bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A284: Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment.
Authors: Lee Kwangho , Kim Hyoung Rae , Cho Sung Yun , Jung Hee Jung , Ha Jae D. , Yun Chang-Soo , Kim Pilho , Park Chi Hoon , Lee Chong Ock 
Published: August 2014

Abstract
Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been recently elucidated as a potential target for various cancers due to its implications of tumorigenesis by ALK gene mutations, overexpressions, and amplifications. ALK was first identified in 1994 as a part of nucleophosmin NPM-ALK fusion gene in 60% of anaplastic large-cell lymphoma (ALCL). In late 2007, EML4-ALK fusion gene was found in 3∼7% of non-small cell lung cancer (NSCLC), and a kind of ALK fusion genes are found one by one in various cancers such as DLBCL, inflammatory myofiblastic tumor (IMT), plasmacytoma, esophageal cancer, and ovarian cancer. More over mutated ALK is much implicated in neuroblastoma and thyroid carcinoma. Crizotinib (Xalkori) was the first small molecule inhibitor which was approved as a treatment of NSCLC including ALK fusion gene by FDA in 2011. Crizotinib, a potent inhibitor of both c-Met and ALK tyrosine kinases is a 3-benzyloxy-2-aminopyridine derivative derived from c-Met inhibitors and surprisingly its overall clinical benefit was 57 %. However, its clinical efficacy is limited by drug-resistance mutations, particularly the gatekeeper L1196M mutation. Unlike their aminopyridine-based core scaffold, a pyrimidine-based inhibitor has been identified for the ALK-related inhibition and shown a potent activity to EML4-ALK wild type and other mutants including EML4-ALK L1196M. In this paper, we designed and synthesized a new series of pyrimidine derivatives to discover a new ALK inhibitor which is well-matched with crizotinib and LDK378 in docking study. KRCA-0008 has been identified as a highly potent and selective ALK inhibitor with potency profiles (ALK wt, IC50=12 nM). It has excellent activities both ALK mutants (L1196M, C1156Y, F1174L, R1275Q) and BaF3 ALK L1196M cell line. PK profiles were excellent and KRCA-0008 was safe in Ames test, chromosomal aberration assay, micronucleus asssay, and acute toxicity. Also, we observed KRCA-0008 is chemically and metabolically very stable and no CYP and hERG inhibitions. In vivo xenograft mouse model (H3122 NSCLC) model study, KRCA-0008 shows moderate tumor growth inhibition without significant body weight change.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A284.
Citation Format: Kwangho Lee, Hyoung Rae Kim, Sung Yun Cho, Hee Jung Jung, Jae Du Ha, Chang-Soo Yun, Pilho Kim, Chi Hoon Park, Chong Ock Lee. Anaplastic lymphoma kinase (ALK) inhibitors for cancer treatment. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A284.
Abstract A294: Antitumor activity of AMG900, an Aurora kinase inhibitor, alone or in combination with chemotherapeutic agents on H295A adrenocortical carcinoma cell line.
Authors: Borges Kleiton S. , Andrade Augusto F. , Silveira Vanessa S. , Antonio David S.M , Vasconcelos Elton J.R. , Antonini Sonir R.R. , Tone Luiz G. , Scrideli Carlos A. 
Published: August 2014

Abstract
Pediatric adrenocortical tumors (ACT) are rare malignancies and in advanced disease the treatment has a small impact on overall survival. Previous study from our group suggests that AURKA and AURKB overexpression in pediatric ACT may be related to more aggressive disease. These genes are involved in the maintenance of the genome integrity during cell cycle division and they have been considered as new targets to cancer treatment. The present study shows the previous results of the effects of the new Aurora kinase inhibitor AMG900, associated or not with standard chemotherapeutic agents on adrenocortical carcinoma cell line H295A.
Cell proliferation was assessed by Giemsa staining and apoptosis was performed by flow cytometry. Quantitative RT-PCR assays were used to determine the mRNA expression after AMG900 exposition. Drug combination analysis was made based on Chou-Talalay method. Hormones dosage assay was carried out to evaluate the effects of the Aurora kinase inhibitor on hormone secretion.
AMG900 inhibited cell proliferation and caused apoptosis in a dose dependent manner in H295A cells. Moreover, it acted synergistically with doxorubicin, cisplatin and etoposide in the apoptosis induction, but only with doxorubicin in the proliferation inhibition. AMG900 treatment induced the mRNA expression of the genes p53, p21, and GDF15 and effectively inhibited dehydroepiandrosterone, androstenedione, cortisol and testosterone secretion.
These data suggest that Aurora kinase inhibition by AMG900 may be a new therapeutic approach to adrenocortical carcinoma treatment.
Financial Support: FAPESP (10/07020-9 and 12/09391-0)
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A294.
Citation Format: Kleiton S. Borges, Augusto F. Andrade, Vanessa S. Silveira, David S.M Antonio, Elton J.R. Vasconcelos, Sonir R.R. Antonini, Luiz G. Tone, Carlos A. Scrideli. Antitumor activity of AMG900, an Aurora kinase inhibitor, alone or in combination with chemotherapeutic agents on H295A adrenocortical carcinoma cell line. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A294.
Abstract A30: The prevalence of RON isoforms in experimental and clinical tumor samples.
Authors: Amatulli Michael 
Published: August 2014

Abstract
The role of the RON receptor or MST1R in tumor development has been demonstrated in multiple tumor models. As a result of alternative pre-mRNA splicing, protein truncation and alternative transcription, several isoforms of RON (WT, delta-55, delta-110, delta-155, delta-160, delta-165, and delta-170) are known to exist. In contrast to WT RON, which localizes to the cell membrane, some RON variants (delta-155, delta-165) are constitutively active in the cytoplasm. Despite the previously documented role of RON in tumor development, the prevalence of individual RON isoforms in different tumor tissues remains largely unknown. Due to a high level of conservation between the RON isoforms which results largely from in frame exon 5, 6 and/or 11 deletions, protein-based variant characterization is unfeasible. We therefore decided to focus on an mRNA-based detection technique using a PCR-based sizing assay. In total 63 samples, including 28 tumor cell lines, 16 patient-derived tumor models and 19 colorectal tumors were analyzed. Total RNA was isolated and converted to cDNA followed by standard PCR amplification and Bio-Analyzer quantification and analysis for specific isoforms including RON delta-155, delta-160, delta-165, and delta-170/WT. In 35/48 samples tested (73%), the most prevalent isoform was RON delta-165 followed by WT RON. FACS analysis of lung adenocarcinoma A549 cells, which displayed only RON delta-165 mRNA expression, confirmed intracellular localization of RON protein.
Analysis of RNA sequencing data in TCGA data sets which include over 5,000 patient tumor samples also demonstrated high prevalence of RON delta-165 expression across different tumor indications. More than 98% of samples, both tumor and normal, showed the RON delta-165 variant. Prevalence, defined as a delta-165: WT ratio &gt; 1, was seen in 28.6% and 24.3% of cases, respectively. Analysis of the lung and colon subsets revealed differentially higher RON delta-165 prevalence in lung (26%) and colon (25%) tumors, compared to respective normal tissue (7% and 0% respectively). Taken together, this data indicates that RON delta-165 is expressed in multiple tumor types and alludes to an altered RON isoform expression pattern in lung and colon cancer. Given a unique biology of this variant (constitutive activation and intracellular localization), isoform-specific targeted therapies should be developed for the inhibition of this pathway.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A30.
Citation Format: Michael Amatulli. The prevalence of RON isoforms in experimental and clinical tumor samples. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A30.
Abstract A83: Combinatorial approach to drastically enhance the monoclonal antibody efficacy in targeted tumor therapy.
Authors: Gilabert-Oriol Roger , Thakur Mayank , von Mallinckrodt Benedicta , Hug Thomas , Wiesner Burkhard , Eichhorst Jenny , Melzig Matthias F. , Fuchs Hendrik , Weng Alexander 
Published: August 2014

Abstract
Antitumor therapy with monoclonal antibodies has shown great therapeutic benefits in clinics and a number of therapeutic antibodies have been approved for use in patients. Nevertheless, their efficacy is limited due to their insufficient inherent cell killing activity. In order to augment their antitumor efficacy, monoclonal antibodies may be modified with natural toxins to create a drug conjugate (immunotoxin) that comprises the dual functionality of monoclonal antibody (antagonistic binding to targeted receptors and interaction with the innate immune system) and the cell-killing activity of the toxin. In our investigations, two immunotoxins were prepared by chemically coupling the monoclonal antibodies trastuzumab (Herceptin®) and cetuximab (Erbitux®) to the plant derived toxin saporin via a cleavable disulfide bond. Impedance-based real-time viability assays and confocal live cell imaging revealed that the toxin is efficiently delivered to the targeted tumor cells. In addition, immunotoxin cytotoxicity was tremendously enhanced in combination with certain plant glycosides, which specifically mediate the endo/lysosmal release of the toxin moiety into the cytosol without damaging the biological membranes. The combinatorial approach was successful in achieving a complete cell death of human breast ductal carcinoma BT-474 cells, at a concentration of 1 nM of trastuzumab-saporin or 0.001 nM cetuximab-saporin in the presence of the glycosides. Furthermore, immunotoxins retained their ability to interact with the innate immune system and trigger antibody-dependent cell-mediated cytotoxicity. The combinatorial approach is conceived as a novel and promising way to increase the efficacy of monoclonal antibodies in targeted tumor therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A83.
Citation Format: Roger Gilabert-Oriol, Mayank Thakur, Benedicta von Mallinckrodt, Thomas Hug, Burkhard Wiesner, Jenny Eichhorst, Matthias F. Melzig, Hendrik Fuchs, Alexander Weng. Combinatorial approach to drastically enhance the monoclonal antibody efficacy in targeted tumor therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A83.
Abstract B246: Overcoming cancer resistance to death receptor targeted therapies.
Authors: Zhang Baolin , Chen Junjie , Di Xu , Zhang Yaqin 
Published: August 2014

Abstract
Multiple clinical trials are underway to evaluate the antitumor activity of a new class of protein products that target the cell surface death receptors (DRs) 4 and 5. These include the recombinant human TNF-related apoptosis inducing ligand (TRAIL) and agonistic antibodies specific to DR4 or DR5. The early-phase clinical data is encouraging in suggesting a tolerated safety profile for these products. However, there is a major concern about the occurrence of drug resistance that has been seen in a large number of human cancer cell lines and primary tumors. There are unmet needs in the development of DR-targeted therapies, in terms of both the ability to predict a tumor response and the selection of combinational drugs for overcoming the resistance towards a better clinical efficacy.
Our laboratory investigates cell death and cell survival mechanisms involved in cancer drug action and resistance. Over the past eight years, we have made significant findings on the molecular determinants of TRAIL resistance. We have shown that deficiency of DR4 and/or DR5 on surface membrane is a critical mechanism of cancer cell resistance to the targeted therapies. In some cancer cells, the two receptors are found to be not properly expressed on surface membrane and, instead, are mislocalized in intracellular compartments. We provide evidence for novel mechanisms of DR surface deficiency, which involve deregulation of endocytosis and autophagy pathways in the TRAIL-resistant cells. These data could help identify biomarkers for predication of a tumor response and novel molecular targets for combination drugs to overcome or bypass the resistance mechanisms. This presentation will give an update of the relevant clinical trails and our research findings on DR-targeted therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B246.
Citation Format: Baolin Zhang, Junjie Chen, Xu Di, Yaqin Zhang. Overcoming cancer resistance to death receptor targeted therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B246.
Abstract B248: Antitumor activity mediated by N-myristoylated cationic peptides (myrCP).
Authors: Krotova Karina , Aslanidi George 
Published: August 2014

Abstract
Although new chemotherapeutic agents are improving the survival rate of cancer patients, all of them have serious toxic side effects. Thus, it is still necessary to search for new agents with minimal side effects or to enhance the effectiveness of known cytotoxic agents at a reduced dose. The modification of peptides by adding myristol group is commonly used to facilitate intracellular delivery. It has been shown recently that the combination of myristoylation and the cationic charge of peptide confer new biological activity to the peptide. We examined the possibility of using such peptides for the treatment of cancer. In present studies, we evaluated the effect of two N-myristoylated cationic peptides (myrCP) on several human cancer cell lines: H1299 (lung), MCF7 (breast), and PC3 (prostate). The first peptide mimics the endogenous Protein kinase C (PKC) pseudosubstrate region and it is considered as a selective inhibitor of PKC (myr-SIYRRGARRWRKL-OH). This peptide has a dual effect on cancer cells as it prevents proliferation by inhibiting PKC and also serves as a cytotoxic agent. The second peptide that is a scrambled version of the first peptide (myr-RLYRKRIWRSAGR-OH) was used as a control to ensure that cytotoxic effect is not only dependent on PKC inhibition. We found that both myrCP had superior cytotoxic effect on cancer cells. Moreover, they dramatically enhanced the activity of commonly used chemotherapeutic agents such as mitoxantrone and cisplatin which were active in combination with peptides at significantly lower concentration. Since the lipophilic nature of myristoylation facilitates penetration of these peptides across cell membranes, we analyzed what lipids can be involved in such interaction. Membrane lipid arrays showed that myrCP preferably binds to PtdIns (3, 4, 5) P3, phosphatidic acid and at less extent to PI (4, 5) P2. Our results suggested that lipid membrane composition of cells could play an essential role in efficacy of myrCP. In summary, the potential outcome of the current studies will be the development of a useful therapeutic tool for efficient killing of tumor cells. Considering that cytotoxic effects of myrCP are non-specific to the type of cancer, a similar strategy can be applied for many different malignancies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B248.
Citation Format: Karina Krotova, George Aslanidi. Antitumor activity mediated by N-myristoylated cationic peptides (myrCP). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B248.
Abstract B259: Novel indolizino[6,7-b]indoles suppress the growth of human non-small cell lung cancer cells in xenografted and orthotopic mouse models via induction of DNA crosslinks and inhibition of topoisomerase I and II.
Authors: Chen Chi-Wei , Chen Yi-Fan , Chao Shu-Hsin , Tala Satishkumar , Su Tsann-Long , Lee Te-Chang 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) remains a global health problem due to the limited therapeutic responses and drug resistance. We have previously demonstrated that indolizino[6,7-b]indoles are potent antitumor agents with DNA cross-linking and topoisomerase I and II inhibition activities (JMC, 56: 1544-1563, 2013). The present study explores its therapeutic activity against NSCLC. Our results showed that BO-1922 and BO-1978, the selected derivatives of indolizino[6,7-b]indoles, effectively repressed the cell growth of several NSCLC lines, including as H460 (KRAS mutation), H1299 (TP53 deficient), A549 (KRAS mutation), CL141T (TP53 mutation), PC9 (EGFR mutation), PC9/gef B4 (EGFR mutation and acquired resistant to TKI), CL100 (EGFR mutation), and CL97 (EGFR mutation and acquired resistant to TKI). Using mouse xenograft models, we found that BO-1922 and BO-1978 could significantly suppress the tumor growth of H460, PC9, and PC9/gef B4 in mice. Furthermore, we demonstrated that these 2 compounds could remarkably inhibit the growth of CL1-5/GFP-Luciferase cells in orthotopic lung cancer model. In addition, we performed preclinical toxicity studies. Accordingly, the LD50 of BO-1922 and BO-1978 to ICR mice are 77.4 and 93.7 mg/kg, respectively. Based on blood cell counts, blood biochemistry, histopathological examination of major organs, BO-1922 and BO-1978 did not cause obvious toxicity at the doses of 20 and 40 mg/kg on day 2 and 14 after injections. Taken together, our present study revealed that BO-1922 and BO-1978 are highly prospective leads for treatment of NSCLC.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B259.
Citation Format: Chi-Wei Chen, Yi-Fan Chen, Shu-Hsin Chao, Satishkumar Tala, Tsann-Long Su, Te-Chang Lee. Novel indolizino[6,7-b]indoles suppress the growth of human non-small cell lung cancer cells in xenografted and orthotopic mouse models via induction of DNA crosslinks and inhibition of topoisomerase I and II. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B259.
Abstract B299: The role of Necl-5 in hepatocarcinogenesis.
Authors: Chen Xue , Yano Yoshihiko , Hayashi Yoshitake 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy of adults and the third leading cause of cancer mortality in the world. Hepatocarcinogenesis is a multistep process, usually caused by disturbing cell-cell adhesion and associated with a change of surface molecules. Recently, it is noticed that Necl-5 (Nectin-like 5) could regulate cell adhesion and migration, moreover, overexpressed in many cancers, such as colon cancer and lung cancer. However, the expression of Necl-5 in HCC is still unknown. Hence, we examined the chemically induced hepatocarcinogenesis using Necl-5 knock out mice and the expression of Necl-5 in human HCC. It was significantly showed that HCC was easily generated in Necl-5 knock out mice compared with wild type mice. In human cancerous tissues, the expression of Necl-5 was significantly higher in well differentiated HCC than moderately and poorly differentiated HCC. The expression of CD226, the ligand of Necl-5, was significantly lower in cancerous tissues compared with non-cancerous tissue. It was suggested that there was a negative regulation between Necl-5 and CD226. It was known that NK cells were activated by CD226 and played a role in early stage of tumorigenesis and participated in immune surveillance. Lacked of the Necl-5 gene indirectly impair immune surveillance to induce mice was easier generated cancer. Those findings suggested that Necl-5 might be a potential target of anti-cancer drugs in the future.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B299.
Citation Format: Xue Chen, Yoshihiko Yano, Yoshitake Hayashi. The role of Necl-5 in hepatocarcinogenesis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B299.
Abstract B4: Evaluation of VEGFxxxb isoforms as a predictive biomarker for anti-VEGF cancer therapy.
Authors: Zhang Wen , Abrahams Cristina , Huang Ying , Li Baosheng , Parveen Asma , Ni Min , Wei Yi , Ding Yueming , Zhang Eric , Lin Hsin Chieh , Thurston Gavin , Zhang Qing 
Published: August 2014

Abstract
Biomarkers are critical tools for measuring efficacy of treatments or predicting which patients are mostly likely to respond to a particular therapy. Recently, the VEGF isoform, VEGF165b, was proposed to be a predictive marker for bevacizumab in metastatic colorectal cancer patients. VEGF165b is an anti-angiogenic splice variant that differs from its pro-angiogenic counterpart, VEGF165, by only six amino acids at the C-terminal end of the protein. Members of the VEGFxxxb isoform family are produced by alternative splicing of the 3’ untranslated region (UTR) to generate exon 8b, instead of the conventional exon 8 which produces exon 8a. The study of VEGF165b in colorectal cancer (Bates et al, Clinical Cancer Research, 2012) reported that patients with low VEGF165b:VEGFtotal ratio had improved PFS following bevacizumab + FOLFOX4 treatment, while individuals with higher VEGF165b:VEGFtotal ratios did not benefit. On the other hand, another recent study (Harris et al, PLoS One, 2012) reported that VEGFxxxb isoforms may be a RT-PCR artifact. In this study, we sought to test the role of VEGF165b in the response to anti-VEGF therapy using preclinical human tumor models, and to evaluate the prevalence of VEGFxxxb isoform in human cancer cells and normal tissues using RNA-Seq, a next generation sequencing (NGS) platform that is independent of RT-PCR. Our results show that xenograft tumors engineered to overexpress VEGF165b had similar growth kinetics, tumor vascular density and were equally sensitive to aflibercept or bevacizumab treatment in humanized VEGF SCID mice compared to their parental counterparts. These results indicate that VEGF165b does not have anti-angiogenic properties, and VEGF165b levels did not correlate with the efficacy of anti-VEGF therapy. Furthermore, although we were able to detect VEGF165b splice variants by NGS profiling in cells engineered to overexpress VEGF165b, no NGS evidence supporting the VEGFxxxb isoforms was found in a panel of 24 human cancer cell lines and 12 different types of human normal tissues. To our knowledge, this is the first report to survey VEGFxxxb isoforms using NGS RNA-seq technology. Overall, these studies suggest that closer inspection of VEGFxxxb isoforms may be required before employing VEGF165b as a predictive biomarker for anti-VEGF therapy.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B4.
Citation Format: Wen Zhang, Cristina Abrahams, Ying Huang, Baosheng Li, Asma Parveen, Min Ni, Yi Wei, Yueming Ding, Eric Zhang, Hsin Chieh Lin, Gavin Thurston, Qing Zhang. Evaluation of VEGFxxxb isoforms as a predictive biomarker for anti-VEGF cancer therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B4.