bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 831: Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters
Authors: Somberg Richard L. , Moravec Rich , Li Dun , Paguio Aileen , Cong Mei 
Published: August 2018

Abstract
The demand for biosimilars and bioassays for biosimilars are increasing as the patent cliff approaches for many blockbuster biologics. Recently, the expanded approval of Actemra (Tocilizumab) to treat CAR T-cell-induced cytokine release syndrome (CRS) demonstrated the role of anti-IL-6 blocking drugs as critical for the treatment of serious diseases such as cancer and autoimmune diseases. Here we describe a portfolio of luciferase reporter-based bioassays to support the development and potency determination of biosimilar drugs targeting cytokines such as IL-2, IL-6, IL-12, IL-15, IL-12/23, IL-17, VEGF, RANK, Epo, IFNs, etc. The availability of quantitative, functional bioassays in Thaw-and-Use format provides the benefit of convenience, reproducibility, and transferability. We demonstrate these assays are able to measure relative potency for antibody biologics and detect potency changes for stressed antibody samples. In summary, the reporter-based bioassay portfolio for biosimilars provides a valuable tool for the development, stability testing, and potency determination in manufacture of biosimilars and biobetters.
Citation Format: Richard L. Somberg, Rich Moravec, Dun Li, Aileen Paguio, Mei Cong. Reproducible, mechanism of action-reflecting reporter based bioassays to enable drug development of biosimilars and biobetters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 831.
Abstract 833: Anti-tumor efficacy of BA3021, a novel Conditionally Active Biologic (CAB) anti-ROR2 ADC
Authors: Sharp Leslie L. , Chang Cathy , Frey Gerhard , Wang Jing , Liu Haizhen , Xing Charles , Yalcin Safak , Walls Marlena , Ben Yong , Boyle William J. , Short Jay M. 
Published: August 2018

Abstract
ROR2 is a developmentally regulated member of the receptor tyrosine kinase orphan receptor (ROR) family and is a non-canonical receptor for selected Wnt family members. Many of the activities associated with ROR2 in development have also been implicated in cancer including cell migration and invasion. In many cancer types, expression of ROR2 correlates with advanced disease or poor prognosis. The high level of expression on the cancer cell surface has made it an attractive target for antibody-drug-conjugates (ADC). The Conditionally Active Biologics (CAB) technology is a patented, proprietary platform that selects antibodies that reversibly bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of the Warburg effect. Using our CAB technology, we have identified anti-ROR2 selective Abs that reversibly bind to recombinant ROR2 and ROR2 expressing cells under conditions that are present in the tumor microenvironment, but not in normal tissues.
BA3021 is a CAB-ROR2-ADC. The pharmacological properties of BA3021 were characterized in a number of in vitro and in vivo pharmacology studies. BA3021 binds selectively to human and cyno ROR2 in conditions reflective of the tumor microenvironment, but has reduced binding under normal tissue conditions. BA3021 demonstrated ability to induce cytotoxicity of cell lines expressing ROR2 in vitro and inhibit tumor growth in LCLC-103H (lung), MDA-MB-436 (breast), HT1080 (sarcoma) and SK-MEL-5 (melanoma) human tumor xenografts and in selected sarcoma cancer patient derived xenograft models in vivo.
In conclusion, our data is consistent with our work on CAB-EGFR-ADC, CAB-AXL-ADC, CAB-PD-1 and other CAB programs and suggests that ADCs generated using the CAB technology provide biologics with increased therapeutic index. Specifically, the CAB-ROR2-ADC is an excellent candidate for evaluation as a treatment for human cancers that are ROR2 positive.
Citation Format: Leslie L. Sharp, Cathy Chang, Gerhard Frey, Jing Wang, Haizhen Liu, Charles Xing, Safak Yalcin, Marlena Walls, Yong Ben, William J. Boyle, Jay M. Short. Anti-tumor efficacy of BA3021, a novel Conditionally Active Biologic (CAB) anti-ROR2 ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 833.
Abstract 845: Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat
Authors: Rosen Elliot T. , Kryndushkin Dmitry , Aryal Baikuntha , Gonzalez Yanira , Chehab Leena , Dickey Jennifer , Mog Steven , Rao V Ashutosh 
Published: August 2018

Abstract
Radiation-induced heart disease (RIHD) presents a significant challenge in the oncology setting. For instance, patients receiving acute doses of irradiation to the thoracic cavity for Hodgkin's lymphoma or breast cancer are subject to an elevated risk of RIHD. Excessive oxidative stress, at least in part, is responsible for some of the tissue damage. The ability to monitor and mitigate the long-term cardiac effects of radiation exposure in these populations by modulating oxidative stress has the potential to lead to improved health outcomes. We utilized the spontaneously hypertensive rat (SHR), which has proven a good model for drug-induced cardiotoxicity, to evaluate irradiation-induced heart damage. SHRs were exposed to low, medium, or high doses of full-body irradiation. Necropsy was performed to collect serum and tissue samples at two and four weeks post-irradiation, as well as followed for one year. Four weeks following gamma irradiation, both males and females showed decreased heart mass and decreased whole body mass after exposure to medium and high doses of radiation and these decreases were sustained in the high dose groups after one year. Serum cardiac troponin I and T analysis revealed signs of cardiomyopathy in both the medium and high dose groups at early time points and this signal was sustained in some animals up to one year later. Echocardiography revealed functional changes in cardiac performance including an increase in left ventricular volume at diastole in males and a decrease in left ventricular mass. Low red blood cell count indicated sustained anemic conditions in both males and females receiving the highest dose of irradiation, yet males appeared to be more sensitive. Levels of pro-inflammatory IL-6 were elevated at four weeks in males receiving the high dose. Finally, multiple animals receiving radiation developed spontaneous tumors after one year. We are currently investigating the oxidative stress-mediated molecular mechanisms behind the radiation-induced cardiac damage.
Citation Format: Elliot T. Rosen, Dmitry Kryndushkin, Baikuntha Aryal, Yanira Gonzalez, Leena Chehab, Jennifer Dickey, Steven Mog, V Ashutosh Rao. Acute irradiation exposure induces long-term cardiac adverse effects in the spontaneously hypertensive rat [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 845.
Abstract 856: Selection of radiosensitizers based on HRAS mutation in bladder cancer
Authors: Fisher Michael M. , Swick Adam D. , Nickel Kwangok P. , Kimple Randall J. 
Published: August 2018

Abstract
Purpose/Objective(s): The ability of activated HRAS to promote radiation resistance and predict for sensitivity to potential radiosensitizers was tested in a bladder cancer model system.
Materials/Methods: Mutations in HRAS, KRAS, and NRAS were analyzed using cBioPortal in a bladder cancer cohort (TCGA). We employed a panel of urothelial carcinoma cell lines-T24 (HRASG12V), J82 and 5637 (RASWT). Cell growth and survival was tested with colony formation and proliferation assays. Radiation survival was assessed by clonogenic survival assay. Immunoblots were used to confirm mutant HRAS expression, and target activation/knockdown in overexpression and knockdown studies. Radiosensitization of mutant-HRAS bladder cancer was tested using a flank cell line xenograft model in nude mice.
Results: Approximately 10% of bladder cancers feature alterations in one of three RAS genes; mutations in HRAS comprise greater than 50% of these. An HRAS activating (G12V) mutation was detected in T24. Consistent with known roles for activated RAS, T24 is relatively insensitive to both cetuximab and radiation. Using both in vivo and in vitro studies, cetuximab exhibited no radiosensitization of T24. Treatment with cetuximab lowered AKT, but not ERK activation. Direct inhibition of the MEK/ERK or PI3K/MTOR pathway by selumetinib or BEZ235, respectively, decreased target protein activation and resulted in significant growth inhibition compared to control (p&lt;0.05). Treatment with either selumetinib or BEZ235 radiosensitized HRASG12V expressing cells (SER 1.3-1.8), but had more modest effects on cells with wild-type HRAS. siRNA knockdown of HRAS radiosensitized T24, but not J82 or 5637 cells relative to non-targeting control. The combination of selumetinib and radiation therapy delayed the growth of T24 tumors in vivo.
Conclusions: Over 10% of bladder cancers feature alterations in the RAS family of genes. These mutations can lead to resistance to cetuximab, either as a single treatment or as a radiosensitizer. Inhibition of downstream MEK/ERK and PI3K/MTOR pathways can radiosensitize tumors with activating mutations in HRAS. Identification of additional mutation/drug combinations that result in radiosensitization may be valuable to advance the design of personalized radiation therapy.
Citation Format: Michael M. Fisher, Adam D. Swick, Kwangok P. Nickel, Randall J. Kimple. Selection of radiosensitizers based on HRAS mutation in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 856.
Abstract 860: Experimental alpha-radioimmunotherapy for liver metastasis of gastric cancer
Authors: Li Huizi Keiko , Hasegawa Sumitaka 
Published: August 2018

Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Early stage of GC is curable by surgical therapy or endoscopic surgery. However, previous studies reported that 35% of patients is present with evidence of distant metastasis at the time of diagnosis of GC. Metastatic GC is fetal and the patients with metastatic GC has extremely poor prognosis because current therapeutic approaches to metastatic GC are still limited. Therefore, the development of new therapeutic options has been eagerly awaited. Liver metastasis of GC (LMGC) is often observed during GC progression. It has been shown that 4-14% of the patients has LMGC. It is believed that LMGC is occurred by blood-borne metastasis of GC cells via blood stream. A previous study reported that approximately 70% of LMGC was positive for human epidermal growth factor receptor 2 (HER2). Therefore, HER2 may be a reliable therapeutic target for LMGC. Alpha-particle radioimmunotherapy (alpha-RIT) is an emerging new therapy, in which radioisotopes emitting cytotoxic alpha-particle radiation are delivered to target cancer cells to kill the cells by target-specific antibody. Among alpha-particle emitters, astatine-211 (At-211) is a promising emitter because it emits highly cytotoxic alpha-particles during its decay process with a half-life of 7.2 hours. The aim of this study is to evaluate the therapeutic efficacy and toxicity of At-211-labled anti-HER2 antibody trastuzumab ([At-211]trastuzumab) in a preclinical mouse model of HER2-positive LMGC. We established a mouse model of LMGC by injection of luciferase-labelled HER2-positive human metastatic GC cells (NCI-N87) into splenic vein of severe combined immunodeficiency mouse. Biodistribution studies revealed that the maximum tumor uptake of [At-211]trastuzumab was about 12% of injected dose per tissue gram 24 hours after injection. In experimental therapies, a systemic injection of [At-211]trastuzumab (1 MBq) significantly reduced a tumor burden in the liver and prolonged the survival. Transient but recoverable leukocytopenia was observed in mice received 1 MBq of [At-211]trastuzumab at 5-7 days after injection. No body weight loss was found during the observation period. In this study, we provides a preclinical evidence that alpha-RIT using [At-211]trastuzumab may be a new therapeutic option against LMGC.
Citation Format: Huizi Keiko Li, Sumitaka Hasegawa. Experimental alpha-radioimmunotherapy for liver metastasis of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 860.
Abstract 87: Nuclear localization of p70 S6 kinase in ovarian cancer
Authors: ZHOU Jing , TO Sally K. , WONG Alice S. 
Published: August 2018

Abstract
Ovarian cancer is highly metastatic with a poor prognosis. The p70 S6 kinase (p70S6K) is a downstream effector of the phosphatidylinositol-3 kinase/Akt pathway that is frequently activated in ovarian cancer. Constitutive activation of p70S6K is significantly more often in malignant ovarian tumors than in normal or benign tissues, suggesting a role for p70S6K in tumor development and progression. In addition to its well-established role in cell growth and survival, we showed for the first time that p70S6K plays a pivotal role in other aspects of tumor progression such as metastasis. Here, we further showed that this was associated with the nuclear localization of p70S6K. Treatment of cells with the CRM1 inhibitor, leptomycin B, retained p70S6K in the nucleus. Growth factor stimuli led to p70S6K phosphorylation and triggered nuclear translocation of p70S6K. The phosphorylation was sensitive to p70S6K inhibitors. We further identified a potential region that was important in its nuclear localization. Expression of nuclear localization signal-p70S6K enhanced tumor cell migration and invasion when compared to non-targeted p70S6K. Our findings identify a region responsible for the nuclear entry of p70S6K and demonstrate a functional significance of nuclear p70S6K in tumor progression (This work is supported by RGC grant 17103417).
Citation Format: Jing ZHOU, Sally K. TO, Alice S. WONG. Nuclear localization of p70 S6 kinase in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 87.
Abstract 891: A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia
Authors: Richard Alexander , Abdel-Rahman Hamdy M. , Kim Jung Hyun , Vukadin Lana , Piazza Gary A. , Ahn Eun-Young E. 
Published: August 2018

Abstract
Cyclic adenosine monophosphate (cAMP) is a secondary messenger that regulates cell proliferation, differentiation, and apoptosis. Phosphodiesterases (PDEs) are enzymes that catabolize cyclic nucleotides to relay cellular signals. Among them, PDE4 is a cAMP-specific PDE isozyme family and several PDE4 inhibitors have been developed to treat a diverse group of diseases, such as asthma and chronic obstructive pulmonary disease. Although PDE4 inhibitors have been demonstrated to induce cell death in solid tumors, their therapeutic potential in treatment of hematopoietic malignancies has not been well studied. Our analysis on the expression pattern of PDE family demonstrated that PDE4B is abundantly expressed in blood cancers compared to other solid tumors, implicating PDE4 as a potential therapeutic target for leukemia. N-acylhydrazone and nitraquazone are potent PDE inhibitors that are structurally unrelated to rolipram, a prototypical PDE4 inhibitor. To develop novel PDE4 inhibitors with increased scaffold rigidity, we hybridized N-acylhydrazone with Nitraquazone, and designed a series of quinazolin-4(3H)-one/schiff base hybrid compounds. Among those, compound 23 (CPD23) showed the best activity in PDE4B inhibition, and was selected for further studies. Our results showed that CPD23 treatment leads to growth inhibition and cell cycle arrest of several human leukemia cell lines. Since cAMP is a well-studied secondary messenger for megakaryopoesis and apoptosis, we continued to elucidate CPD23's mechanism of action in several megakaryoblastic leukemia cell lines. While other well-known PDE4 inhibitors, such as rolipram, did not show any effect in cell viability, CPD23 significantly decreases the viability of megakaryoblastic cell lines. Further studies on molecular actions revealed that CPD23 caused double-stranded DNA breaks, which was detected by increased ϒH2AX levels. Quantitative RT-PCR experiments also demonstrated that CPD23 induces transcriptional activation of megakaryocytic differentiation markers, such as CD61, in selective cell lines. Taken together, our study shows that CPD23, synthesized as a quinazolin-4(3H)-one/schiff base hybrid PDE4 inhibitor, decreases proliferation, induces double-stranded DNA breaks, and differentiation in megakaryoblastic leukemia cell lines. Further studies will enhance our knowledge on detailed molecular actions of CPD23 and its therapeutic value for leukemia.
Citation Format: Alexander Richard, Hamdy M. Abdel-Rahman, Jung Hyun Kim, Lana Vukadin, Gary A. Piazza, Eun-Young E. Ahn. A novel quinazolin-4(3H)-one/Schiff base hybrid phosphodiesterase 4 inhibitor as a potential therapeutic agent for leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 891.
Abstract 901: Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma
Authors: Tong Man , Che Noelia , Zhou Lei , Kau Phillis W. , Luk Steve T. , Chen Xin , Ding Jin , Lee Terence K. , Ma Stephanie 
Published: August 2018

Abstract
Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA approved first-line targeted drug for advanced HCC, but its effect on patients' survival gain is limited and patients ultimately present disease progression. Molecular mechanism underlying acquired resistance are still far from being well understood. A better understanding of causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. In this study, we uncovered a role of annexin A3 (ANXA3) in conferring ability of HCC cells to resist sorafenib. ANXA3 was found highly enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, we found overexpression of ANXA3 in sorafenib-resistant HCC cells to suppress PKCδ/p38 associated apoptosis and activate autophagy for cell survival. ANXA3 expression correlated positively with LC3B, an indicator of autophagy induction, in HCC specimens and was associated with a worst overall survival in HCC patients who went on to receive sorafenib treatment. Anti-ANXA3 therapy, alone or combined with sorafenib and regorafenib, the standard of care for advanced HCC, impaired tumor growth in vivo and significantly increased survival. In sum, we found anti-ANXA3 therapy to exhibit abilities to reduce tumor growth and sensitize HCC cells to sorafenib and regorafenib treatment via suppressing autophagy and activating apoptosis. Inhibition of ANXA3 would benefit a subset of patients after sorafenib progression. ANXA3 can also serve as a useful predictive biomarker for patient response to sorafenib treatment.
Citation Format: Man Tong, Noelia Che, Lei Zhou, Phillis W. Kau, Steve T. Luk, Xin Chen, Jin Ding, Terence K. Lee, Stephanie Ma. Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 901.
Abstract 911: Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer
Authors: Wu Rentian , Nie Qian , Kubica Phillip A. , Wang Zhiquan , Shrestha Shikshya , Trogstad-Isaacson Colbren S. , Jerde Calvin R. , Tapper Erin E. , Bouchonville Kelly J. , Offer Steven M. , Diasio Robert B. 
Published: August 2018

Abstract
Colorectal cancer (CRC) is the third most common cancer and is expected to cause approximately 50,000 deaths in the US in 2017. The antimetabolite 5-fluorouracil (5-FU) is the cornerstone of first-line adjuvant chemotherapy regimens for CRC. Resistance to 5-FU-based chemotherapies develops over time and is the greatest obstacle to effective management in this disease. However, the resistance mechanisms of 5-FU are largely unknown. Approximately 50% of the CRC cases have activating mutations in KRAS or BRAF. Based on recent clinical data, it is now appreciated that KRAS/BRAF mutations are associated with worse survival in 5-FU-based chemotherapies for CRC. Therefore, there is an urgent unmet need for improved therapeutic options to treat mutant KRAS/BRAF tumors. We analyzed the differential activation status of enhancers in KRAS/BRAF mutant and wildtype CRC cell lines. Enhancers that associated with genes regulating pyrimidine metabolism were significantly enriched in KRAS/BRAF mutant CRC cells. Among them, the differential activation of an enhancer located ~400kb upstream of the DPYD promoter was most significant. By using CRISPR-dCas9 system, specifically targeting of p300 to the enhancer significantly increased DPYD expression, and Ezh2 significantly decreased expression. Knockout (KO) of this enhancer resulted in reductions in DPD expression and increased resistance to 5-FU. In mouse xenograft studies, enhancer-KO cells responded to doses of 5-FU that were otherwise ineffective against control cells. Treating KRAS mutant CRC cells with CBP30, H3K27 acetyl-transferase inhibitor, significantly reduced DPYD expression. Synergistic interactions was identified between CBP30 and 5-FU. Finally, mouse xenograft studies strongly suggest that inhibition of H3K27ac may significantly improve 5-FU effectiveness against KRAS mutant tumors. In summary, the present studies advance our understanding of how mutant KRAS/BRAF epigenetically regulates DPYD expression and results in 5-FU resistance in CRC. We showed that clinical treatment of CRC might be significantly improved by the development of future pharmacologic approaches targeting enhancers that are activated by mutant KRAS/BRAF.
Citation Format: Rentian Wu, Qian Nie, Phillip A. Kubica, Zhiquan Wang, Shikshya Shrestha, Colbren S. Trogstad-Isaacson, Calvin R. Jerde, Erin E. Tapper, Kelly J. Bouchonville, Steven M. Offer, Robert B. Diasio. Targeting the mutant KRAS/BRAF-induced enhancer as an approach to overcome resistance to 5-fluorouracil-based chemotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 911.