bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3964: Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins
Authors: El-Behaedi Salma , Landsman Rebekah , Rudloff Michael , Kolyvas Emily , AlBalawy Rakan , Alewine Christine 
Published: August 2018

Abstract
Recombinant immunotoxins are antibody-based therapies that carry a bacterial toxin payload. LMB-100 is a next generation immunotoxin currently being tested in clinical trial. It targets the human cell surface antigen mesothelin (MSLN). MSLN is made by many solid tumors but has no expression in the parenchyma of vital organs. LMB-100 carries a Pseudomonas exotoxin payload that works by irreversibly modifying elongation factor-2 (EF-2), inactivating it and halting protein synthesis. To determine whether non-lethal doses of LMB-100 might inhibit tumor cell secretion of cytokines and growth factors that maintain the pancreatic cancer microenvironment, human pancreatic cancer cells were treated with LMB-100 and conditioned medium was assayed for tumor-secreted factors by ELISA and Luminex assays. Decreased levels of multiple secreted factors were detected including VEGF, PDGF, MMP-1, SPARC, and OPN. Conversely, levels of MIF, a stored cytokine released under stress conditions, increased dramatically upon LMB-100 treatment. To determine whether this also occurs in vivo, tumor-bearing athymic nude mice were treated with LMB-100 and levels of tumor-secreted factors in intratumoral fluid were measured. A statistically significant decrease in the same factors was found in treated mice compared to control mice. To determine whether these decreases in tumor-secreted factors could change the tumor microenvironment and alter the immune milieu, a mouse syngeneic model of pancreas cancer sensitive to LMB-100 was developed. LMB-100 treatment of this mouse cell model caused a statistically significant decrease in the angiogenesis factors VEGF and Angiopoietin-2 in conditioned medium. To determine if this also occurs in vivo, immune-competent mice bearing intraperitoneal or orthotopic tumors were treated with immunotoxin or vehicle then intratumoral fluid was assayed for secreted proteins contributed by both tumor and stromal cells. No detectable change in intratumoral fluid concentration was seen for VEGF, Antiopoietin-2 or a panel of 11 other secreted factors. In conclusion, LMB-100 does inhibit tumor cell production of secreted proteins, but this change is insufficient to alter the total concentration of secreted factors in the tumor microenvironment.
Citation Format: Salma El-Behaedi, Rebekah Landsman, Michael Rudloff, Emily Kolyvas, Rakan AlBalawy, Christine Alewine. Mesothelin targeting immunotoxin LMB-100 alters the profile of tumor-secreted proteins [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 3964.
Abstract 3969: Lipocalin-2-targeted small interference RNA for inflammatory breast cancer treatment
Authors: Santiago-Sanchez Ginette S. , Valiyeva Fatma , Debeb Bisrat , Mejia Pablo E. 
Published: August 2018

Abstract
Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer with low survival rate. Available therapies to treat this type of cancer are almost limited to surgery and radiation therapy. Potential therapeutic targets for IBC treatment include the oncogene Her2 and the Epidermal Growth Factor Receptor (EGFR). However, these therapies have not been successful since not all IBC tumors are Her2-amplified and development of resistance to treatment has also been observed. Hence, there is a critical need for novel therapeutic targets for IBC treatment. One of such possibilities is Lipocalin-2 (LNC2). LCN-2 is a secreted glycoprotein and an adipokine superfamily member that posses roles in transport of small lipophilic molecules in circulation, innate immunity, and iron homeostasis. High levels of LCN2 have been observed in invasive breast cancer human tissue. Additionally, LCN2 has been linked with breast cancer tumorigenesis and metastasis. Therefore, the purpose of our study is to assess if LCN2 is a plausible therapeutic target to treat IBC. Western blot analysis was used to assess the LCN2 protein level in a panel of IBC (MDA-IBC-3, SUM-149) and non-IBC cell lines (MCF-7, MDA-MB-231, MDA-MB-438). IBC cell lines showed a significantly higher expression of the LCN2 protein in comparison to the non-IBC cell lines. We decreased the expression of the LCN2 protein with small interference RNA (siRNA) molecules. Silencing of IBC cells with LCN2-targeted siRNA molecules decreased the LCN2 protein expression levels in almost fifty percent. Colony formation assay demonstrated that siRNA-mediated LCN2 silencing in MDA-IBC-3 and SUM-149 cell lines resulted in a significant decrease in cell proliferation. Taken together these results suggest that LCN2 may become a right target for IBC treatment. Ongoing experiments include cell invasion assays to determine if LCN2-targeted siRNAs reduce the metastatic potential, increase apoptosis and block cell cycle progression. Acknowledgements: This work is supported by the University of Puerto Rico Comprehensive Cancer Center and the U54 partnership with MD Anderson Cancer Research Center.
Citation Format: Ginette S. Santiago-Sanchez, Fatma Valiyeva, Bisrat Debeb, Pablo E. Mejia. Lipocalin-2-targeted small interference RNA for inflammatory breast cancer treatment [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 3969.
Abstract 3973: Dabrafenib suppresses the growth of BRAF-WT cancers through inhibition of novel targets Nek9 and Cdk16
Authors: Phadke Manali S. , Rix Lily , Smalley Inna , Bryant Annamarie , Lawrence Harshani , Schaible Braydon , Chen Ann , Rix Uwe , Smalley Keiran 
Published: August 2018

Abstract
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS and KRAS-mutant cancer cells by dabrafenib but not vemurafenib. Combined silencing of NEK9 and CDK16 were associated with enhanced inhibition of melanoma cell proliferation and a greater induction of cell cycle arrest. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations.
Citation Format: Manali S. Phadke, Lily Rix, Inna Smalley, Annamarie Bryant, Harshani Lawrence, Braydon Schaible, Ann Chen, Uwe Rix, Keiran Smalley. Dabrafenib suppresses the growth of BRAF-WT cancers through inhibition of novel targets Nek9 and Cdk16 [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 3973.
Abstract 3975: Target engagement, thrombocytopenia, and efficacy induced by the dual Bcl2/xL inhibitor AZD4320 are quantitatively linked by a PK/PD model in leukemia xenografts
Authors: Gibbons Francis D. , Adam Ammar , Beaudoin Marie-Eve , Gangl Eric , Secrist Paul 
Published: August 2018

Abstract
The proteins Bcl2 and Bcl-xL are often up-regulated in cancer, and hold in check the apoptosis that would normally be initiated by accumulation of the BH3-only proteins Bax and Bak in response to genomic dysregulation. AZD4320 potently disrupts that interaction, initiating the apoptotic cascade in Bcl-2 or Bcl-xL-dependent tumors. Because platelets are known to be dependent on Bcl-xL, thrombocytopenia is an expected on-target effect. AZD4320 was administered at dose levels 0.5-10 mg/kg, both intravenously and extravascularly, to immune-compromised mice inoculated subcutaneously with the RS4;11 model of acute lymphocytic leukemia (ALL). Drug concentrations were measured by liquid chromatography-mass spectrometry (LC-MS) in plasma and tumor. A cleaved-caspase-3 ELISA was used to assess apoptotic activity in the tumor. Parallel efficacy studies, were used to assess tumor growth compared to vehicle, following tumors from initial regression at tolerated doses to regrowth. Tumors were measured using calipers, and tumor volumes computed using an ellipsoid approximation. We present a mini-physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model that links drug concentrations in plasma and tumor to observed caspase activity and efficacy in an integrated manner, across multiple dose levels and schedules. The tumor is modeled as a pool of sensitive cells which can be triggered rapidly by AZD4320 to apoptose, from which point they transition gradually to death, reducing tumor volume. Cleaved caspase-3 is used as a marker of apoptosis, and modeled using a sigmoidal response function with steep slope parameter. In this way, we effectively capture the transient nature of the response, despite AZD4320's long residence in the tumor. Thrombocytopenia is described not as an effect on the megakaryocyte precursors, but as a linear concentration-dependent effect on circulating platelets. Feedback from the circulation to megakaryocytes drives increased production to fill the deficit. Parameters are well-estimated throughout. Together, these components provide a comprehensive means to investigate the effects of dose and schedule with a dual Bcl2/BCL-xL inhibitor.
Citation Format: Francis D. Gibbons, Ammar Adam, Marie-Eve Beaudoin, Eric Gangl, Paul Secrist. Target engagement, thrombocytopenia, and efficacy induced by the dual Bcl2/xL inhibitor AZD4320 are quantitatively linked by a PK/PD model in leukemia xenografts [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 3975.
Abstract 3979: Active components of Alpinia katsumadai-induced cell apoptosis and autophagy in human pancreatic cancer cells
Authors: An Weixiao , Lai Honglin , Zhang Yangyyang , Lin Xiukun , Cao Shousong 
Published: August 2018

Abstract
Alpinia katsumadai, as a traditional Chinese medicine, exhibited potent anti-oxidative and anticancer effects. Studies have shown that the effect of the active components of Alpinia katsumadai (ACAK) on anticancer is via apoptosis or autophagy in colorectal and glioblastoma cancer cells. However, the effects of ACAK on anticancer effect and inducation of apoptosis and autophagy in pancreatic cancer cells are still unknown. Therefore, we investigated the effects of ACAK on cytotocixity, apoptosis and autophagy as well as associated mechanisms in pancreatic cancers Panc-1 and Panc-28 cells. We found that ACAK showed greater inhibitory effects on the proliferation of Panc-1 and Panc-28 cells in a dose- and time-dependent manners (IC50 0.1692 and 0.1554mg/ml, respectively) compared to a variety of other cancer cells including breast cancer MDA-MB-468 cells, melamoma A875 cells, lung cancer A549 cells, colon cancer HCT-116 cells, and glioblastoma cancer U87 cells (IC50 0.2302, 0.2586, 0.2642, 0.3006, and 0.4298, respectively) by CCK-8 assay. Furthermore, ACAK induced cell apoptosis in pancreatic cancer Panc-1 and Panc-28 cells in a dose- dependent manner by Hochest 33342-PI and AnnexinV-PI dual staining analysis. Moreover, the expression levels of apoptosis related proteins casepase 3, casepase 9, and PARP were significantly up-regulated by Western blotting analysis. The study of cell autophagy was dectected by mRFP -GFP-LC3 adenovirus and western-blotting. and the results showed that the expression levels of autophagy-related protein beclin-1 and LC3-II were significanlt up-regulated by mRFP-GFP-LC3 adenovirus and western-blotting analysis. Our findings demonstrated that ACAK had greater cytotoxicity than a variety of other cancer cells by inducing apoptosis and autophagy in pancreatic cancer Panc-1 and Panc-28 cells. Therefore, ACAK may be developed as a novel anticancer agent for the treatment of pancreatic cancer clinically.
Citation Format: Weixiao An, Honglin Lai, Yangyyang Zhang, Xiukun Lin, Shousong Cao. Active components of Alpinia katsumadai-induced cell apoptosis and autophagy in human pancreatic cancer cells [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 3979.
Abstract 3981: Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2
Authors: Rather Gulam M. , Kerrigan John E. , Scotto Kathleen W. , Bertino Joseph R. 
Published: August 2018

Abstract
The mitochondrial folate enzyme, methylene tetrahydrofolate dehydrogenase (MTHFD2), is a promising anticancer target because 1) it is required for the generation of one-carbon units required for purine synthesis and generation of NADH/NADPH necessary for protection from ROS in the mitochondria; 2) it is markedly distinct from the cytoplasmic MTHFD1 enzyme with respect to location, catalytic activity and cofactors; 3) it is expressed at low levels in proliferating normal cells; 4) in contrast, it is highly expressed in a variety of rapidly proliferating malignant tumors; 5) knockdown (KD) of MTHFD2 has been shown to inhibit proliferation in a subset of tumor cells in vitro; and 6) MTHFD2 KD is predicted to have metabolic consequences (glycine auxotrophy, folate deficiency) that could be exploited for combination therapy. In this study we tested the hypotheses that downregulation of MTHFD2 will result in relative folate deficiency, which can be exploited by using a folate-depleting enzyme, carboxypeptidase G2 (CPG2), to enhance tumor cell kill. CPG2 is approved by the FDA for the treatment of methotrexate overdose in patients. It acts to inactivate MTX or naturally occurring folates by hydrolyzing the terminal glutamate from folates and MTX, generating a pteroate and glutamate. As pteroates cannot be used to resynthesize folates, or MTX, this treatment depletes cells from MTX or folates. The combination of CPG2 in cell lines, MCF7 and T47D with MTHFD2 KD, was done and the actual increase in growth inhibition showed enhanced antitumor effects, indicating that when effective inhibitors of MTHFD2 are available, this combination may have widespread clinical usefulness, especially in rapidly proliferating tumors that express high levels of MTHFD2.
Citation Format: Gulam M. Rather, John E. Kerrigan, Kathleen W. Scotto, Joseph R. Bertino. Enhancement of the anticancer activity of methylenetetrahydrofolate dehydrogenase knockdown by folate depletion with carboxypeptidase G2 [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 3981.
Abstract 3982: Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma
Authors: Ronecker Jennifer S. , Pazniokas Julia , Amin Anubhav G. , Medeiros Raphael Salles Scortegagna de , Epelman Sidnei , Ghandi Chirag , Zanon Nelci , Schmidt Meic H. , Jhanwar-Uniyal Meena 
Published: August 2018

Abstract
Comprehensive studies of the medulloblastoma (MB) genome, epigenome and transcriptome have placed MB in four molecular subgroups: WNT, SHH, and two non-WNT/non-SHH: Group 3 and Group 4. Furthermore, studies suggest that p53-mutated SHH MBs frequently harbor genetic anomalies involving MYCN and GLI2 amplifications, which confer poor prognosis and resistance to treatments. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway that regulates cell growth, survival and invasion, is commonly deregulated in MB. Therefore, the PI3K/Akt/mTOR pathway may be a suitable target for therapeutic intervention. Moreover, Histone deacetylases (HDAC) regulate cancer initiation and progression, and studies have shown that small molecule inhibitors of HDAC can effectively limit MB proliferation. We aim to determine the status of tumor suppressor gene p53 in defining metastatic potential in SHH-MB and to establish the therapeutic efficacy of targeting these pathways in p53-driven MB cells with a dual agent or individual agents. Immunohistochemistry and FISH were used to determine the status of mutant p53 and MYC amplification or iso-p53, respectively, in MB tumors (n=41). p53-mutant MB cell line was used to investigate the signaling pathway that regulates proliferation, migration, and drug resistance using inhibitors of HDAC (LBH-589) and PI3K/mTOR (BKM-120/rapamycin) or CUDC-907 (dual inhibitor of HDACs and the PI3K/AKT). Results demonstrated that: 1) GAB-1 was highly expressed in the Shh group (82%) and KV1 expression was evenly distributed in all subtypes; 2) loss of p53 and overexpression of MYC varied in each subtype, but did not correlate with metastasis; 3) combined treatment with LBH-589 and BKM-120 or single treatment with CUDC-907 reduced cell proliferation, migration and S-phase entry; 4) MB cells were resistant to BKM -120, while LBH-589 or CUDC-907 caused apoptosis; 5) tumor formation was suppressed by BKM-120 given with mTOR inhibitors; 6) AKT and 4E-BP1 dephosphorylated following treatments with BKM-120 or CUDC-907. In conclusion, despite current clinical limitations, dual HDAC and PI3K inhibitors may benefit the understanding of aberrant signaling pathways in genetically driven MB, and may provide basis for future targeted therapies.
Citation Format: Jennifer S. Ronecker, Julia Pazniokas, Anubhav G. Amin, Raphael Salles Scortegagna de Medeiros, Sidnei Epelman, Chirag Ghandi, Nelci Zanon, Meic H. Schmidt, Meena Jhanwar-Uniyal. Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma [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 3982.
Abstract 3986: HDAC4 degradation by combined TRAIL and valproic acid treatment induces apoptotic cell death of TRAIL-resistant head and neck cancer cells
Authors: Lee Bok-Soon , Kim Yeon Soo , Jang Jeon Yeob , Kim Hyo Jeong , Lee Myeong-Hoon , Chang Jae Won , Koo Bon Seok , Won Ho-Ryun , Kim Yong-Sung , Kim Chul-Ho 
Published: August 2018

Abstract
Purpose: Although TRAIL can directly induce death in cancer cells via DR4 and DR5 receptors, it appears that TRAIL resistance exists in many cancers. This study focuses on anti-cancer drugs for TRAIL-resistant head and neck cancer (HNC) to provide a further step toward effective cancer therapy.
Materials and Methods: The combined effects of TRAIL and VPA on cell viability were assessed via MTT and flow cytometric assays. Western blotting was used to determine cell death signaling.
Results: The results indicate that combined TRAIL and VPA treatment greatly reduced the cell viability and thus induced cell death relative to treatment with TRAIL or VPA alone in TRAIL-resistant HNC cells. A caspase-dependent signaling pathway was shown, and combined treatment with TRAIL and VPA also significantly decreased the expression of HDAC4. When we pretreated cells with z-VAD followed by combined treatment with TRAIL and VPA, the cell death was blocked with no decreased expression of HDAC4. To confirm the cell death involved in HDAC4 in HNC cells, we pretreated siRNA of the HDAC 4, followed by treating the TRAIL and VPA. The results showed that the knock down of HDAC4 sensitized the TRAIL-resistant HNC cells to apoptotic cell death. Finally, we showed a high expression of HDAC4 in HNC tissues compared to normal tissues obtained from the same patients.
Conclusion: Combined VPA and TRAIL treatment may be a promising therapy for HNC via HDAC4 degradation.
Citation Format: Bok-Soon Lee, Yeon Soo Kim, Jeon Yeob Jang, Hyo Jeong Kim, Myeong-Hoon Lee, Jae Won Chang, Bon Seok Koo, Ho-Ryun Won, Yong-Sung Kim, Chul-Ho Kim. HDAC4 degradation by combined TRAIL and valproic acid treatment induces apoptotic cell death of TRAIL-resistant head and neck cancer cells [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 3986.
Abstract 3993: Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF
Authors: Bivona Trever G. , Nichols Robert , Haderk Franziska , Stahlhut Carlos , Schulze Christopher , Hemmati Golzar , Wildes David 
Published: August 2018

Abstract
Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including oncogenic KRAS, NF1 loss, and non-V600E oncogenic BRAF. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective in human cancer models bearing nucleotide-cycling oncogenic RAS (e.g. KRASG12C), NF1 loss, or RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants). SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers.
Citation Format: Trever G. Bivona, Robert Nichols, Franziska Haderk, Carlos Stahlhut,Christopher Schulze, Golzar Hemmati, David Wildes. Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF [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 3993.