bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2601: A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer in vitro and in vivo
Authors: Lim Do Young , Shin Seung Ho , Malakhova Margarita , Lee Mee-Hyun , Bode Ann M. , Dong Zigang 
Published: August 2015

Abstract
For decades, lung cancer has been a leading cause of death in the U.S., mainly due to oncogenic signaling pathways activated by carcinogens such as smoking. Various carcinogens induce EGFR/RAS/MAPK signaling that is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 against lung carcinogenesis will be beneficial to these patients. Herein, we examined the therapeutic effects of catechol (also known as pyrocatechol or 1,2-dihydroxybenzene), a naturally occurring chemical in many foods such as apple, banana, apricot, grape, plum, avocado and mushroom. Co-crystallography results suggested that ERK2 is a direct target of catechol. In agreement with the co-crystallography result, catechol was confirmed to inhibit ERK2 kinase activity in vitro. Catechol inhibited anchorage-independent KP2 and H460 lung cancer cell growth in a dose-dependent manner. Phosphorylation of c-Myc, a substrate of ERK2, was reduced in catechol-treated lung cancer cells compared to untreated controls. Decreased c-Myc phosphorylation resulted in its reduced protein stability and subsequent down-regulation of total c-Myc levels. Treatment with catechol induced G1 cell cycle arrest and resulted in a decrease of G1 phase related proteins, CDK2 and cyclin D1. In vivo study results also revealed that catechol inhibited growth of KP2 and H460 xenograft tumors. Phosphorylation levels of c-Myc were also strongly decreased by catechol treatment in vivo. Taken together, we have shown that catechol exerts inhibitory effects on the ERK2/c-Myc signaling axis in lung cancer cells to reduce tumor growth in vitro and in vivo. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis.
Citation Format: Do Young Lim, Seung Ho Shin, Margarita Malakhova, Mee-Hyun Lee, Ann M. Bode, Zigang Dong. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2601. doi:10.1158/1538-7445.AM2015-2601
Abstract 2604: Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]
Authors: Santag Susann , Siegel Franziska , Wegner Antje Margret , Schneider Claudia , Boemer Ulf , Eis Knut , Puehler Florian , Michels Martin , von Nussbaum Franz , Ziegelbauer Karl , Mumberg Dominik , Petersen Kirstin 
Published: August 2015

Abstract
MKNK1 (MAP kinase-interacting serine/threonine-protein kinase, also known as Mnk1) is activated by the mitogen-activated protein kinases ERK1/2 and p38. Thus, MKNK1 signaling is involved in the cellular response to environmental stress factors and cytokines. Of particular interest, MKNK1 kinase was shown to regulate mRNA translation by phosphorylating the translation initiation factor eIF4E (eukaryotic translation initiation factor 4E), known to be critical for malignant transformation but dispensable for translation in normal cells. In addition, MKNK is involved in resistance mechanisms to cancer therapeutics. Thus, the inhibition of MKNK1 activity may provide an innovative approach for anti-cancer therapy.
BAY 1143269 was identified as a potent and selective inhibitor of MKNK1 activity with an unprecedented mode of action.
It inhibits the phosphorylation of eIF4E in various cancer cell lines in vitro and leads to reduced expression of MKNK-regulated translational downstream targets, including survivin, Cdc25C and cyclin B1. In addition, BAY 1143269 potently inhibits cytokine release in LPS stimulated human blood.
In vivo, BAY 1143269 shows a significant monotherapy efficacy in non-small cell lung cancer (NSCLC), colorectal cancer and melanoma xenograft models after an once daily, oral application of 200 mg/kg in mice and 70 mg/kg in rats.
Furthermore, combination treatment with chemotherapy and BAY 1143269 gives additive efficacy in several NSCLC cell lines and patient-derived xenograft models leading to partial response (Lu7558, A549), stable disease (Lu7187, Lu7166) or significant delay in tumor re-growth versus chemotherapy alone after stop of treatment (Lu7558).
In summary, BAY 1143269 is a selective, orally available MKNK1 inhibitor that demonstrates preclinical in vivo efficacy in mono- and combination therapy and may provide therapeutic benefit for patients with solid tumors.
Citation Format: Susann Santag, Franziska Siegel, Antje Margret Wegner, Claudia Schneider, Ulf Boemer, Knut Eis, Florian Puehler, Martin Michels, Franz von Nussbaum, Karl Ziegelbauer, Dominik Mumberg, Kirstin Petersen. Preclinical anti-tumor efficacy and mode of action of a novel, orally available, selective MKNK1 inhibitor [BAY 1143269]. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2604. doi:10.1158/1538-7445.AM2015-2604
Abstract 2606: Antitumor activity of the selective RAF inhibitor HM95573 in melanoma
Authors: Bae InHwan , Ahn YoungGil , GwangMo Namgoong , Kim SuHyeon , Song JiYeon , Song TaeHun , Lee JaeHo , Lee KyuHang , Lee Young-Mi , Kim YoungHoon , Suh KweeHyun 
Published: August 2015

Abstract
The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF and NRAS is considered one of the causes of melanoma.
HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM).
HM95573 potently inhibited the growth of mutant BRAF melanoma cell lines such asA375 (IC50: 57nM) and SK-MEL-28 (69nM) and of mutant NRAS melanoma cell lines such asSK-MEL-2 (53nM) and SK-MEL-30 (24nM). In addition, the phosphorylations of MEK and ERK downstream kinases associated with cell proliferation were effectively inhibited with treatment of HM95573in mutant BRAF and mutant NRAS melanoma cells.HM95573inhibited the downstream signaling in melanoma cells even in the presence of HGF which is known to mediate innate resistance to RAF inhibitors.
HM95573 showed the excellent antitumor activity in mouse models xenografted with both of BRAF mutation cell lines (e.g. A375 and SK-MEL-28) and NRAS mutation cell lines (such as SK-MEL-2 and SK-MEL-30) compared to two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. Furthermore, HM95573 did not show a potential to paradoxical activation inducing tumor growth in mouse xenograft study using A431 cuSCC (cutaneous squamous cell carcinoma)cancer cell.
Now, HM95573 is currently in phase I development in patients with advanced solid tumors including melanoma in Korea.
Citation Format: InHwan Bae, YoungGil Ahn, Namgoong GwangMo, SuHyeon Kim, JiYeon Song, TaeHun Song, JaeHo Lee, KyuHang Lee, Young-Mi Lee, YoungHoon Kim, KweeHyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2015-2606
Abstract 2621: Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice
Authors: Thakkar Arvind , Chenreddy Sushma , Wang Jeffrey , Prabhu Sunil 
Published: August 2015

Abstract
The present study aims to evaluate the preclinical systemic toxicity profile of chitosan-solid lipid nanoparticles (c-SLNs) encapsulated aspirin (ASP), curcumin (CUR), and free sulforaphane (SFN) combination (ACS) in BALB/c mice. Recently, we demonstrated pancreatic cancer chemopreventive efficacy using ACS-SLNs delivery system in the BOP carcinogen induced pancreatic cancer hamster model. In order to develop safe ACS c-SLNs for clinical applications, it is vital to investigate their toxicity. Thus, we performed acute 3-day, sub-acute 28-day and sub-chronic 90-day toxicity studies of ACS c-SLNs in the BALB/c mice model. The mice were orally gavaged once every 24h with 200 μl ACS c-SLNs at three concentrations: low dose ACS (2+4.5+0.16 mg/kg; 1/30th of high dose), medium dose ACS (20+45+1.6 mg/kg; 1/3rd of high dose) and high dose ACS (60+135+4.8 mg/kg). Total of 60 mice were used for this study (4 mice each group X 3 timepoints X 5 groups). A standard evaluation was performed, which included daily clinical signs, weekly body weight, end-of-study blood hematology, blood clinical chemistry, gross necropsy on all animals and hematoxylin and eosin-stained examination of range of tissues from each animal. The clinical chemistry tests include blood urea nitrogen (BUN) and creatine (CRE), which indicate renal toxicity. Alanine transaminase (ALT) and alkaline phosphatase (ALP) levels indicate hepatic toxicity, while glucose (GLU) and total protein are measures of healthy growth. At the end-of-study, data revealed that mean body weight gain was consistent with low-, medium- and high-ACS c-SLN dose during acute, sub-acute and sub-chronic treatment period. The blood count and blood chemistry profiles revealed lack of systemic toxicity as the numbers were within normal ranges. Extensive histopathological examination of liver, kidney, heart, brain and pancreatic tissues showed no increase in treatment-related microscopic lesions in any of the three ACS c-SLN dose groups. Collectively, these findings demonstrate that repetitive oral administration of ACS c-SLN even at high concentrations was not associated with local or systemic toxicity and did not adversely affect the blood clinical chemistry of mice. Hence, long-term ACS c-SLN oral therapy is deemed safe for prevention of pancreatic cancer.
Citation Format: Arvind Thakkar, Sushma Chenreddy, Jeffrey Wang, Sunil Prabhu. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2621. doi:10.1158/1538-7445.AM2015-2621
Abstract 2624: Pre-clinical studies of a mutant p53 reactivating drug in pancreatic cancer
Authors: Yu Xin , Tsang Ashley T. , Li Zhe , Eng Oliver S. , Lin Hongxia , Gounder Murugesan , Carpizo Darren R. 
Published: August 2015

Abstract
Pancreatic cancer therapy suffers from a lack of effective chemotherapy. TP53 is second only to Kras as the most commonly mutated gene in pancreatic cancer with point mutations occurring in 75% of patients. Recently, our laboratory identified ZMC1 as an allele specific p53 mutant reactivating compound. This compound selectively kills cancer cells that express the p53-R175H mutation by restoring wildtype structure and function to this mutant. It does not reactivate the DNA contact mutant, p53-R273H or p53-R248H. This established ZMC1 as a lead compound for mutant p53 targeted drug development. We are currently investigating the potential of ZMC1 as novel anti-cancer drug through pre-clinical studies in pancreatic cancer. Previously we reported the ZMC1 allele specificity in murine pancreatic cancer cell lines derived from the KPC mouse model expressing mutant KrasG12D and different alleles of TP53 (WT, null, p53R172H, p53R270H). We have investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of ZMC1 in the KPC mouse model. Using LC/MS/MS we developed a sensitive assay for detection of ZMC1 in mouse plasma. We measured drug concentrations in mouse plasma and tumor tissues in different delivery routes and different dosages in the PK studies. We have developed a PD assay for ZMC1 with cleaved caspase-3 immunostaining with which we have tested several doses of ZMC1 and found that we detect activity of ZMC1 in KPCp53-R172H xenograft tumors while at the same time relatively no activity in KPCp53-R270H tumors. These same assays were also performed on KPC autochthanous tumors and again revealed activity of ZMC1 in the KPCp53-R172H mice. Efficacy studies in the KPCp53-R172H xenografts showed potent tumor growth inhibition at both intravenous (1mg/kg) and intraperitoneal (5mg/kg) dosing while no evidence of growth inhibition in KPCp53-R270H. Furthermore, ZMC1 extended the survival days from average 15 days to 26 days in the KPCp53-R172H mice but it was not significantly observed in the KPCp53-R270H mice. The tumor growth rate was also decreased in the KPCp53-R172H but not in the KPCp53-R270H mice. These studies indicated that ZMC1 is an allele-specific p53 mutant reactivating compound and holds promise for future applications in pancreatic cancer.
Citation Format: Xin Yu, Ashley T. Tsang, Zhe Li, Oliver S. Eng, Hongxia Lin, Murugesan Gounder, Darren R. Carpizo. Pre-clinical studies of a mutant p53 reactivating drug in pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2624. doi:10.1158/1538-7445.AM2015-2624
Abstract 2655: Determinants of sensitivity to PI3K inhibitors in PIK3CA wildtype gastric tumor cells
Authors: Chong Mei Ling , Bhattacharya Bhaskar , Voon Dominic , Koh King Xin , Low Hong Hui , Chang Ti Ling , Wu Mengchu , Tan Patrick Boon Ooi , Loh Marie Chiew Shia , Benoukraf Touati , Hung Huynh The , Politz Oliver , Liu Ningshu , Soong Richie Chuan Teck 
Published: August 2015

Abstract
Background: PIK3CA mutations are emerging as useful indicators of sensitivity to PI3K inhibitors, However many PIK3CA wildtype cells are also sensitive to PI3K inhibitors, and a biomarker of these cells is desirable This study aimed to identify and functionally verify determinants of sensitivity to PI3K inhibitors in PIK3CA wildtype cells.
Materials and Methods: Eight PIK3CA wildtype gastric cancer cell lines were screened by MTS assay for their sensitivity to 6 PI3K inhibitors (BAY 806946 (Copanlisib), BAY 1082439, GDC-0941, BKM120, BYL719, XL147). Categorization of cells was performed by unsupervised clustering of quantile normalized IC50 values. RNA sequencing was performed using the ScriptSeqv2 mRNA-Seq kit, Illumina HiSeq 2000, and Partek software. Functional evaluation was performed by lentivirus modulation and standard phenotypic analyses. Six patient-derived PIK3CA wildtype gastric tumor xenograft models (PDXs) were also evaluated for sensitivity to PI3K inhibition and candidate expression.
Results: Unsupervised clustering revealed two subgroups, comprising 3 resistant and 5 sensitive cell lines. Among differentially expressed genes, IGFBP3 had the highest overexpression (67-fold) in sensitive cells. IGFBP3 encodes insulin growth factor binding protein 3, which sequesters insulin growth factor (IGF) from binding to its receptor (IGF-1R). The sequestration of IGF by IGFBP3 may repress alternative activation of PI3K pathways through IGF signaling. Consistent with this, overexpression of IGFBP3 increased cell sensitivity to PI3K inhibitors and was accompanied by reduced IGF-1R, Akt and S6 phosphorylation and increased G1 arrest. IGFBP3 expression was also significantly higher in PDXs responsive to PI3K inhibitors than in those resistant.
Conclusions: High IGFBP3 may be a useful biomarker of sensitivity to PI3K inhibitors in PIK3CA wildtype gastric tumor cells.
Citation Format: Mei Ling Chong, Bhaskar Bhattacharya, Dominic Voon, King Xin Koh, Hong Hui Low, Ti Ling Chang, Mengchu Wu, Patrick Boon Ooi Tan, Marie Chiew Shia Loh, Touati Benoukraf, Huynh The Hung, Oliver Politz, Ningshu Liu, Richie Chuan Teck Soong. Determinants of sensitivity to PI3K inhibitors in PIK3CA wildtype gastric tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2655. doi:10.1158/1538-7445.AM2015-2655
Abstract 2699: Targeting GSK-3: a novel approach to enhance glioblastoma chemosensitivity
Authors: Ugolkov Andrey , Dubrovskyi Oleksii , Gaisina Irina , Yemelyanov Alex , Bondarenko Gennadiy , James Charles , Chandler James , O'Halloran Thomas , Kozikowski Alan , Raizer Jeffry , Mazar Andrew 
Published: August 2015

Abstract
Glioblastoma (GBM) is, in essence, an incurable cancer, with most patients surviving 12-15 months following initial diagnosis. Previously published studies identified Glycogen Synthase Kinase-3 (GSK-3) as a new therapeutic target in GBM. Because GSK-3beta is a positive regulator of NF-kappaB-mediated survival and chemoresistance in cancer cells, we hypothesize that the inhibition of GSK-3 may overcome NF-kappaB-mediated chemoresistance to conventional drugs in human GBM. Using IVIS imaging of live mice, we found that: 1) NF-kappaB is constitutively active in orthotopic GBM patient-derived xenograft (PDX) tumors expressing an NF-kappa luciferase reporter; and 2) a single intravenous injection of our novel GSK-3 inhibitor 9-ING-41 (25 mg/kg) significantly reduced NF-kappaB transcriptional activity in orthotopic GBM PDX. Using 3 different orthotopic GBM PDX- tumor models, enabled for bioluminescence imaging through luciferase modification, we evaluated antitumor effects of 9-ING-41, alone as well as in combination with irinotecan, CCNU and temozolomide. Our in vivo results revealed that treatment with a combination of 9-ING-41 and irinotecan delays GBM PDX tumor growth, relative to either agent as a monotherapy, and, even more promising, 9-ING-41+CCNU leads to a complete tumor regression. Histological evaluation of mouse brain confirmed the absence of cancer cells and a formation of cyst at the location of intracranial tumor in mice treated with 9-ING-41+CCNU. Our results provide a rationale to advance 9-ING-41 for clinical evaluation in treating GBM, especially when combined with CCNU cytotoxic therapy.
Citation Format: Andrey Ugolkov, Oleksii Dubrovskyi, Irina Gaisina, Alex Yemelyanov, Gennadiy Bondarenko, Charles James, James Chandler, Thomas O'Halloran, Alan Kozikowski, Jeffry Raizer, Andrew Mazar. Targeting GSK-3: a novel approach to enhance glioblastoma chemosensitivity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2699. doi:10.1158/1538-7445.AM2015-2699
Abstract 271: Targeting PD-1, TIM-3 and LAG-3 in combination for improved immunotherapy combinations
Authors: Kehry Marilyn , Horlick Robert , Bowers Peter , Jun Toni , da Silva Correia Jean , Graves Jonathan , Wang Yan , Laken Haley , King David J. 
Published: August 2015

Abstract
Antibodies that inhibit the CTLA-4 and PD-1 checkpoint pathways have shown significant activity as either single agents or in combination in both mouse models and clinical studies. TIM-3 and LAG-3 have been reported to function as additional immune checkpoints which limit anti-tumor T cell responses and represent an opportunity for additional combination approaches to improve patient response to immunotherapy. To explore the potential for targeting other immune checkpoints in combination with anti-PD-1, studies were conducted in syngeneic mouse models and in human in vitro assays.
A series of surrogate mouse specific reagents targeting TIM-3, LAG-3 and PD-1 have been generated to improve understanding of combination checkpoint therapy in several syngeneic models. Mouse tumor models were characterized by IHC and FACS for relevant markers including PD-L1, Foxp3, TIM3and LAG3, to identify those most likely to be subject to immunosuppressive mechanisms contributing to tumor growth and immune evasion. Initial syngeneic studies in MC38 and Colon 26 demonstrated that combinations of antibodies to murine PD-1, TIM-3 and LAG-3 improved efficacy over single agent therapy, suggesting that combinations of these checkpoint inhibitors might have therapeutic potential in the clinic. The results of ongoing studies to evaluate the dose response of the combinations as well as the contribution of the antibody isotype will be reported.
Potent anti-human PD-1, -TIM-3 and LAG-3 clinical candidates have been identified using SHM-XEL™, which combines mammalian cell display of human IgG with somatic hypermutation in vitro to select and mature antibodies with desired biological activities. In a DC/T cell MLR assay, combination of the anti-LAG-3 antibody with a novel anti-PD-1 antibody could further increase T cell secretion of IL-2 up to 30-fold compared to anti-LAG-3 alone. Anti-TIM-3 in combination with anti-PD-1 also improved the EC50 up to 6-fold. Staining of activated purified CD4+ or CD8+ T-cells demonstrate that co-expression of PD-1 and LAG-3 increases upon activation compared to naïve T-cells, suggesting combination therapy may be particularly effective against activated or exhausted T-cells. These in vitro data and in vivo pre-clinical model results support evaluating combination immunotherapy with anti-LAG-3, anti-TIM-3, and anti-PD-1 in cancer patients.
Citation Format: Marilyn Kehry, Robert Horlick, Peter Bowers, Toni Jun, Jean da Silva Correia, Jonathan Graves, Yan Wang, Haley Laken, David J. King. Targeting PD-1, TIM-3 and LAG-3 in combination for improved immunotherapy combinations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 271. doi:10.1158/1538-7445.AM2015-271