bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4359: Characterization of GalNAc-conjugated generation 2.5 ASOs in DEN and DEN/CCL4-induced HCC tumors
Authors: Schmidt Joanna , Jo Minji , Zhou Tianyuan , Kim Youngsoo , MacLeod A. R. 
Published: August 2015

Abstract
The worldwide rate of hepatocellular carcinoma (HCC) occurrence is rising rapidly; however, outside of transplantation, few effective treatment options are available. Hepatocellular carcinogenesis is a complex, multistep process involving many genetic alterations, often occurring in targets that are considered “undruggable” by conventional therapeutic modalities. Antisense oligonucleotide (ASO) technology offers the potential to target these undruggable pathways in HCC tumors in vivo and to determine the sensitivity of HCC to the ablation of these pathways. Using either the diethylnitrosamine (DEN) induced mouse HCC model or DEN in combination with the profibrotic agent carbon tetrachloride (CCl4), we first examined gene expression changes in induced HCC tumors. DEN-induced HCC has a very long latency period (∼8 months). We demonstrate that mice injected with DEN and CCl4 developed HCC with a shorter latency and a higher tumor incidence. We also identified several genes of interest that could potentially be HCC drivers and targets for ASO therapy. Conjugation of ASOs with N-acetyl D-galactosamine (GalNAc) has been shown to increase ASO activity &gt;10x in normal liver. Here we demonstrate that GalNAc conjugated ASOs show similar increased potency in HCC tumors and the complete depletion of Myd88 protein levels. Importantly, in addition to the ability to potently inhibit Myd88 levels in tumors, GalNAc-conjugated Myd88 ASOs also resulted in significantly reduced tumor burden. These data demonstrate that GalNAc-conjugated Gen 2.5 ASOs have potent activity in HCC tumors and that Myd88 maybe be an attractive therapeutic target in this disease.
Citation Format: Joanna Schmidt, Minji Jo, Tianyuan Zhou, Youngsoo Kim, A. R. MacLeod. Characterization of GalNAc-conjugated generation 2.5 ASOs in DEN and DEN/CCL4-induced HCC tumors. [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 4359. doi:10.1158/1538-7445.AM2015-4359
Abstract 4372: Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling
Authors: Zhu Bing , Lee Kevin , Canzoneri Joshua , Ramirez-Alcantara Veronica , Sigler Sara , Gary Bernard , Butler Ethan , Keeton Adam , Chen Xi , Boyd Michael , Piazza Gary 
Published: August 2015

Abstract
We recently reported that phosphodiesterase 10A (PDE10) is overexpressed in colon tumors and essential for colon tumor cell growth (Li et al., Oncogene 2014), but a role in lung cancer has not been well studied. Human non-small cell lung cancer (NSCLC) cell lines were found to express appreciably higher PDE10 levels compared with normal airway epithelial cells, while silencing of PDE10 expression with siRNA or inhibition of PDE10 activity with small molecule inhibitors selectively inhibits NSCLC cell growth. Here we study the mechanism by which PDE10 inhibitors suppress NSCLC cell growth. At concentrations effective for inhibiting NSCLC cell growth, the PDE10 inhibitor, PQ10 rapidly increases intracellular cGMP levels as determined by a luminescence biosensor assay. Within the same concentration range and time period, PQ10 activates PKA and PKG, demonstrated by an increase in phosphorylation of the substrate, VASP at Ser157 and Ser239, respectively. Under the same conditions, PQ10 suppresses the phosphorylation of Erk1/2 (Thr202/Tyr204), MEK1/2 (Ser217/Ser221) and down-stream p90RSK (Ser380). Similarly, PQ10 increases the phosphorylation of β-catenin at Ser552, but showed no effect on phospho-Ser675 levels. After longer durations of treatment, PQ10 reduces β-catenin levels, as well as proteins that are regulated by β-catenin-dependent TCF/LEF-transcriptional activity, such as survivin and cyclin D1. These effects were mimicked by a novel structurally unrelated PDE10 inhibitor, ADT-020 that selectively inhibits the growth of NSCLC cells and increases cGMP levels in a manner similar to PQ10. ADT-020 also activates PKG in NSCLC cells demonstrated by higher phospho-Ser239 VASP levels and lower β-catenin and survivin levels. These observations suggest that PDE10 inhibition and activation of PKG can simultaneously suppress ras and Wnt signaling that are essential for lung tumor cell growth. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza).
Citation Format: Bing Zhu, Kevin Lee, Joshua Canzoneri, Veronica Ramirez-Alcantara, Sara Sigler, Bernard Gary, Ethan Butler, Adam Keeton, Xi Chen, Michael Boyd, Gary Piazza. Phosphodiesterase 10A inhibition suppresses lung tumor cell growth by activating PKG to inhibit ras and Wnt signaling. [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 4372. doi:10.1158/1538-7445.AM2015-4372
Abstract 4395: Strategy to overcome inherent TRAIL-based therapeutic limitations
Authors: Oh Yumin , Swierczewska Maggie , Lee Seulki 
Published: August 2015

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent because of its selective ability to induce apoptosis in activated immune cells or cancer cells with minimal toxicity in normal cells. However, a short biological half-life and the development of inherent TRAIL resistance in a variety of cancer cells, including colorectal cancer cells (CRC), results in the poor performance of TRAIL as a chemotherapeutic agent. To overcome these limitation, we developed PEGylated TRAIL (PEG-TRAIL) to compensate the short half-life of TRAIL offering improved pharmacokinetics in non-human primates. In parallel, we found that pre-sensitization with doxorubicin resulted in the upregulated expression of the functional TRAIL receptor, DR5, in highly TRAIL-resistant HT-29 cells by Western blotting and qRT-PCR. Although neither individual treatment of doxorubicin nor TRAILPEG induced apoptosis, pre-sensitization with doxorubicin followed by PEG-TRAIL induced significant apoptosis through the activation of both extrinsic and intrinsic apoptotic pathways promoted by the cleavage of caspases 8, 9, and 3. DR5, but not DR4, was recruited to the TRAIL-induced Death-Inducing Signaling Complex (DISC) within HT-29 cells pre-sensitized with doxorubicin, suggesting a TRAIL/DR5 specific pathway in CRC. To maximize the therapeutic efficacy of the sensitizer in vivo, doxorubicin was encapsulated in tumor-homing hyaluronic acid nanoparticles (HAC/DOX). Confocal microscopy and HPLC analysis enabled us to observe the efficient uptake and biodistribution of HAC/DOX in tumor tissues from xenografted HT-29 cells. HAC/DOX effectively sensitized the xenograft tumor, bearing the highly TRAIL-resistant HT-29 cells to TRAIL-induced apoptosis through the upregulated expression of DR5 and activation of caspases. Our study suggests an innovative approach to overcome the inherent TRAIL-based therapeutic limitations by introducing long-acting TRAIL and a tumor-homing TRAIL sensitizer to induce cancer cell-specific apoptosis in TRAIL-resistant CRC, particularly in physiological conditions.
Citation Format: Yumin Oh, Maggie Swierczewska, Seulki Lee. Strategy to overcome inherent TRAIL-based therapeutic limitations. [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 4395. doi:10.1158/1538-7445.AM2015-4395
Abstract 4400: Anti-tumor activity of liposomal docetaxel prodrug MNK-010 on PC3 human prostate xenografts in mice
Authors: Fitch Richard M. , Wojdyla Jolette K. , Blackledge James A. , McGhee William D. 
Published: August 2015

Abstract
The anti-mitotic taxanes are one of the most important families of anticancer drugs that have broad anti-tumor activity and are widely used for a variety of human cancer types. However, the taxanes are limited by a number of serious pharmacological and toxicological effects, including dose limiting myelosuppression, neurotoxicity and serious hypersensitivity reactions. We are developing a unique delivery system for docetaxel, comprised of a PEGylated liposomal nanoparticle containing a prodrug of docetaxel to improve solubility, tolerability and increase efficacy through improved pharmacokinetics and biodistribution. In this study we evaluated the antitumor activity of MNK-010 on the growth of established human PC3 xenografts in male immunodeficient mice. This study tested the hypothesis that MNK-010 can provide greater efficacy than Taxotere (docetaxel) at equivalent maximum tolerated doses (MTD) in mice implanted with human PC3 tumor cells. Male nude mice bearing PC3 human prostate xenografts were given two or four intravenous (IV) doses of MNK-010, Taxotere or saline. Dosing intervals were twenty-one days for two cycles or every four days for four cycles. The doses of Taxotere and MNK-010 were based on maximum tolerated dose (MTD) or highest dose tested for a given dose interval. Tumor volume was measured twice per week using the Biopticon tumor imaging system and tumor volume data was analyzed to determine tumor growth delay and partial tumor regression. Survival analysis was conducted and median survival time determined. MNK-010 significantly (p &lt;0.05) inhibited PC3 human tumor growth in nude mice at all dose regimens evaluated compared to saline and Taxotere treatment. MNK-010 delayed tumor growth up to 145 days, which was 59 days longer than Taxotere at its MTD. MNK-010 also partially regressed 90% - 100% of tumors in all dose groups. This antitumor activity contributed to achieving median survival of 177 days, which was 150 days longer than saline control and 80 days longer than Taxotere at its MTD. This study demonstrated that Mallinckrodt Pharmaceuticals’ PEGylated liposomal docetaxel prodrug nanoparticle MNK-010 is an active antitumor agent in the PC3 prostate xenograft and possess significantly greater antitumor activity compared to the standard of care Taxotere.
Citation Format: Richard M. Fitch, Jolette K. Wojdyla, James A. Blackledge, William D. McGhee. Anti-tumor activity of liposomal docetaxel prodrug MNK-010 on PC3 human prostate xenografts in mice. [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 4400. doi:10.1158/1538-7445.AM2015-4400
Abstract 4401: Tumor-associated antigen gene-loading polyplex micelle is a promising platform for anti-cancer DNA vaccine
Authors: Cui Lin , Furugaki Kouichi , Osada Kensuke , Kataoka Kazunori , Nakano Kenji 
Published: August 2015

Abstract
Backgrounds: Polyplex micelle attracts an increasing attention as a gene carrier, because of efficient gene transduction and biocompatibility in vivo. In this study, we examined the potential of polyplex micelle carrying genes encoding tumor-associated antigen (TAA): squamous cell carcinoma antigen recognized by T cells-3, CD40L and GM-CSF as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC).
Methods and Results: Intraperitoneal administration of polyplex micelles were predominantly distributed and expressed in the lymph nodes, spleen and liver. The triple DNA vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer compared with mock controls, of which long-survivor mice induced complete rejection of re-challenged CT26 tumors. The DNA vaccine also inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung cancers in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+-DC, CD4+ and CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ cells using their neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine.
Conclusions: TAA/CD40L+GM-CSF gene-loaded polyplex micelle is a novel vaccine platform to elicit tumor rejection immunity regardless of recipient's MHC-haplotype.
Note: This abstract was not presented at the meeting.
Citation Format: Lin Cui, Kouichi Furugaki, Kensuke Osada, Kazunori Kataoka, Kenji Nakano. Tumor-associated antigen gene-loading polyplex micelle is a promising platform for anti-cancer DNA vaccine. [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 4401. doi:10.1158/1538-7445.AM2015-4401
Abstract 4407: Novel mitochondria-targeted Doxorubicin Prodrug for colorectal cancer and hepatocellular carcinoma: In vitro studies
Authors: Jia Jemianne , Xing Minzhi , Ling Xiaoxi , Bai Mingfeng , Kim Hyun S. 
Published: August 2015

Abstract
Purpose:
The 18-kDa translocator protein (TSPO) in mitochondria is proapoptotic and upregulated in several types of cancers, particularly in colorectal cancer (CRC). This study aimed to develop a mitochondria-targeted doxorubicin prodrug and to investigate its cytotoxicity in human CRC (TSPO positive) and HCC (TSPO negative) cell lines.
Methods:
Mitochondria-targeted Doxorubicin Prodrug was synthesized by conjugation of a functional TSPO ligand with doxorubicin via an enzyme-cleavable linkage. Fluorescence cell viability assays in HT29, HCT116, HepG2 and Hep3B cells incubated with 5, 10, 25 and 50μM of Prodrug vs. Doxorubicin alone were performed using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, MI, USA) at 6, 12, 24, 48, 60 and 72 hrs. T-tests were used for all comparisons (significance &lt;.05).
Results:
Significantly decreased cell viability in TSPO positive CRC cell lines (HCT116 and HT-29) with both the prodrug and doxorubicin vs. controls was observed (p&lt;0.05). In HCT116, 10 and 25μM prodrug demonstrated significantly higher cytotoxicity vs. doxorubicin at 48 and 60 hrs, with plateau in effect at 72 hrs; 50μM prodrug had significantly higher cytotoxicity vs. doxorubicin alone at all time points (p&lt;.05 for all). In HT-29, 25 and 50μM prodrug had significantly higher cytotoxicity vs. doxorubicin at 48 and 60 hrs (p&lt;.05). In TSPO negative HCC cell lines (Hep3B and HepG2), prodrug and doxorubicin vs. control showed significantly decreased cell viability at all time points except for 10μM at 24 hrs; 25 and 50μM prodrug demonstrated similar cytotoxicity vs. doxorubicin at all time points except at 60 hours (p&lt;.05 for all).
Conclusion:
Our novel mitochondria-targeted doxorubicin prodrug demonstrated superior cytotoxicity compared to doxorubicin in human CRC cell lines.
Citation Format: Jemianne Jia, Minzhi Xing, Xiaoxi Ling, Mingfeng Bai, Hyun S. Kim. Novel mitochondria-targeted Doxorubicin Prodrug for colorectal cancer and hepatocellular carcinoma: In vitro studies. [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 4407. doi:10.1158/1538-7445.AM2015-4407
Abstract 4432: A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo
Authors: Anreddy Nagaraju , Patel Atish , Zhang Yun-Kai , Wang Yi-Jun , Shukla Suneet , Kathawala Rishil J. , Kumar Priyank , Gupta Pranav , Ambudkar Suresh V. , Wurpel John ND , Chen Zhe-Sheng 
Published: August 2015

Abstract
ABCG2 is a member of the ABC transporter superfamily, which has been implicated in the development of multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been significantly increased in some solid tumors and hematologic malignancies, which is correlated to poorer clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter impacts resistance to the chemotherapeutic drugs. To enhance the chemosensitivity of cancer cells, attention has been focused on MDR modulators. In this study, we investigated the ability of a tetrodotoxin-resistant sodium channel blocker, A-803467 to reverse ABCG2-mediated MDR. We found that A-803467 at non-toxic concentration could significantly increase the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. Mechanistic studies indicated that A-803467 (7.5 μM) significantly increased the intracellular accumulation of mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression level. In addition, A-803467 stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that A-803467 might be a substrate of ABCG2. Binding interactions of A-803467 were found to be in transmembrane region of homology modeled human ABCG2. Interactions of A-803467 with ABCG2 were relatively stronger when compared to the interactions of topotecan with ABCG2. Furthermore, A-803467 (30 mg/kg) with topotecan (3 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. Our findings indicate that A-803467 has the potential to be used in combination with ABCG2 chemotherapeutic substrates to improve the response in drug resistant cancers.
Citation Format: Nagaraju Anreddy, Atish Patel, Yun-Kai Zhang, Yi-Jun Wang, Suneet Shukla, Rishil J. Kathawala, Priyank Kumar, Pranav Gupta, Suresh V. Ambudkar, John ND Wurpel, Zhe-Sheng Chen. A-803467, a tetrodotoxin-resistant sodium channel blocker, modulates ABCG2-mediated MDR in vitro and in vivo. [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 4432. doi:10.1158/1538-7445.AM2015-4432
Abstract 4477: A 5-nitrobenzoate-derived compound elicits anti-cancer metastatic activity by inhibition of poloplanin-stimulated tumor cell-induced platelet aggregation
Authors: Chang Yao-Wen , Hsieh Pei-Wen , Chong Kowit-Yu , Tseng Ching-Ping 
Published: August 2015

Abstract
Tumor cells dissemination and survival within the vascular system play an important role in cancer metastasis and is a clinical challenge for post-surgical cancer management. Podoplanin (PDPN) is one of the frequently over-expressed proteins in squamous cell carcinoma. By binding to platelet C-type lectin-like receptor 2 (CLEC-2), PDPN stimulates tumor cell-induced platelet aggregation (TCIPA) and facilitates cancer cell metastasis. In this study, a series of 5-nitrobenzoate-derived compounds were synthesized to screen for anti-cancer metastasis compounds that elicit functional blockage of PDPN-stimulated CLEC-2 activation and TCIPA. Platelet aggregation assays indicate that the small molecule compound 2CP selectively inhibited PDPN-induced platelet aggregation and the TCIPA of C6/Lung and osteosarcoma cells which expressed high levels of PDPN protein. Mouse tail bleeding time assay revealed that 2CP did not cause deleterious effects on normal blood hemostasis. In xenograft experimental metastasis model, 2CP possessed in vivo anti-cancer metastatic activity and augments the therapeutic efficacy of cisplatin; both the formation of pulmonary tumor foci and the body weight loss associated with the increased tumor burden were attenuated by combined treatment of 2CP and cisplatin. In conclusion, we present a novel and non-cytotoxic small molecule compound 2CP that elicits specific inhibitory effects on tumor cells-platelet interaction through intervening PDPN/CLEC-2 interaction and PDPN-mediated TCIPA. The findings are valuable for future application of 2CP in the prevention and treatment of cancer metastasis.
Citation Format: Yao-Wen Chang, Pei-Wen Hsieh, Kowit-Yu Chong, Ching-Ping Tseng. A 5-nitrobenzoate-derived compound elicits anti-cancer metastatic activity by inhibition of poloplanin-stimulated tumor cell-induced platelet aggregation. [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 4477. doi:10.1158/1538-7445.AM2015-4477
Abstract 4484: BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition
Authors: Moreau Benoit , Alargova Rossitza , Brockman Adam , Whalen Kerry , Quinn Jamie , Meetze Kristan , Bazinet Patrick , DuPont Michelle , Krawiec Beata , Kriksciukaite Kristina , Lemelin Charles , LimSoo Patrick , Oller Haley , Ramstack Mike , Rockwood Danielle , Shinde Rajesh , Singh Sukhjeet , White Brian , AuYeung Tsun , Dunbar Craig , Bilodeau Mark , Wooster Richard 
Published: August 2015

Abstract
Platinum drugs have proven to be effective in treating cancer, for example &gt;90% of men with testicular cancer are cured with a platinum therapeutic. Platinum drugs are also widely used for the adjuvant treatment of common cancers such as those of the lung, colon and ovary. However for the majority of tumor types the clinical response rates for platinum therapies are low, for example the 1 year survival rate for lung cancer patients treated with platinum therapeutics is ∼30%. The key limitations of the existing platinum therapies are the dose limiting toxicities that restrict dose and/or duration of therapy and the absence of personalization that targets the drugs to the patients most likely to benefit. To address these issues we have designed a novel prodrug of cisplatin, BTP-114. On infusion into the blood a maleimide group on BTP-114 covalently attaches to serum albumin. This prolongs the circulation of BTP-114 in plasma and alters the biodistribution of the compound. Importantly the dose of platinum can be increased and the amount of platinum that accumulated in xenograft tumor tissue and the amount of platinum bound to tumor DNA are both increased relative to cisplatin. An elevation of DNA damage in tumor cells in vivo is observed with BTP-114. Together the properties of BTP-114 result in pronounced and sustained tumor growth inhibition compared to cisplatin. In parallel to the discovery of BTP-114 we have explored potential biomarkers to predict which tumors are most likely to respond. These data will be presented towards developing BTP-114 as a personalized platinum medicine for cancer patients.
BM and RA contributed equally to this work.
Citation Format: Benoit Moreau, Rossitza Alargova, Adam Brockman, Kerry Whalen, Jamie Quinn, Kristan Meetze, Patrick Bazinet, Michelle DuPont, Beata Krawiec, Kristina Kriksciukaite, Charles Lemelin, Patrick LimSoo, Haley Oller, Mike Ramstack, Danielle Rockwood, Rajesh Shinde, Sukhjeet Singh, Brian White, Tsun AuYeung, Craig Dunbar, Mark Bilodeau, Richard Wooster. BTP-114: An albumin binding cisplatin prodrug with improved and sustained tumor growth inhibition. [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 4484. doi:10.1158/1538-7445.AM2015-4484