bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3213: A rapid, sensitive and quantitative method to measure protein biomarkers MUC16 and MSLN from archived clinical samples using TaqMan proximity ligation assays.
Authors: Ryner Lisa , Fourie Aimee , Tsai Siao Ping , Scales Suzie , Kozak Kathy , Firestein Ron , Guan Yinghui , Do An , Wang Yulei 
Published: August 2014

Abstract
MUC16 and MSLN are tumor-specific antigens highly prevalent in ovarian and pancreatic cancers and have been used as targets in developing antibody-drug conjugates (ADCs). Development of a sensitive method to quantitatively measure these protein biomarkers in archival clinical samples may enable potential companion diagnostics to these novel therapeutic agents. Here we report the development of a method to quantitatively measure these biomarkers from formalin fixed paraffin embedded (FFPE) tumor samples using TaqMan proximity ligation assays (PLA). Monoclonal antibodies that recognize the extracellular domains of MUC16 and MSLN were conjugated to amplicon forming oligonucleotides to generate proximity ligation probes for TaqMan quantification. Using purified MUC16 and MSLN recombinant protein the assay sensitivities were determined to be lower than single-digit ng/mL concentrations for both MUC16 and MSLN and the dynamic ranges were &gt;3 logs and ∼2 logs, respectively. In addition, the assays were demonstrated to be highly selective by testing lysates from expressing and non-expressing cell lines as determined by qRT-PCR. For clinical application of these assays, we further developed and optimized a simple two-step method for extraction and antigen retrieval of protein from archival FFPE tissues. FFPE extracts were prepared from a set of 10um sections of ovarian tumor tissue blocks and analyzed to determine relative MUC16 and MSLN protein expression levels. We benchmarked these results from the FFPE protocol with PLA data generated from matched fresh frozen tumor tissue as well as expression level determined by immunohistochemistry (IHC) and gene expression level determined by qRT-PCR assays from the same FFPE tissue blocks. All three comparisons with FFPE PLA were remarkably well correlated. In conclusion, we have established the technical feasibility and clinical utility of TaqMan PLA-based protein assays for sensitive and quantitative measurement of protein biomarkers in archival clinical samples. The methodology developed in this study represents a promising approach in companion diagnostic development for quantitative protein biomarker assessment.
Citation Format: Lisa Ryner, Aimee Fourie, Siao Ping Tsai, Suzie Scales, Kathy Kozak, Ron Firestein, Yinghui Guan, An Do, Yulei Wang. A rapid, sensitive and quantitative method to measure protein biomarkers MUC16 and MSLN from archived clinical samples using TaqMan proximity ligation assays. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3213. doi:10.1158/1538-7445.AM2013-3213
Abstract 3238: A novel natural product disrupts androgen receptor signaling in prostate cancer cells.
Authors: Amin Karishma , Jagadeesh Shankar , Barua Nabin , Bhattacharya Samir , Banerjee Partha P. 
Published: August 2014

Abstract
Continued reliance on androgen receptor (AR) signaling is a hallmark of prostate cancer, including the development of castration-resistant prostate cancer (CRPC), making it an attractive therapeutic target for prostate cancer treatment. Mahanine is a novel carbazole alkaloid derived from the leaves of Murraya koenigii, commonly known as the curry leaf plant, which grows widely across East Asia. We have reported previously that mahanine possesses the ability to inhibit prostate cancer cell growth. Since sustained AR signaling is associated with the development of CRPC, we investigated the effect of mahanine treatment on AR signaling in prostate cancer cells. Using reverse transcriptase polymerase chain reaction, we observed that AR signaling was disrupted by mahanine treatment, leading to a prominent decline in the expression of a number of AR target genes. Androgen response element-luciferase and PSA promoter-luciferase assays showed that androgen-induced AR transcriptional activity diminished by approximately 85% upon mahanine treatment. Furthermore, mahanine induced the export of the AR from the nucleus, resulting in its accumulation in the cytoplasm. Cellular levels of the AR were found to decrease in a time- and dose-dependent manner following mahanine treatment, without any noticeable change in its message levels, suggesting that mahanine affected AR protein levels post-translationally, without any effect on its gene expression. Concomitant administration of a proteasome inhibitor, MG132, significantly rescued the decline in AR levels observed upon mahanine treatment, indicating that mahanine induced proteasomal degradation of the AR. Collectively, these data demonstrate that mahanine treatment disrupts AR signaling in prostate cancer cells, leading to its cytoplasmic accumulation and subsequent degradation by proteasomal mechanisms, and suggest a potential therapeutic role for mahanine in prostate cancer treatment. This work is supported by NIH R01 CA131123.
Citation Format: Karishma Amin, Shankar Jagadeesh, Nabin Barua, Samir Bhattacharya, Partha P. Banerjee. A novel natural product disrupts androgen receptor signaling in prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3238. doi:10.1158/1538-7445.AM2013-3238
Abstract 3248: Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer.
Authors: Takaoka Munenori , Hao Hui-fang , Bao Xiao-hong , Tomono Yasuko , Sakurama Kazufumi , Ohara Toshiaki , Fukazawa Takuya , Yamatsuji Tomoki , Naomoto Yoshio 
Published: August 2014

Abstract
Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contacts. Interestingly, the treatment of mice before and after inoculation significantly suppressed the cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK, including TAE226, appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.
Citation Format: Munenori Takaoka, Hui-fang Hao, Xiao-hong Bao, Yasuko Tomono, Kazufumi Sakurama, Toshiaki Ohara, Takuya Fukazawa, Tomoki Yamatsuji, Yoshio Naomoto. Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3248. doi:10.1158/1538-7445.AM2013-3248
Abstract 3267: Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis.
Authors: Ying Meidan , Zhang Lei , Zhong Like , Shao Xuejing , Luo Peihua , Yang Xiaochun , Yang Bo , He Qiaojun 
Published: August 2014

Abstract
All-Trans-Retinoic Acid (ATRA) has held great promise for differentiation-based therapy, but reportedly down-regulates retinoic acid receptor alpha (RARα) in a proteasome-dependent manner, which leads to decreased AML cell differentiation efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond APL are key investigative avenues. Here, we demonstrate that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes indicative of myeloid differentiation, without cell death. Additionally, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (p&lt;0.05). These enhanced differentiation effects were accompanied by RARα stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib and ATRA synergy in AML cell differentiation and to assess new opportunities for bortezomib and ATRA combination as a promising approach for future differentiation therapy.
Citation Format: Meidan Ying, Lei Zhang, Like Zhong, Xuejing Shao, Peihua Luo, Xiaochun Yang, Bo Yang, Qiaojun He. Bortezomib sensitizes human acute myeloid leukemia cells to all-trans-retinoic acid-induced differentiation by modifying the RARα/STAT1 axis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3267. doi:10.1158/1538-7445.AM2013-3267
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 3269: Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery .
Authors: Rodriguez-Aguayo Cristian , Shen Haifa , Gonzalez-Villasana Vianey , Zhang Guodong , Deng Xiaoyong , Aslan Burcu , Liu Xuewu , Sakamoto Jason , Chavez-Reyes Arturo , Han Hee-Dong , Sood Anil K. , Ferrari1 Mauro , Lopez-Berestein Gabriel 
Published: August 2014

Abstract
RNA interference has the potential to specifically knock down the expression of target genes, and thereby transform cancer therapy. However, lack of effective delivery of small inhibitory RNA (siRNA) has dramatically limited its in vivo applications. We have developed a multistage vector (MSV) system, composed of discoidal porous silicon particles loaded with siRNA oligos packaged in dioleoyl phosphatidylcholine (DOPC) nanoliposomes, that directs effective delivery and sustained release of siRNA in tumor tissues. Tumor accumulation of siRNA was observed after i.v. administration of MSV/siRNA, and sustained release of siRNA from DMSV maintained high levels of siRNA in tumor for over one week after a single dose of DMSV/siRNA. Treatment of SKOV3ip2 tumor mice with DMSV carrying siRNA oligos specific for the human EphA2 gene (MSV/EphA2) biweekly for 6 weeks resulted in dose-dependent (5, 10 and 15 μg/mice) reduction of tumor weight (36%, 64%, and 83%) and number of tumor nodules compared with the control groups. In addition, tumor growth was completely inhibited when mice were treated with MSV/EphA2 in combination with paclitaxel. Furthermore, combination treatment with MSV/EphA2 and docetaxel inhibited growth of HeyA8-MDR tumors, which were otherwise resistant to docetaxel treatment. Taken together, MSV/EphA2 merits further development as a therapeutic approach for ovarian cancer.
Citation Format: Cristian Rodriguez-Aguayo, Haifa Shen, Vianey Gonzalez-Villasana, Guodong Zhang, Xiaoyong Deng, Burcu Aslan, Xuewu Liu, Jason Sakamoto, Arturo Chavez-Reyes, Hee-Dong Han, Anil K. Sood, Mauro Ferrari1, Gabriel Lopez-Berestein. Enhancing chemotherapy response with sustained EphA2 silencing using multistage vector delivery . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3269. doi:10.1158/1538-7445.AM2013-3269
Abstract 3323: E7449, a potent inhibitor of PARP 1 and 2, is active in acute myeloid leukemia.
Authors: McGonigle Sharon , Chen Zhihong , Wu Jiayi , Kolber-Simonds Donna , McGrath Shannon , TenDyke Karen , Wang Zichun , Nomoto Kenichi 
Published: August 2014

Abstract
Leukemic cells, like many other cancer cells, are often deficient in DNA repair capacity. PARP inhibitors have demonstrated synthetic lethality in cancer cells with defective DNA repair. E7449 is an orally bioavailable, potent, small molecule inhibitor of poly(ADP-ribose) polymerase (PARP)1 and PARP2. In this study we describe the therapeutic potential of the PARP inhibitor E7449 in acute myeloid leukemia (AML). E7449 inhibited proliferation of leukemia cells in a long term in vitro growth inhibition assay in a panel of leukemic cell lines. The MV-4-11 AML cell line was identified as particularly sensitive to E7449 PARP inhibition, and induction of apoptosis was observed in these cells. An in vivo survival model of acute myeloid leukemia (AML) was established in NSG mice using MV-4-11-luc2/AcGFP human AML cells. Daily dosing of E7449 at 100 mg/kg resulted in statistically significant anticancer activity in this model. Reduced disease burden as measured by luciferase signal was observed. This decrease in leukemic load also translated into a statistically significant survival benefit in E7449 treated mice. In AML cells, high P-glycoprotein (P-gp) expression is often observed, particularly in older patients, and this often leads to resistance to typical therapies. E7449 anti-proliferative activity was assessed in paired murine leukemia cells with basal (P388/S) and overexpressed P-gp protein (P388/VMDRC.04). E7449 effectively inhibited growth of the high P-gp expressing cells as well as the parent P388/S cells, with no significant difference in the presence or absence of verapamil, in contrast to data obtained for the P-gp substrate doxorubicin. These data demonstrate that E7449 is not a substrate for P-gp transport. Importantly, E7449 also significantly inhibited proliferation of primary patient AML cells ex vivo. In addition, E7449 proved highly potent at inhibiting colony formation in the majority of primary patient AML specimens assessed in long term (14 day) clonogenic survival assays. Studies to discern the mechanism underlying sensitivity to E7449 in AML cells are underway. Conclusion: In this study, E7449 possessed potent anti-cancer activity against AML cell lines and primary patient AML cells in vitro and ex vivo, it was not a substrate for P-gp transport, and it reduced disease burden and increased survival in an AML in vivo model. These data support the assessment of E7449 as a therapy for AML in the clinic.
Citation Format: Sharon McGonigle, Zhihong Chen, Jiayi Wu, Donna Kolber-Simonds, Shannon McGrath, Karen TenDyke, Zichun Wang, Kenichi Nomoto. E7449, a potent inhibitor of PARP 1 and 2, is active in acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3323. doi:10.1158/1538-7445.AM2013-3323
Abstract 337: A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib.
Authors: Cai Jie , Yang Mengmeng , Deng Jianyun , Song Xiaoming , Huang Xuesong , Chen Taiping , Wery Jean Pierre , Chen Yiyou , Li Henry QX 
Published: August 2014

Abstract
Non-small cell lung cancer (NSCLC) has the highest mortality among all malignances while with limited treatment options. Among the most significant treatment advancement in recent years are the introduction of target therapies of EGFR-TKIs (Erlotinib and Gefitinib) for adenocarcinoma with EGFR activating mutations, and Crizotinib for NSCLC with ALK activation (EML4-ALK fusion)1. ALK activation are associated with a subset of NSCLC patients (3∼5%).Crizotinib is considered not a particularly potent ALK inhibitor, with IC50 at range of tens of nanomoles. It may not be an ideal agent for treating NSCLC with activating ALK. Therefore, a new ALK inhibitor with better potency and specificity could be of particularly medical importance. Currently, the industry is actively searching for such new agents. A relevant experimental model could also greatly facilitate evaluating and validating these new drug candidates.
Patient derived xenografts (PDX) (including NSCLC PDX) mirror patients’ histopathology and genetic profiles2, thus known as “patient avatar”. It has improved predictive power as preclinical cancer models, and enables discovery of predictive biomarkers for targeted therapeutics. We have established a large collection of NSCLC PDX models (NSCLC-HuPrime®) by engrafting naïve patient tumor tissues into immune-compromised mice2.
Among these models, we have identified one model, LU1656, of NSCL carcinosarcoma histology and with EML4-ALK fusion mutation. This mutation apparently causes over-expression of ALK as measured at mRNA level. This model has wild-type KRAS, c-MET and EGFR genes. Treatment of LU1656 with Crizotinib caused significant but not complete tumor response, suggesting ALK activation is one of the oncogenic drivers of this model. In addition, LU1656 also responded to Cetuximab, but respond poorly to Erlotinib. It would be interesting to examine the combination of these treatments. This model is, to our knowledge, the first reported PDX model with EML4-ALK fusion mutation. We believe that LU1656 would be a useful model to evaluate investigational ALK inhibitors, and new combination treatment regimens of Crizotinib and standard of care chemotherapies.
Citation Format: Jie Cai, Mengmeng Yang, Jianyun Deng, Xiaoming Song, Xuesong Huang, Taiping Chen, Jean Pierre Wery, Yiyou Chen, Henry QX Li. A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 337. doi:10.1158/1538-7445.AM2013-337
Abstract 3385: Increased eIF4E phosphorylation prevents response of prostate cancer cells to mTOR inhibitors.
Authors: D'Abronzo Leandro S. , Beggs Ryan , Bose Swagata , Ghosh Paramita 
Published: August 2014

Abstract
Inhibitors of the mammalian target of rapamycin (mTOR) had been used in various clinical trials, but with limited efficacy. The overall goal of the present studies was to identify predictive markers of response to mTOR inhibitors in prostate cancer (PCa) cells. We previously showed that the mTOR pathway is activated in castration resistant PCa (CRPC), while its inhibition upregulates androgen receptor (AR) signaling, resulting in resistance to mTOR inhibitors (Wang et al, Oncogene, 2008). mTOR forms two complexes, mTORC1 and mTORC2: in this study we compared the effects of RAD001, an mTORC1 inhibitor, BEZ235, a dual mTOR/PI3K inhibitor, and Torin1, which inhibits both mTORC1 and mTORC2. Comparison of the effects of RAD001, alone, or in combination with the AR inhibitor bicalutamide in various CRPC cell lines showed that although C4-2 cells responded well to the combination, other cell lines, such as LNCaP-AI, PC-346C and CWR-R1, did not. The resistance of LNCaP-AI and CWR-R1 was partially overcome by treatment with BEZ-235 or Torin1, alone or in combination with bicalutamide; however, PC-346C cells were resistant to all three drugs. In an effort to identify the mechanism of resistance to mTOR inhibitors, therefore, the molecular effects of the drugs in downstream targets p70S6 kinase, 4E-BP1, eIF4G, Akt and eIF4E were compared in C4-2 (least resistant) and PC-346C (most resistant) cell lines. Western blots revealed that p70S6 kinase was downregulated by all the drugs whereas 4E-BP1 phosphorylation was effectively downregulated by BEZ235, but not Torin1, or RAD001. Phosphorylation of both p70S6K and 4E-BP1 results in activation of the translation initiation complex: a complex of eIF4E and eIF4G, therefore, inactivation of the translation initiation complex requires inhibition of eIF4E phosphorylation, which is independent of mTOR activation. In C4-2 cells, eIF4E phosphorylation was increased by RAD001 but suppressed by the other two drugs. However, in PC-346C cells, despite inhibition of 4E-BP1 phosphorylation, eIF4E phosphorylation was increased by all 3 drugs. Our data indicate eIF4E phosphorylation as a likely cause of resistance to mTOR inhibitors in PCa.
Citation Format: Leandro S. D'Abronzo, Ryan Beggs, Swagata Bose, Paramita Ghosh. Increased eIF4E phosphorylation prevents response of prostate cancer cells to mTOR inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3385. doi:10.1158/1538-7445.AM2013-3385