bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1623: Targeted therapy of Ewing's Sarcoma and childhood leukemia (ALL) by hybrid polymerized liposomal nanoparticles (HPLN)
Authors: Kang Hyunggyoo , Shahbazian Violette , Holly Ryan , Nagy Jon , Triche Timothy 
Published: August 2015

Abstract
Poor selectivity of the current cancer therapies causes a variety of side effects such as secondary cancers, heart or lung damage, infertility or chronic hepatitis. Therefore a reliable tumor specific therapy is urgently needed to treat cancer patients. It has been widely recognized that the recent chemotherapy could be far more effective if higher doses could be specifically delivered to the tumor and not to normal tissues. Targeted nanoparticles have shown the potential to deliver anticancer drugs to cancer cells selectively and thus to overcome unexpected cytotoxicity and limited efficacy of the chemotherapy caused by the unselective delivery to normal cells. However in addition to the selectivity the efficacy of the targeted nanoparticles depends upon two more requirements: immune evasion and timely release of contents in target cells. In spite of a lot of effort still the optimal formulation of nanoparticle for the actual translational applications was not established yet. PLN (Polymerized Liposomal Nanoparticles) can be synthesized to a variety of physiochemical properties including a broad range of composition and size. By refining the early formulations and after extensive testing, recently we could invent HPLN (Hybrid Polymerized Liposomal Nanoparticles) and demonstrate that this new type of polymeric nanoparticle overcomes many, if not most, of the deficiencies noted and has tremendous potential as an effective delivery vehicle for treating many types of cancer. In our study it was shown that the targeted HPLN with antibodies (antiCD99 or antiCD19) can inhibit the growth of Ewing's sarcoma and childhood leukemia (ALL) in a murine model. The antitumor effects were diminished pretty much by the removal of antibody or drug (Doxorubicin), which proves efficacy of the targeted HPLNs is specifically dependent upon the targeting antibody and drug. In addition, no abnormalities in liver and kidney function tests, complete blood counts or pathology of major organs are observed from tail-vein administrations. These data provide strong evidence for the safety and efficacy of this targeted HPLN delivery system of anticancer drugs to Ewing's sarcoma and childhood leukemia (ALL). In conclusion, our result showed a potential of targeted HPLN as a selective delivery vehicle of cytotoxic drugs to cancers. Hopefully this technology will be applied to treat many other different types of tumor cells in the future.
Citation Format: Hyunggyoo Kang, Violette Shahbazian, Ryan Holly, Jon Nagy, Timothy Triche. Targeted therapy of Ewing's Sarcoma and childhood leukemia (ALL) by hybrid polymerized liposomal nanoparticles (HPLN). [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 1623. doi:10.1158/1538-7445.AM2015-1623
Abstract 1632: Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma
Authors: Kock Anna , Larsson Karin , Joan Raouf , Korotkova Marina , Johnsen John-Inge , Jakobsson Per-Johan , Kogner Per 
Published: August 2015

Abstract
Background:
Tumor promoting inflammation is important for Neuroblastoma development and progression. We have previously shown that the inflammatory prostaglandin E2 (PGE2) acts as an autocrine survival factor in NB and that high expression of microsomal prostaglandin E synthase-1 (mPGES-1), essential for PGE2 synthesis, is coupled to poor clinical outcome in high risk NB. We have also shown that mPGES-1 promotes growth and survival of several malignancies.
In this study we investigate the impact of specific PGE2 targeting in NB by using a novel mPGES-1 inhibitor in vivo.
Methods: The in vivo effect of the mPGES-1 inhibitor on tumor growth was carried out using the MYCN driven transgenic mouse model that spontaneously develops an aggressive form of neuroblastoma (tg TH-MYCN model). Protein and mRNA expression of mPGES-1 and the COX enzymes in the tumors was determined by immunohistochemistry (IHC) and RT-qPCR.
Infiltration and polarization of macrophages in treated and nontreated tumors was assessed by IHC using the PAN-marker F4/80 and the M2 polarized macrophage marker CD206.
The effect of mPGES-1 inhibition on angiogenesis was determined by IHC by using the endothelial marker CD31.
Results: Expression of mPGES-1 and COX-1 could be detected in tumours from the tg TH-MYCN model. By treating the animals with the mPGES-1 inhibitor we could significantly delay the tumor growth with reduced tumor weights at sacrifice compared to tumors from untreated control animals.
To study the effect of inflammation we analyzed macrophage abundance and polarization in the treated and untreated tumors. There was no diffrence in the total level of macrophage infiltration while a significant decrese of M2 polarized macrophages was seen in the treated tumors.
Furthermore, mPGES-1 inhibition significantly reduced angiogenesis in the tumors.
Conclusion: Our results demonstrate that specific PGE2 inhibition by targeting mPGES-1 is a way of reducing NB growth.
Note: This abstract was not presented at the meeting.
Citation Format: Anna Kock, Karin Larsson, Raouf Joan, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Microsomal prostaglandin E synthase 1: a novel therapeutic target of neuroblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1632. doi:10.1158/1538-7445.AM2015-1632
Abstract 1657: The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents
Authors: Nakajima Wataru , Sharma Kanika , Hicks Mark A. , Lee June Y. , Tanaka Nobuyuki , Harada Hisashi 
Published: August 2015

Abstract
DNA damaging agents, such as cisplatin and etoposide, are employed for the treatment of a wide array of solid tumors, but the prolonged use of chemotherapeutic drugs is limited by their toxicity and by the development of resistance. To overcome these major roadblocks to improved prognosis requires mechanism-based therapeutic strategies that maximize the antitumor effect of drugs while limiting their toxicities. These agents exert anticancer effects via multiple mechanisms, yet its most prominent mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of BCL-2 family-dependent mitochondrial apoptosis. Direct therapeutic targeting of the BCL-2 family in cancer is therefore conceptually appealing but has proved remarkably challenging. This is due, in part, to the difficulty in producing effective drugs and in achieving a satisfactory therapeutic index. Also important, but less appreciated in this regard, are the potentially complex, tissue-specific interactions among the BCL-2 family members observed in different tumor types.
We have found that the expression of pro-apoptotic Noxa and anti-apoptotic MCL-1 proteins of the BCL-2 family is a critical determinant of the sensitivity to DNA-damaging agents in solid tumors; (1) MCL-1 is a labile protein and its stability is regulated by phosphorylation followed by ubiquitination and proteasome-mediated degradation; (2) Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria. Translocation of MCL-1 initiates its phosphorylation and subsequent ubiquitination, which triggers proteasome-mediated degradation; (3) The Noxa-dependent phosphorylation sites are regulated by CDK2 and are different from those phosphorylated by CDK1 in response to paclitaxel treatment; (4) Noxa is transcriptionally induced by cisplatin or etoposide. Downregulation of Noxa by shRNA strongly inhibits cisplatin-induced apoptosis. These results suggest that the Noxa/MCL-1 axis plays a critical role in apoptosis induced by DNA damaging agents and targeting Noxa/MCL-1 could be an alternative strategy to overcome the resistance to these agents.
Citation Format: Wataru Nakajima, Kanika Sharma, Mark A. Hicks, June Y. Lee, Nobuyuki Tanaka, Hisashi Harada. The role of Noxa/MCL-1 axis in solid tumors treated with DNA damaging agents. [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 1657. doi:10.1158/1538-7445.AM2015-1657
Abstract 1674: HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC
Authors: Davis Kara S. , Khan Nayel , Kemp Carolyn , Kulkarni Sucheta , Alvarado Diego , LaVallee Theresa , Grandis Jennifer R. , Duvvuri Umamaheswar 
Published: August 2015

Abstract
Background: The phosphoinositide 3-kinase (PI3K) pathway is thought to be the most frequently mutated oncogenic pathway in head and neck squamous cell carcinoma (HNSCC). This pathway is often further activated by deregulated receptors such as the epidermal growth factor receptor family. HER3 has a direct phosphorylation site with the regulatory subunit of PIK3CA, and is being investigated as a potential co-target to increase anti-tumor effects of PI3K inhibition. In this investigation, we use blocking antibodies against HER3 and its ligand, neuregulin β-1, (KTN3379) and PIK3CA (BYL719) to investigate the effect of HER3 in modulating response to PI3K inhibition.
Methods and Results: Treatment with neuregulin β-1 significantly increased phosphorylation of HER3, AKT, and S6 across HNSCC, regardless of baseline level of HER3 expression. HER3 inhibition (KTN3379) consistently abrogated these effects, and decreased baseline phosphorylation of HER3. Combined blockade of HER3 (KTN3379) and PI3K (BYL719) inhibits the growth of HNSCC cell lines more effectively than inhibition of a single receptor alone, in both cell proliferation and colony formation assays. Combined treatment decreases phosphorylation of AKT and S6 more effectively than inhibition with either drug in some HNSCC cell lines. Treatment with neuregulin β-1 diminishes the inhibitory effect of BYL719 on HNSCC cell growth. Furthermore, treatment of some HNSCC cell lines with BYL719 led to upregulation of the HER3 pathway in HNSCC cell lines by Western blotting analysis, suggesting a possible role of HER3 in PI3K resistance.
Conclusion: HER3 interacts with PI3KCA, and the PI3K pathway in multiple HNSCC cell lines, and combined blockade leads to pronounced effects in pre-clinical models of HNSCC. These findings suggest that HER3 blockade, may be efficacious when combined with PI3K pathway inhibition.
Citation Format: Kara S. Davis, Nayel Khan, Carolyn Kemp, Sucheta Kulkarni, Diego Alvarado, Theresa LaVallee, Jennifer R. Grandis, Umamaheswar Duvvuri. HER3 inhibition potentiates anti-tumor effects of PI3K inhibitors in pre-clinical models of HNSCC. [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 1674. doi:10.1158/1538-7445.AM2015-1674
Abstract 1676: An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma
Authors: Kato Kazunori , Sakamoto Atsushi , Kojima Taro , Hasegawa Toshio , Ikeda Shigaku 
Published: August 2015

Abstract
EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in aggressive human cancers, including melanoma. Recently, EphA2 has been found to be integral player in cancer formation and expected as a target for antibody therapy. In this study, we have investigated the therapeutic effect of various anti-EphA2 mAbs that were recently established in our laboratory. Cell surface expression of EphA2 on melanoma cell lines was analyzed by flow cytometry and therapeutic effects of anti-EphA2 mAbs were investigated using cell proliferation, cell migration, invasion and antibody-mediated drug cytotoxicity assays. We found that human melanoma cell lines expressed EphA2 on their surface, while normal dermal fibroblasts and melanocytes were negative for EphA2. Recombinant human protein of EphrinA1 (a natural ligand for EphA2) and anti-EphA2 mAbs could not suppress melanoma cell proliferation, however, one of agonistic anti-EphA2 mAb, termed SHM16, inhibited metastatic potential such as migration and invasive properties of human melanoma. In contrast, an antagonistic anti-EphA2 mAb, SHM17, had no effect on migration and invasive assay. In addition, drastic growth inhibition and cell cytotoxicity were found in targeted delivery of immunotoxin by SHM16. In conclusion, these findings indicate a promising role for EphA2 as a target for antibody treatment in melanoma and enhance the therapeutic effect as an agonistic antibody to EphA2.
Citation Format: Kazunori Kato, Atsushi Sakamoto, Taro Kojima, Toshio Hasegawa, Shigaku Ikeda. An agonistic antibody to EphA2 exhibits anti-tumor effect to human melanoma. [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 1676. doi:10.1158/1538-7445.AM2015-1676
Abstract 1681: Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4
Authors: Flanagan Ken , Li Lauri W. , Lorenzana Carlos , Tam Stephen J. , Liu Yue , Dolan Philip J. , Alexander Lana , Salmans Josh , Barbour Robin M. , Higaki Jeffrey N. , Nijjar Tarlochan , Zago Wagner , Yednock Ted A. , Kinney Gene 
Published: August 2015

Abstract
Melanoma cell adhesion molecule (MCAM/CD146) is highly expressed on a subset of many tumor types including melanoma and glioblastoma, and expression of MCAM correlates with enhanced cellular invasion, increased metastasis, and poor patient prognosis. The expression of MCAM on tumor cells confers unique migratory and adhesion capacity, which, if specifically targeted, could result in interruption of multiple biological processes required for tumor growth and spread. Although a role for MCAM in tumor progression has long been appreciated, the unidentified ligand for MCAM precluded the development of targeted approaches to inhibit extracellular interactions mediated by MCAM. Recently, we identified the MCAM ligand as laminin alpha 4. Laminin alpha 4 is present within the extracellular matrix of the tumor in addition to the vasculature throughout the body, providing an adhesive substrate for MCAM expressing tumor cells both within the tumor microenvironment and the blood vessels. The presence of laminin alpha 4 within the tumor and the vasculature may allow for a biological interaction by which MCAM mediated adhesion could be involved in both the homotypic aggregation required for tumor growth, in addition to the vascular adhesion required for the processes of metastasis and angiotropism. We generated monoclonal antibodies that bind to the epitope required for MCAM interactions with laminin alpha 4. Such antibodies entirely abrogate interactions of the tumor cell with laminin alpha 4 in vitro. Furthermore, we characterized the inhibition of tumor growth in vivo mediated by neutralization of MCAM/laminin alpha 4 interactions. Notably, tumor growth was delayed by blockade of MCAM, but required inhibition of both the MCAM expressed by the tumor, as well as vascular MCAM. We further characterize the unique pattern of MCAM expression on tumor cells within the perivascular extracellular matrix in human tumors, which suggest that these interactions are involved in human disease pathogenesis. Thus, antibodies neutralizing the interaction between MCAM and laminin alpha 4 have potential to inhibit a critical molecular interaction used by myriad tumor types.
Citation Format: Ken Flanagan, Lauri W. Li, Carlos Lorenzana, Stephen J. Tam, Yue Liu, Philip J. Dolan, Lana Alexander, Josh Salmans, Robin M. Barbour, Jeffrey N. Higaki, Tarlochan Nijjar, Wagner Zago, Ted A. Yednock, Gene Kinney. Inhibition of tumor growth in vivo through neutralization of the interaction of MCAM with laminin alpha 4. [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 1681. doi:10.1158/1538-7445.AM2015-1681
Abstract 1684: Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models
Authors: Sommer Anette , Kopitz Charlotte , Schatz Christoph , Zierz Ruprecht , Schuhmacher Joachim , Wittemer-Rump Sabine , Prins Klaas , Braun Manuela , Reetz Frank , Kreft Bertolt , Huynh Hung T. , Ziegelbauer Karl 
Published: August 2015

Abstract
Antibody-drug conjugates (ADC) represent a promising therapeutic approach for treatment of cancer. We have developed a novel ADC directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric, breast, and ovarian cancer and thus represents a potential therapeutic target for treatment of FGFR2-positive cancer patients with ADC-based therapy.
FGFR2-ADC consists of a fully human anti-FGFR2-Ab (BAY 1179470) conjugated via a stable linker to a novel auristatin cytotoxic agent licensed from Seattle Genetics. FGFR2-ADC exhibits low nM to sub-nM potency in vitro in a panel of FGFR2-positive cancer cells lines (SNU-16, MFM-223, NCI-H716) while being inactive against FGFR2-low or -negative cell lines (MDA-MB-231, HEK-293, BaF/3) and highly selective versus a control ADC.
FGFR2-ADC is highly efficacious in monotherapy and results in tumor growth inhibition in the gastric cancer xenograft model SNU-16 and tumor regression in the breast cancer xenograft model MFM-223. FGFR2-ADC induces tumor stasis in the colorectal cancer xenograft model NCI-H716 and regrown tumors are sensitive to a second treatment cycle of FGFR2-ADC.
FGFR2-ADC shows high efficacy in vivo in monotherapy in patient-derived (PDX) FGFR2-positive murine xenograft models, e.g. in the ovarian cancer model OV30-0511A. FGFR2-ADC is also efficacious in the gastric cancer PDX model GC10-0608 and the breast cancer model MAXF857.
The toxophore metabolite of FGFR2-ADC was more than 30-fold enriched in tumors versus other organs (liver, spleen, kidneys) in NCI-H716 tumor-bearing mice.
Based on the preclinical efficacy, PK and tolerability data, evaluation of FGFR2-ADC in cancer patients appears warranted. A Phase I study is planned.
Citation Format: Anette Sommer, Charlotte Kopitz, Christoph Schatz, Ruprecht Zierz, Joachim Schuhmacher, Sabine Wittemer-Rump, Klaas Prins, Manuela Braun, Frank Reetz, Bertolt Kreft, Hung T. Huynh, Karl Ziegelbauer. Preclinical anti-tumor efficacy of FGFR2-ADC BAY 1187982 in patient-derived gastric, breast and ovarian cancer models. [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 1684. doi:10.1158/1538-7445.AM2015-1684
Abstract 1693: ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models
Authors: Smith Roger A. , Damle Nitin K. , Reddy Sanjeeva P. , Yurkovetskiy Alex , Bodyak Natalya , Yin Mao , Gumerov Dmitry , Ter-Ovanesyan Elena , Qin Liu , Park Peter U. , Lowinger Timothy B. , Gupta Sandeep 
Published: August 2015

Abstract
ASN004 is an Antibody Drug Conjugate (ADC) that targets the 5T4 oncofetal antigen (trophoblast glycoprotein), which is highly expressed in a wide range of malignant tumors, while having very limited expression in normal tissues. ASN004 incorporates a novel single-chain homo-dimer antibody, Fleximer® linker technology (Mersana Therapeutics), and several cytotoxic dolastatin (auristatin) analog warheads per ADC molecule (drug/antibody ratio ∼15). ASN004 shows high affinity for the 5T4 antigen and for 5T4-expressing tumor cells. As well, ASN004 shows potent cytotoxicity that is selective for 5T4-expressing tumor cells. ASN004 provides strong tumor regression and tumor-free survivors in multiple tumor xenograft models, at well-tolerated doses as low as 0.3 mg/kg iv. Furthermore, ASN004 causes tumor regression when administered to xenografts bearing more advanced (500 mm3) tumors. Robust, potent efficacy for ASN004 has also been demonstrated in head-to-head comparison studies with relevant reference ADCs. A favorable pharmacokinetics profile was observed in rodents and primates. Dose-range finding exploratory toxicology studies have been completed in both pharmacological and non-pharmacological non-clinical species. Efforts toward IND-enabling safety studies with this promising new agent are in progress.
Citation Format: Roger A. Smith, Nitin K. Damle, Sanjeeva P. Reddy, Alex Yurkovetskiy, Natalya Bodyak, Mao Yin, Dmitry Gumerov, Elena Ter-Ovanesyan, Liu Qin, Peter U. Park, Timothy B. Lowinger, Sandeep Gupta. ASN004, a novel 5T4-targeted Dolaflexin™ antibody drug conjugate, causes complete regression in multiple solid tumor models. [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 1693. doi:10.1158/1538-7445.AM2015-1693