tbuckley/cabot-search huggingface dataset:
Abstract 4884: To Investigate the mechanism and function of nucleobindin-2 in human hepatoma cells
Authors: Jui-Hsiang Hung, Hsiu-Ping Tsao, Ren-Hao Li, Chih-Han Li, Hut-Min Chang
Journal: Cancer Research (2020)

Abstract Hepatocellular carcinoma is a common malignancy affecting approximately one million people worldwide annually. Recent studies have shown that appetite-associated nucleobindin-2 (NUCB-2) is over-expressed in clinical tumor samples such as gastric cancer, prostate cancer, renal cell carcinoma, endometrial carcinoma cells, colon cancer and breast cancer. The survival rate of high-level expression of NUCB-2 in cancer patients was lower than cancer patients with low-level expression of NUCB-2. In addition, overexpression of NUCB-2 was observed in liver cancer by using bioinformatics analysis. The liver cancer patients with NUCB-2 overexpression are associated with poor prognosis. However, the effect of NUCB-2 overexpression on tumor cells is still unclear. In this project, we evaluated the novel role and mechanisms of NUCB-2 overexpression in hepatoma cells. Our results indicated NUCB-2 mRNA expression level was induced by ER stress as determined with RT-PCR and real-time PCR, and induction of NUCB-2 protein level was significantly increased by ER stress. Increased ER stress by pre-S2Δ protein was significantly enhanced NUCB-2 expression. We also observed that the overexpression of NUCB-2 was corrected with ER stress in human hepatocellular carcinoma tumor samples. Consequently, this mechanistic research may provide a molecular basis to develop a biomarker and novel cancer chemotherapeutic agent for high level expression of NUCB-2 in cancer patients. keywords:Endoplasmic reticulum stress, Nucleobindin-2, real-time PCR, RT-PCR, HBV large surface mutant protein pre-S2Δ, Hepatocellular carcinoma, Huh-7, HepG2, MCF-7, Tunicamycin, Brefeldin A. Citation Format: Jui-Hsiang Hung, Hsiu-Ping Tsao, Ren-Hao Li, Chih-Han Li, Hut-Min Chang. To Investigate the mechanism and function of nucleobindin-2 in human hepatoma cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4884.
Abstract 3732: Characterization of tumor relevant isocitrate dehydrogenase 1 (IDH1)
Authors: Nalani J. Coleman, Ella Thornberg, Danielle Caliger, Lucas Luna, Christal D. Sohl
Journal: Cancer Research (2020)

Abstract Isocitrate dehydrogenase 1 (IDH1) is found commonly mutated in grade II and III gliomas and secondary glioblastomas. Normally, IDH1 catalyzes the conversion of isocitrate and NADP+ to α-ketoglutarate and NADPH. However, in mutated form, IDH1 catalyzes α-ketoglutarate and NADPH into NADP+ and D-2-hydroxyglutarate, an oncometabolite. D-2-hydroxyglutarate is toxic to cells and drives a number of pro-tumorigenic pathways. To understand the molecular mechanisms of how mutated IDH1 can lead to brain cancer, we created point mutations in IDH1 to understand the effects on enzyme activity. Site-directed mutagenesis was used to generate mutations at residue 132, the most common site of mutations in cancer patients. Wild type (WT) IDH1 and mutant IDH1 were heterologously expressed in bacteria . Following purification using affinity column chromatography, steady-state kinetic assays were used to compare the catalytic activity of WT versus mutant IDH1. By elucidating the types of mutations at R132 that facilitate D2HG production, we can have a better understanding of how IDH1 mutations affect prognosis and therapeutic response. This work was funded by a Research Scholar Grant, RSG-19-075-01-TBE, from the American Cancer Society (CDS), National Institutes of Health R00 CA187594 (CDS), National Institutes of Health U54CA132384 (SDSU) &amp; U54CA132379 (UC San Diego), MARC 5T34GM008303 (SDSU), and IMSD 5R25GM058906 (SDSU), and the California Metabolic Research Foundation (SDSU). Citation Format: Nalani J. Coleman, Ella Thornberg, Danielle Caliger, Lucas Luna, Christal D. Sohl. Characterization of tumor relevant isocitrate dehydrogenase 1 (IDH1) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3732.
Abstract 4451: Combination of local mRNA immunotherapy with systemic immune checkpoint blockade demonstrates anti-tumor activity across a diverse range of preclinical syngeneic tumor models
Authors: Natalia V. Malkova, Tatiana Tolstykh, Mikhail Levit, Joachim Theilhaber, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Christian Hotz, Ugur Sahin, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Dmitri Wiederschain, Timothy R. Wagenaar
Journal: Cancer Research (2020)

Abstract Cancer immunotherapies with anti-PD-1/PD-L1 checkpoint blockade antibodies have revolutionized the treatment of a wide variety of malignancies. However, immunotherapy is ineffective in a significant subset of patients, or eventually results in the development of resistance with relapsed disease. Therefore, the future of immuno-oncology is identification of new agents that can be combined to increase the depth and breadth of anti-PD-1/PD-L1 therapies. Local intratumoral delivery of messenger RNA (mRNA)-based immunotherapies provides an opportunity to stimulate innate and adaptive immune responses against tumors and modulate tumor microenvironment, while limiting the side-effects related to systemic administration of immuno-modulatory therapeutics. We examined the local immunotherapy of synthetic mRNAs encoding immunomodulatory cytokines (single chain interleukin-12 (IL-12), interferon alpha (IFN-α), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-15 sushi(IL-15)) alone and in combination with anti-PD-1 antibodies across 12 syngeneic mouse tumor models representing a diverse range of murine tumor types. Single agent treatment with cytokine mRNAs resulted in a significant anti-tumor response in 8 out of 12 tumor models. Combining cytokine mRNA with systemic anti-PD-1 immunotherapy further improved the anti-tumor response and resulted in tumor growth inhibition in two additional models otherwise unresponsive to single agent treatments. Transcriptome and cytokine analyses have been performed to understand factors which determine sensitivity to single agent and combination treatments with cytokine mRNA and anti-PD-1 antibodies. In summary, the combination of local cytokine mRNA immunotherapy with immune checkpoint blockade demonstrated improvement in the anti-tumor activity in a range of preclinical cancer models representing different murine tumor types. Based on these and other data, clinical testing of cytokine encoding mRNA mixture has recently been initiated (NCT03871348). Citation Format: Natalia V. Malkova, Tatiana Tolstykh, Mikhail Levit, Joachim Theilhaber, Andrew Hebert, Kevin Atchison, Adalis Maisonet, Christian Hotz, Ugur Sahin, Alexei Protopopov, Jack Pollard, Sukhvinder Sidhu, Dmitri Wiederschain, Timothy R. Wagenaar. Combination of local mRNA immunotherapy with systemic immune checkpoint blockade demonstrates anti-tumor activity across a diverse range of preclinical syngeneic tumor models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4451.
Anti-Inflammatory Actions of Soluble Ninjurin-1 Ameliorate Atherosclerosis
Authors: Sejin Jeon, Tae Kyeong Kim, Se-Jin Jeong, In-Hyuk Jung, Nayoung Kim, Mi-Ni Lee, Seong-Keun Sonn, Seungwoon Seo, Jing Jin, Hyae Yon Kweon, Sinai Kim, Dahee Shim, Young Mi Park, Sang-Hak Lee, Kyu-Won Kim, Myron I. Cybulsky, Hyunbo Shim, Tae-Young Roh, Woong-Yang Park, Hae-Ock Lee, Jae-Hoon Choi, Sung Ho Park, Goo Taeg Oh
Journal: Circulation (2020)

Macrophages produce many inflammation-associated molecules, released by matrix metalloproteinases, such as adhesion molecules, and cytokines, as well, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (Ninj1 [nerve injury-induced protein]), a novel matrix metalloproteinase 9 substrate, expression, and atherosclerosis progression.Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from patients with coronary artery disease and healthy controls, and atheroprone apolipoprotein e-deficient (Apoe-/-) and wild-type mice, as well. Apoe-/- mice lacking systemic Ninj1 expression (Ninj1-/-Apoe-/-) were generated to assess the functional effects of Ninj1. Bone marrow transplantation was also used to generate low-density lipoprotein receptor-deficient (Ldlr-/-) mice that lack Ninj1 specifically in bone marrow-derived cells. Mice were fed a Western diet for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj11-56 (ML56) and Ninj126-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1).Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted proinflammatory gene expression by activating mitogen-activated protein kinase and inhibiting the phosphoinositide 3-kinase/Akt signaling pathway. Whole-body and bone marrow-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by matrix metalloproteinase 9 to generate a soluble form that exhibited antiatherosclerotic effects, as assessed in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1.Ninj1 is a novel matrix metalloproteinase 9 substrate in macrophages, and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.
Abstract 643: Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene
Authors: Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara
Journal: Cancer Research (2020)

Abstract Mixed-lineage leukemia (MLL)-related leukemia which has MLL rearrangement is an intractable disease. Recently, bromodomain and extra-terminal (BET) inhibitors are promising agents, and clinical trials are undergone. However, drug resistance against BET inhibitors has been reported, therefore, it is important to elucidate its mechanism. In this study, we established OTX015-resistant leukemic cells with MLL-AF5q31 fusion gene (OTX015-R cells) and identified molecules that contribute to drug resistance. In addition, we evaluated whether identified molecules are effective as therapeutic target for BET inhibitor-resistant MLL-related leukemia. To generate OTX015-R cell line, we cultured MLL-AF5q31 cells in the complete medium containing OTX015 with stepwise increasing concentrations. OTX015-R cells exhibited cross-resistance to various BET inhibitors. In addition, protein expressions of bromodomain-containing protein 4 (Brd4) and Brd4-regulated molecules c-Myc, Cdk6 and Bcl-2 were remarkably increased in OTX015-R cells compared with the parental cells. Furthermore, treatment of Cdk4/6 inhibitor Abemaciclib showed a significant antitumor effect on OTX015-R cells and protein expressions of Brd4 and Brd4-regulated molecules were decreased after Abemaciclib treatment. Abemaciclib exhibits antitumor effects on the parental MLL-AF5q31 cells by induction of cell cycle arrest. On the other hand, interestingly, apoptosis in the OTX015-R cells was induced without cell cycle arrest. These results suggest that Abemaciclib induces apoptosis in OTX015-R cells by another mechanism different from cell cycle regulation. We are going to clarify this mechanism. In conclusion, BET inhibitor-resistant MLL-AF5q31 cells upregulated expression levels of BRD4 and its downstream molecules. We suggest that Cdk6 is a potent therapeutic target for BET inhibitor-resistant MLL-related leukemias. Citation Format: Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara. Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 643.
Abstract 307: KSR1-dependent modulation of the translational landscape in Ras-driven colorectal cancer
Authors: Heidi Vieira, Chaitra Rao, Adrian R. Black, Siddesh Southekal, Tomohiro Mizutani, Babu Guda, Hans Clevers, Jennifer D. Black, Robert E. Lewis
Journal: Cancer Research (2020)

Abstract KRAS is mutated and activated in an estimated 40% of colon cancers but has proven difficult to target directly due to the lack of drug-binding pockets on the surface of Ras. Thus, identifying effectors that transmit signals from oncogenic Ras is a critical step in targeting vulnerabilities in the tumors of patients with colorectal cancer (CRC). Kinase Suppressor of Ras 1 (KSR1) is a molecular scaffold that coordinates the interaction of effectors in the Raf/MEK/ERK signaling cascade downstream of Ras. KSR1 is necessary for oncogenic transformation of cells expressing mutated Ras but is dispensable for normal cell growth making KSR1 an attractive therapeutic target for Ras-driven colon cancers. In CRC cells, KSR1 and ERK mediate Ras-dependent effects on protein translation, notably driving cap-dependent and cap-independent translation of the Myc oncogene. Depletion of KSR1 or treatment with ERK inhibitor (SCH772984) leads to a decrease in phophorylated 4EBP1 and a decrease in PDCD4, which collectively impair protein translation, notably leading to a decrease in Myc translation. Patient-derived CRC organoids with deletion of APC, p53, and SMAD4, and an activating G12D mutation in KRAS treated with ERK inhibitor show a marked decrease in Myc protein expression, coincident with changes in PDCD4 and 4EBP1 that impair protein translation. These observations indicate that the KSR1-dependent ERK activation observed in CRC cell lines is present in pre-clinical colon tumoroid models. Genome-wide polysome profiling in CRC cell lines HCT116 and HCT15 depleted of KSR1 identified mRNAs that were preferentially translated in a KSR1 and ERK-dependent manner. Several of these mRNAs were previously predicted by our Functional Signature Ontology (FUSION) screen to be critical to CRC viability but dispensable for normal cell growth. GSEA identified functional classes of mRNAs whose translation is KSR1-dependent, including mediators of oncogenic signaling in pathways that regulate mTOR, MAPK, WNT and JAK-STAT. Our data suggest that an essential component of oncogenic Ras-induced and KSR1-dependent signaling is the preferential translation of mRNAs supporting the transformed phenotype of CRC cells. Citation Format: Heidi Vieira, Chaitra Rao, Adrian R. Black, Siddesh Southekal, Tomohiro Mizutani, Babu Guda, Hans Clevers, Jennifer D. Black, Robert E. Lewis. KSR1-dependent modulation of the translational landscape in Ras-driven colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 307.
Abstract 4074: Reversing acquired PARPi resistance of TNBC through combined inhibition of cMet and EGFR
Authors: Yu Yi Chu, Clinton Yam, Mei-Kuang Chen, Li-Chuan Chan, Lei Nie, Mien-Chie Hung
Journal: Cancer Research (2020)

Abstract Front line therapeutic failure happened to half of triple-negative breast cancer (TNBC) patients represent the effective treatment strategies for these patients are urgently needed. Poly (ADP-ribose) polymerase (PARP) is currently the most promising drug target for BRCA-mutated TNBC, and PARP inhibitors (PARPi), olaparib and talazoparib, were recently approved for the treatment of metastatic breast cancer (including TNBC) in patients with germline BRCA1/2 mutations. Despite impressive response rates of ~60%, the prolongation in median progression-free survival with a PARPi is modest, suggesting the emergence of resistance. Several studies have reported that receptor tyrosine kinases (RTKs), such as c-MET (also known as hepatocyte growth factor receptor), are involved in resistance to various anti-neoplastic agents, including PARPi. However, the mechanism by which c-MET contributes to acquired resistance to PARPi in TNBC is not fully understood. In this study, we analyzed acquired PARPi resistant TNBC cells and found c-Met is hyperactivated in these cells with PARPi treatment. We further treated these cells with talazoparib and crizotinib (a multi-kinase inhibitor that inhibits c-MET) and found synergistic inhibition effects of cell proliferation. Unexpectedly, limited effects of talazoparib sensitivity showed while depleting c-MET in PARPi-resistant cells. Interestingly, we found epidermal growth factor receptor (EGFR) is also hyperactivated and interaction of EGFR/c-Met in these cells. Notably, combination of c-MET and EGFR inhibitors increased sensitivity to talazoparib in TNBC cells with acquired resistance to PARPi. Combining EGFR and PARP inhibitors also resulted in greater inhibition of proliferation in c-MET-depleted TNBC cells. Collectively, our findings suggested a potential combination therapy of inhibiting c-MET and EGFR to overcome acquired PARPi resistance in TNBC. Citation Format: Yu Yi Chu, Clinton Yam, Mei-Kuang Chen, Li-Chuan Chan, Lei Nie, Mien-Chie Hung. Reversing acquired PARPi resistance of TNBC through combined inhibition of cMet and EGFR [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4074.
Abstract 4241: Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer
Authors: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang
Journal: Cancer Research (2020)

Abstract Introduction: Patients with microsatellite stable (MSS) metastatic colorectal cancer (MCRC) are considered resistant to immunotherapy with PD-1 and PD-L1 inhibitors. However, a recent study of regorafenib and nivolumab (REGONIVO) reported high response rates and a median progression free survival (PFS) of more than 6 months (mo) in a cohort of 24 Japanese patients (pts) with MSS chemo-resistant MCRC. Methods: We evaluated the outcome of advanced MSS MCRC pts who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib 80 mg PO QD x 21 days every 28 days in a single US center. We report their response rate (RR), PFS, and overall survival (OS). Results: 16 pts (15 males) were treated with a combination of regorafenib + PD-1 inhibitors and were evaluable for response. 14 pts received regorafenib + nivolumab (5 with prior anti-PD-1 treatment) and 2 pts received regorafenib + pembrolizumab (both following pembrolizumab treatment). No treatment-related G3 or above toxicities were attributed to the combination therapy. No objective responses were noted on treatment. 11 pts had progressive disease (PD) and 5 pts experienced stable disease (SD) as best response at 2 mo. The duration of SD was 4 mo in 2 pts (1 pt with prior anti-PD1 exposure), 6 mo in 1 pt (prior anti-PD1 exposure), 5 mo+ in 2 pt (1 with prior anti-PD1 exposure). When limiting the analysis to the 9 regorafenib and checkpoint-inhibitor naïve patients, 2 pts were noted to have SD (4 months and 5 mo+). ctDNA assays were evaluated at baseline and at 4 weeks of treatment in 11 patients. All 9 patients with a rise in ctDNA at 4 weeks had PD at the 2-mo imaging point. 2 patients with declining ctDNA at 4 weeks experienced SD for 4 mo 5 mo+, each. OS analysis remains immature as the median follow-up is only 5 mo. Conclusions: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant MCRC. This US-based small retrospective trial is at odds with the Japanese REGONIVO trial. ctDNA may represent a powerful tool for predicting progression prior to radiographic staging. Citation Format: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang. Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4241.
Endoscopic ultrasound-directed transgastric ERCP (EDGE): a retrospective multicenter study
Authors: Thomas M. Runge, Austin L. Chiang, Thomas E. Kowalski, Theodore W. James, Todd H. Baron, Jose Nieto, David L. Diehl, Matthew R. Krafft, John Y. Nasr, Vikas Kumar, Harshit S. Khara, Shayan Irani, Arpan Patel, Ryan J. Law, David E. Loren, Alex Schlachterman, William Hsueh, Bradley D. Confer, Tyler K. Stevens, Prabhleen Chahal, Mohammad A. Al-Haddad, Fahad Faisal Mir, Douglas K. Pleskow, Matthew T. Huggett, Bharat Paranandi, Arvind J. Trindade, Olaya I. Brewer-Gutierrez, Yervant Ichkhanian, Mohamad Dbouk, Vivek Kumbhari, Mouen A. Khashab
Journal: Endoscopy (2020)

Endoscopic ultrasound-directed transgastric endoscopic retrograde cholangiopancreatography (ERCP; EDGE) is an alternative to enteroscopy- and laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass anatomy. Although short-term results are promising, the long-term outcomes are not known. The aims of this study were: (1) to determine the rates of long-term adverse events after EDGE, with a focus on rates of persistent gastrogastric or jejunogastric fistula; (2) to identify predictors of persistent fistula; (3) to assess the outcomes of endoscopic closure when persistent fistula is encountered.This was a multicenter retrospective study involving 13 centers between February 2015 and March 2019. Adverse events were defined according to the ASGE lexicon. Persistent fistula was defined as an upper gastrointestinal series or esophagogastroduodenoscopy showing evidence of fistula.178 patients (mean age 58 years, 79 % women) underwent EDGE. Technical success was achieved in 98 % of cases (175/178), with a mean procedure time of 92 minutes. Periprocedural adverse events occurred in 28 patients (15.7 %; mild 10.1 %, moderate 3.4 %, severe 2.2 %). The four severe adverse events were managed laparoscopically. Persistent fistula was diagnosed in 10 % of those sent for objective testing (9/90). Following identification of a fistula, 5 /9 patients underwent endoscopic closure procedures, which were successful in all cases.The EDGE procedure is associated with high clinical success rates and an acceptable risk profile. Persistent fistulas after lumen-apposing stent removal are uncommon, but objective testing is recommended to identify their presence. When persistent fistulas are identified, endoscopic treatment is warranted, and should be successful in closing the fistula.