear isolation procedure, we showed that the presence of GC enhanced the intracellular tumor accumulation in vivo by a factor 1.9 (p &lt; 0.05). In contrast, the accumulation within normal heart tissue was not elevated. The latter data are in agreement with in vitro experiments using cultured cardiac myocytes. When compared to either clinically available formulations of doxorubicin (free or PEGylated liposomal doxorubicin) a favorable efficacy, pharmacokinetic and toxicity profile was obtained by co-formulation of GC with doxorubicin. CONCLUSION: The short-chain sphingolipid GC improves the therapeutic ratio in multi-drug resistant GEM breast tumors by enhancing the intracellular tumor accumulation of doxorubicin while limiting normal tissue exposure.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2761. doi:1538-7445.AM2012-2761