bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2586: Bortezomib reduces preexisting antibodies to recombinant immunotoxins in mice
Authors: Manning Michael L. , Mason-Osann Emily , Onda Masanori , Pastan Ira 
Published: May 2015

Abstract
Recombinant immunotoxin (RIT) therapy is limited in patients by neutralizing antibody responses. Most patients with normal immune systems make neutralizing antibodies after one cycle (three doses) of RIT, preventing repeated dosing. Furthermore, some patients have preexisting antibodies from environmental exposure to Pseudomonas exotoxin (PE), the component of the RIT that elicits the neutralizing antibody response. Bortezomib is an FDA-approved proteasome inhibitor which selectively targets and kills plasma cells which are necessary for a neutralizing antibody response. Bortezomib, in combination with methotrexate, rituximab, and cyclophosphamide, was shown to reduce antibody levels &gt;64-fold following enzyme replacement therapy in the clinical setting of Pompe disease. We hypothesized bortezomib may abrogate the neutralizing antibody levels, making dosing of RIT possible in mice already immune to RIT.
We immunized BALB/c mice with multiple doses of SS1P, a RIT whose antibody portion targets mesothelin. Antibody titers were determined by immune-capture ELISA. Mice with elevated levels were separated into groups to receive bortezomib (1mg/kg i.v., twice a week for 5.5 weeks) or saline control. Bortezomib treatment lowered the starting antibody titer in mice previously immunized with RIT by an average of 50%, while antibody titers in control mice increased by an average of 20%. Despite success in lowering titers, bortezomib did not abrogate titer in any mice.
To further diminish preexisting antibodies, we performed a separate experiment in which mice with preexisting anti-SS1P antibodies received bortezomib with concomitant pentostatin and cyclophosphamide (P/C) therapy. P/C is an immune-depleting regimen already shown to be effective in preventing the onset of new neutralizing antibodies. Combination treatment lowered the starting antibody titer in mice previously immunized with RIT by an average of 73%, while antibody titers in control mice increased by an average of 80%.
We have shown that bortezomib reduces, but does not eliminate, antibody titer in mice with preexisting antibodies to RIT. Addition of the immune-depleting P/C regimen further diminishes antibody titers. We are investigating remaining plasma cell populations as a potential source of remaining antibody. Ongoing experiments also include incorporating other FDA-approved agents into our study.
Citation Format: Michael L. Manning, Emily Mason-Osann, Masanori Onda, Ira Pastan. Bortezomib reduces preexisting antibodies to recombinant immunotoxins in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2586. doi:10.1158/1538-7445.AM2014-2586
Abstract 2601: EphB4/EphrinB2 targeting increases the efficacy of cisplatin in triple negative breast cancer
Authors: Yang-Kolodji Gloria W. , Liu Ren , Mehta Arjun , Gill Parkash , Tripathy Debu 
Published: May 2015

Abstract
Triple negative breast cancer (TNBC) represents a heterogeneous group of breast cancers that do not respond to either HER2 or hormonally targeted therapy and for which, chemotherapy is the only proven therapeutic option. However, certain biological pathways are known to be activated to a greater extent in TNBC.
The EphB4 receptor and its ligand EphrinB2 are expressed aberrantly in several types of cancer to promote angiogenesis and cell survival. In breast cancer, including TNBC, EphB4 expression is associated with a worse prognosis. An EphB4/Ephrin B2 inhibitor, sEphB4-HAS or SB4 (soluble protein EphB4 peptide stabilized with human serum albumin), developed at our institution, has shown inhibitory effects on cancer cell growth in both cell and animal models. Our goal here is to test the feasibility of EphB4 targeting in triple negative breast cancer cells, study the synergistic effects of SB4 and cisplatin, a common chemotherapy drug used for triple negative breast cancers, and to determine optimal combination doses of SB4 and cisplatin for eventual clinical trials.
Using two representative triple negative breast cancer cell lines MDA-MB-231 and HCC 1937, we show that SB4 inhibits cell growth in a dose dependent manner (IC50: 216.5μg/ml and 207.1 μg/ml, respectively). When SB4 is used in combination with cisplatin, synergy is observed. HCC 1937 cells treated with 200 μg/ml of sEphB4-HSA or 50 nM cisplatin for 7days, viability is decreased by 57 % and 8 %, and by 71% when given in combination. Similar results are seen in MDA-MB-231 cells, at 55%, 11%, and 63 % viability reduction. Mouse MDA-MB-231 xenografts are inhibited by SB4 treatment, with 20% reduction compared to control.
In addition, cell proliferation marker Ki67 assessed by immunohistochemical staining and pS6 (phosphorylated ribosomal protein S6) expression studied by immunoblotting demonstrate that SB4 in combination with cisplatin generates greater growth inhibitory effects on cell proliferation and pS6 expression than either alone.
In conclusion, EphB4 signaling in TNBC provides a niche to apply targeted therapy in combination with chemotherapy. The growth inhibitory effect of SB4 on TNBC cells and mouse xenografts supports the feasibility of EphB4 targeting. The effects of SB4 and cisplatin using xenograft models will be analyzed for synergy to provide a rationale to combine SB4 and chemotherapy in the clinic.
Citation Format: Gloria W. Yang-Kolodji, Ren Liu, Arjun Mehta, Parkash Gill, Debu Tripathy. EphB4/EphrinB2 targeting increases the efficacy of cisplatin in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2601. doi:10.1158/1538-7445.AM2014-2601
Abstract 2602: KRAS G12D and G12V specific alkylating agent (KR12) inhibits growth of colon cancer with those KRAS mutations in vitro as well as in vivo
Authors: Nagase Hiroki , Hiraoka Kiriko , Inoue Takahiro , Watanabe Takayoshi , Shinohara Ken-Ichi , Koshikawa Nobuko , Toshinori Ozaki 
Published: May 2015

Abstract
Despite extensive efforts to develop chemotherapeutic drug(s) targeting mutated RAS, the successful drug discovery, especially targeting KRAS codon 12 mutation, has never been made. We have found that Pyrrole-Imidazole polyamide seco-CBI conjugate (KR12) selectively recognized mutated KRAS sequence (ACGCCT-A/T-CA) at codon 12 and significantly suppressed tumor growth specifically in human colon cancer cells with G12D or G12V mutation. KRAS expression suppressed preferentially at mutated allele and active KRAS were markedly reduced. G2/M arrest, senescence and subsequent apoptosis by activating the p53 pathway were observed in KR12-exposed LS180 cells with G12D heterozygous mutation. In LS180 and SW480 (G12V homozygous mutation) xenograft colon cancer models, KR12 treatment induced massive tumor growth suppression with low host toxicity. Collectively, our current results strongly suggest that KR12 is a specific alkylating agent against KRAS codon 12 mutations, and could become a powerful candidate compound for the unmet need of KRAS-mutant tumor treatment.
Citation Format: Hiroki Nagase, Kiriko Hiraoka, Takahiro Inoue, Takayoshi Watanabe, Ken-Ichi Shinohara, Nobuko Koshikawa, Ozaki Toshinori. KRAS G12D and G12V specific alkylating agent (KR12) inhibits growth of colon cancer with those KRAS mutations in vitro as well as in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2602. doi:10.1158/1538-7445.AM2014-2602
Abstract 2606: Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGF-R but not the K-RAS/B-RAF mutational status in colorectal cancer
Authors: Ishii Yoshiyuki , Seo Yuki , Akimoto Shingo , Fukuda Kazumasa , Hayashida Tetsu , Okabayashi Koji , Tsuruta Masashi , Hasegawa Hirotoshi , Kitagawa Yuko 
Published: May 2015

Abstract
Cetuximab, an IgG1 monoclonal antibody against epidermal growth factor receptor (EGF-R), is widely used for the treatment of metastatic colorectal cancer (mCRC). One of the working mechanisms is considered to be antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by Fcγ−R on natural killer cells. However, whether ADCC is associated with EGF-R expression and/or the mutational status of EGF downstream effectors (K-RAS and B-RAF etc.) in colorectal cancer (CRC) remains unclear. The aim of this study was to verify whether ADCC activities are associated with the cell surface expression levels of EGF-R and/or the mutational status of K-RAS and B-RAF. Five human CRC cell lines with different cell surface expression levels of EGF-R and different K-RAS and B-RAF mutational statuses were selected to evaluate ADCC activity using peripheral blood mononuclear cells (PBMC) from healthy human donors. Furthermore, tumor cells from resected specimens of CRC patients were used to evaluate the cell surface expression level of EGF-R using immunohistochemistry and the K-RAS and B-RAF mutational statuses using direct sequencing, while the ADCC activity was examined using PBMCs from the same CRC patients. A strong correlation was observed between the expression levels of EGF-R and the ADCC activities in the cell lines (correlation coefficient: 0.949; P = 0.003). Of the 13 resected specimens, a high ADCC activity level was significantly observed in tumor cells with high expression levels, compared with those with low expression levels, of cell surface EGF-R (P = 0.027). In both CRC cell lines and tumor cells from CRC patients, the ADCC activities were significantly associated with the cell surface expression levels of EGF-R (standard partial regression coefficients: 0.911 [P = 0.017] and 0.660 [P = 0.018], respectively), but not the mutational status of K-RAS and B-RAF (standard partial regression coefficient: -0.101 [P = 0.631] and 0.160 [P =0.510], respectively). Cetuximab-mediated ADCC activity may be correlated with the cell surface expression level of EGF-R, regardless of the mutational statuses of K-RAS and B-RAF, in CRC.
Citation Format: Yoshiyuki Ishii, Yuki Seo, Shingo Akimoto, Kazumasa Fukuda, Tetsu Hayashida, Koji Okabayashi, Masashi Tsuruta, Hirotoshi Hasegawa, Yuko Kitagawa. Cetuximab-mediated ADCC activity is correlated with the cell surface expression level of EGF-R but not the K-RAS/B-RAF mutational status in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2014-2606
Abstract 2616: RFX1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells
Authors: Su Jung-Chen 
Published: May 2015

Abstract
Obatoclax is under clinical trial currently. Previously, we have demonstrated that SC-2001, an obatoclax analogue, has potent anti-tumor effect in HCC cells through the SHP-1/p-STAT3 cascade. However, the molecular mechanism by which SC-2001 activates SHP-1 is still elusive. Regulatory factor X (RFX) 1 is a transcription factor that has been linked to negative regulation of tumor progression. Nevertheless, its biological function in HCC cells is far from clear. In this study, by modulating its expression, we demonstrated that RFX1 is important in regulating SHP-1 in HCC cells. Ectopic expression of RFX1 can lead to activation of SHP-1 and inhibition of colony forming in HCC cells. Importantly, in a xenograft mouse model, RFX-1 overexpression obviously inhibited the growth rate of HCC tumors, indicating its tumor suppressor role. In addition, we found that SC-2001-induced apoptosis effect is regulated by RFX1. We showed that SC-2001 enhanced RFX1 nuclear translocation and binded to SHP-1 promoter to activate SHP-1 transcription. Moreover, knockdown of RFX1 reversed the anti-tumor effect of SC-2001 in vivo. Most important, we proved that SC-2001 displayed more potent anti-tumor effect than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Furthermore, combination treatment of SC-2001 and sorafenib showed synergistic effect in HCC cells. Collectively, our study confirmed that RFX1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for target therapy via the activation of the RFX1/SHP-1 pathway. (Supported by NSC-102-2325-B-010-007)
Citation Format: Jung-Chen Su. RFX1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2616. doi:10.1158/1538-7445.AM2014-2616
Abstract 2659: The MedImmune ADC platform: Building highly potent and specific cancer drugs
Authors: Hollingsworth Robert E. , Kamal Adeela , Howard Philip W. , Hartley John A. , Tice David , Gao Changshou , Dimasi Nazzareno , Zhong Haihong , Harper Jay , Xiao Zhan , Toader Dorin , Martin Chris , Wu Herren , Greenberg Norman , Jallal Bahija 
Published: May 2015

Abstract
MedImmune has made a major commitment to developing antibody-drug conjugates for cancer. Our ADC initiative builds on our previous experience with this area and with other armed antibody technologies, which have generated several drugs currently undergoing clinical development. We have leveraged our expertise in antibody engineering to develop new antibody constructs for ADC development, including variants that facilitate site-specific conjugation of the payload to the antibody. This technology circumvents problems associated with random payload conjugation, resulting in a more homogeneous drug product as well as improving the stability and potency of the ADC. We have developed new, potent payloads, teaming up with Spirogen to apply their expertise in the pyrrolobenzodiazapine (PBD) dimer payload technology. The PBD payloads are versatile and potent, allowing use of multiple types of linkers and adjustment of potency to very high levels (picomolar IC50 range). The mechanism of action of the PBDs is different from other commonly used ADC payloads, inducing DNA damage that may evade DNA repair mechanisms and killing both bulk cancer cells and cancer stem cells. We have also developed other, novel ADC payloads. Our ADC target discovery approach permits rapid identification and validation of targets specifically suited for this technology. This includes the early generation and use of tool ADCs for target evaluation. We are applying this state-of-the-art ADC platform to advancing multiple projects as a major component of our oncology drug development strategy.
Citation Format: Robert E. Hollingsworth, Adeela Kamal, Philip W. Howard, John A. Hartley, David Tice, Changshou Gao, Nazzareno Dimasi, Haihong Zhong, Jay Harper, Zhan Xiao, Dorin Toader, Chris Martin, Herren Wu, Norman Greenberg, Bahija Jallal. The MedImmune ADC platform: Building highly potent and specific cancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2659. doi:10.1158/1538-7445.AM2014-2659
Abstract 2662: Site specific ADC generation using SMARTag technology with programmable payload placement
Authors: Rabuka David 
Published: May 2015

Abstract
Antibody-drug conjugates (ADCs) are an exciting, new therapeutic option for cancer treatment. ADCs offer the promise of targeted drug delivery with increased efficacy and safety. Currently approved ADCs are heterogeneous mixtures resulting from nonselective ligation of drug to either cysteine or lysine residues. This heterogeneity complicates the pharmacokinetics and pharmacodynamics of these drugs.
Redwood Bioscience, Inc. has developed the SMARTagTM technology platform that enables precise, programmable, site-selective chemical protein modification and stable bioconjugate generation. Leveraging the target sequence of Formylglycine Generating Enzyme (FGE), proteins are chemoenzymatically modified to generate a precisely placed aldehyde functionality that can be chemically elaborated. Subsequently, novel ligation chemistry is employed that exploits this “aldehyde tag” site. This new reaction, the hydrazino-iso-Pictet-Spengler (HIPS) ligation, possesses two distinct advantages over current carbonyl ligations. First, the HIPS ligation proceeds quickly at near neutral pH in the absence of catalysts, allowing for one-step labeling of aldehyde-functionalized proteins under mild conditions. Second, HIPS ligation products are very stable in human plasma relative to an oxime-linked conjugates. Thus, the HIPS ligation exhibits a combination of stability and speed at near neutral pH that is unmatched by current carbonyl bioconjugation chemistries. We will present our novel protein modification platform and its application to generating ADCs, including our new conjugation chemistries and linker libraries. These technologies have been applied to the generation of a panel of site-specifically modified bioconjugates. Data from preclinical tumor models and PK studies highlighting the efficacy and safety of these ADCs and how these results are impacted by payload placement to the antibody will be presented.
Citation Format: David Rabuka. Site specific ADC generation using SMARTag technology with programmable payload placement. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2662. doi:10.1158/1538-7445.AM2014-2662
Abstract 2689: Breast cancer inhibition by a novel and potent biguanide, N1-hexyl-N5-benzyl-biguanide
Authors: Guo Zhijun , Chavez Kathryn J. , Alvarez Juan , Zhang Xia , Norris Beverly , Maher Michael , Morgan Monique , Schumacher Robert J. , Cuellar Rebecca , Sevrioukova Irina F. , Poulos Thomas L. , Denisov Ilia , Sligar Stephen G. , Gupta Kalpna , Blair Ian A. , Capdevila Jorge , Kelekar Ameeta , Amin Elizabeth , Georg Gunda , Potter David A. 
Published: May 2015

Abstract
Metformin is a widely used biguanide diabetes drug that is associated with decreased breast cancer risk and is currently being studied for treatment and prevention of breast cancer. While metformin and biguanides buformin and phenformin exhibit inhibitory activity against breast cancer in vitro and in vivo, they lack potency (IC50=5-20 mM) and their mechanisms of action remain unclear. More potent biguanides may provide insights into biguanide anti-cancer activity and we therefore studied the novel biguanide N1-hexyl-N5-benzyl-biguanide mesylate (HBB), which potently inhibits the MCF-7 and MDA-MB-231 breast cancer lines (IC50=20 uM for both lines). HBB induces AMPK phosphorylation in both lines at 10 uM concentration, whereas similarly dosed metformin, buformin or phenformin exhibits no activity. HBB also inhibits STAT3 phosphorylation at 10 uM concentration, whereas metformin dosed at 10 uM exhibits no activity. HBB reduced the mitochondrial membrane potential of both lines, but the effect was more prominent in the MDA-MB-231 line. HBB also induced ROS within 2.5 hours of exposure in the MCF-7 and MDA-MB-231 lines and caused rapid necrosis, but not apoptosis. N-acetylcysteine provides partial protection from HBB for MDA-231 line, but not the MCF-7 line. HBB provides proof of principle that highly potent biguanides can be synthesized with at least 250-fold greater potency than metformin, which can provide insights into the cancer inhibitory mechanisms of biguanide drugs. R01 CA113570, Randy Shaver Foundation, CTSI University of Minnesota
Citation Format: Zhijun Guo, Kathryn J. Chavez, Juan Alvarez, Xia Zhang, Beverly Norris, Michael Maher, Monique Morgan, Robert J. Schumacher, Rebecca Cuellar, Irina F. Sevrioukova, Thomas L. Poulos, Ilia Denisov, Stephen G. Sligar, Kalpna Gupta, Ian A. Blair, Jorge Capdevila, Ameeta Kelekar, Elizabeth Amin, Gunda Georg, David A. Potter. Breast cancer inhibition by a novel and potent biguanide, N1-hexyl-N5-benzyl-biguanide. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2689. doi:10.1158/1538-7445.AM2014-2689
Abstract 2709: Identification of Aurintricarboxylic Acid (ATA) as an inhibitor of TWEAK-Fn14 signaling in glioblastoma cells
Authors: Dhruv Harshil D. , Holiday Ethan , Chow Donald , Yin Holly , Berens Michael E. , Tran Nhan L. 
Published: May 2015

Abstract
The long-term survival of patients with glioblastoma (GB) is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor necrosis factor superfamily, can stimulate glioma cell invasion via binding to fibroblast growth factor-inducible 14 (Fn14) and subsequent activation of the transcription factor NF-κB. In order to discover a small molecule inhibitors that disrupt Fn14-TWEAK signaling axis and subsequently glioma cell invasion, we developed a cell-based drug screening assay using HEK293 cells that overexpresses Fn14 and harbors NF-κB driven Firefly luciferase protein expression. In preliminary drug screening assay using LOPAC1280 library of 1280 pharmacologically active compound, Aurintricarboxylic Acid (ATA) showed suppression of NF-κB driven Firefly Luciferase activity downstreatm of TWEAK-Fn14 signaling. Conversely, ATA did not show any suppression in NF-κB driven Firefly Luciferase activity downstream of TNFα-TNFR1 signaling, suggesting that ATA is a specific inhibitor of TWEAK-Fn14-NF-κB signaling. In vitro, we demonstrated that ATA suppresses TWEAK induced chemotactic migration of glioma cells (T98G and A172) and display no general cytotoxicity. In summary, this work reports a new small molecule inhibitor of TWEAK-Fn14 signaling that could be useful in enhancing the therapeutic targeting of this deadly disease.
Citation Format: Harshil D. Dhruv, Ethan Holiday, Donald Chow, Holly Yin, Michael E. Berens, Nhan L. Tran. Identification of Aurintricarboxylic Acid (ATA) as an inhibitor of TWEAK-Fn14 signaling in glioblastoma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2709. doi:10.1158/1538-7445.AM2014-2709