tbuckley/cabot-search huggingface dataset:
Abstract 4097: Src-met signaling confers apoptosis resistance to the combination of BKM120 and erlotinib in head and neck cancer
Authors: A.R.M. Ruhul Amin, Abu Anisuzzaman, Abedul Haque, Zhuo Chen, Dong Shin
Journal: Cancer Research (2017)

Abstract Purpose: Molecularly targeted agents will play a major role in the next generation of personalized cancer therapies. However, intrinsic and acquired resistance to targeted agents poses challenges to the success of such treatments. The purpose of the current study was to investigate the intrinsic resistance of head and neck cancer (HNC) cell lines to apoptosis induced by the combination of EGFR inhibitor erlotinib and PI3K inhibitor BKM120. Methods: In a panel of 10 malignant and 1 premalignant HN cell lines, we evaluated cell growth inhibition (by SRB assay), IC50, combination index, dose reduction index (by CalcuSyn Software), and apoptosis (by Annexin-V staining). Protein expression levels were measured by Western blotting. Small molecule chemical inhibitors and siRNA-mediated knockdown strategies were used to inactivate and shut down the expression of the relevant proteins, respectively. Results: Single targeting of EGFR with erlotinib or PI3K with BKM120 (pan-PI3K inhibitor) suppressed cellular growth without inducing significant apoptosis. Co-targeting EGFR and PI3K demonstrated in vitro synergy in all except one cell line (based on combination index and dose reduction index) and more effectively inhibited HNC xenograft growth in vivo. The combination of erlotinib and BKM120 induced variable apoptosis: some cell lines were very sensitive (Tu686, 686LN, 93-VU-147T), some moderately (Fadu, SqCCy1, 1483, UMSSC90) and others were resistant (UD-SCC2, MSK-LEUK1, JHU022) to apoptosis induction. JHU022 and 1483 cell lines expressed very high levels of p-cMet. Targeting cMet with the small molecule inhibitor crizotinib or siRNA rendered these cell lines highly sensitive to erlotinib and BKM120 induced apoptosis. Moreover, inhibition of Src family kinases with the small molecule inhibitor dasatinib or with c-Src-specific siRNA inhibited p-cMet. In addition, inhibition of SFK in these cell lines conferred sensitivity to erlotinib and BKM120 induced apoptosis. Conclusions: Our results strongly suggest that co-targeting of EGFR and PI3K has synergistic activity, is effective in vivo, and induces apoptosis of some HNC cell lines. Two of the resistant cell lines express a high level of p-cMet as a downstream target of SFK, which confers resistance of these cells to the combination of erlotinib and BKM120. Citation Format: A.R.M. Ruhul Amin, Abu Anisuzzaman, Abedul Haque, Zhuo Chen, Dong Shin. Src-met signaling confers apoptosis resistance to the combination of BKM120 and erlotinib in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4097. doi:10.1158/1538-7445.AM2017-4097
Abstract 5749: VCAN promotes clear cell renal cell carcinoma tumor progression and metastasis, and predicts poor prognosis
Authors: Yozo Mitsui, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Mitsuho Imai Sumida, Ryan Kenji Wong, Soichiro Yamamura, Varahram Shahryari, Shahana Majid, Sharanjot Saini, Guoren Deng, Rajvir Dahiya, Koichi Nakajima, Yuichiro Tanaka
Journal: Cancer Research (2017)

Abstract Introduction and Objectives: Although versican (VCAN) is known to promote tumor progression and enhance metastasis of several types of cancers, its role in clear cell renal cell carcinoma (ccRCC) remains unknown. Interestingly, a recent report showed that VCAN is an important target of chromosomal 5q gain, one of the most prevalent genetic abnormalities in ccRCC cases. In the present study, we investigated whether VCAN expression is associated with the pathogenesis of ccRCC. Methods: VCAN expression was analyzed in 3 RCC and normal kidney cell lines, as well as 84 matched ccRCC and normal renal tissues. We also performed various functional analyses of growth and progression properties using VCAN-depleted ccRCC cells. Microarray analysis was then employed to investigate the target genes of the pathway involved in ccRCC tumorigenesis and development. Results: There are 4 isoforms of VCAN containing the N-terminal globular (G1 domain) and C-terminal globular (G3 domain) domains, each of which was found to be over-expressed in the ccRCC samples as compared to the controls. Higher VCAN expression was significantly correlated with metastasis (p&amp;lt;0.001) and worse 5-year overall survival after a radical nephrectomy (p=0.014). In vitro, VCAN knockdown by siRNA in Caki-2 and 786-O cells significantly decreased cell proliferation and increased apoptosis, and was also found to be associated with alteration of several TNF signaling-related genes, such as TNF-α, BID, and BAK. Furthermore, VCAN depletion markedly decreased cell migration and invasion associated with reduced MMP7 and CXCR4 levels. Conclusion: Our results demonstrate that VCAN promotes ccRCC tumorigenesis and metastasis, showing it to be an attractive novel target for diagnostic, prognostic, and therapeutic strategies for affected patients. Note: This abstract was not presented at the meeting. Citation Format: Yozo Mitsui, Taku Kato, Shigekatsu Maekawa, Yutaka Hashimoto, Marisa Shiina, Mitsuho Imai Sumida, Ryan Kenji Wong, Soichiro Yamamura, Varahram Shahryari, Shahana Majid, Sharanjot Saini, Guoren Deng, Rajvir Dahiya, Koichi Nakajima, Yuichiro Tanaka. VCAN promotes clear cell renal cell carcinoma tumor progression and metastasis, and predicts poor prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5749. doi:10.1158/1538-7445.AM2017-5749
Abstract 5586: PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies
Authors: Lilin Zhang, Fumiko Nomura, Yoichi Aikawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo
Journal: Cancer Research (2017)

Abstract Transferrin receptor1 (TfR1) is a type II transmembrane glycoprotein that involves intracellular uptake of iron. TfR1 is ubiquitously expressed at low levels in normal cells except erythroblasts and placental trophoblasts, which express high levels of TfR1 due to the need of up taking a large amount of iron. Accumulating studies have shown elevated levels of TfR1 in both solid tumor cells, as well as hematologic malignant cells when compared to their normal counterparts. Since TfR1 is implicated in growth and survival in various cancer cells, targeting TfR1 could be attractive strategy for cancer therapeutics. To this end, we have developed a fully human antibody against TfR1, PPMX-T003, which displayed potent anti-tumor activity in vitro and in vivo. PPMX-T003 induced apoptosis or cell cycle arrest with EC50s of 3~200ng/ml in various tumor cell lines. Mechanistically, PPMX-T003 triggers apoptosis or cell growth arrest by inhibiting binding of TfR1 to its ligand transferrin and blocking iron uptake. In addition, PPMX-T003 elicits antibody dependent cellular cytotoxicity (ADCC) activity in cancer cells. Importantly, PPMX-T003 showed potent efficacy against several blood cancer xenograft models. PPMX-T003 completely eradicated established subcutaneous tumors in two acute myeloid leukemia (AML) models generated by Kasumi-1 and HL-60, at a dose of 10 mg/kg when administrated (I.V.) once a week for 4 weeks. Moreover, PPMX-T003 completely eradicated established tumors in a lymphoma xenograft model (SU-DHL-2) at a dose of 3 mg/kg. Furthermore, PPMX-T003 greatly prolonged mice survival in a disseminated leukemia model (CCRF-CEM: acute lymphoblastic leukemia cell line). The control mice engrafted with CCRF-CEM cells (n=10) developed leukemia and died within 42 days, whereas 8 of the 10 mice treated with PPMX-T003 survived 179 days until the experiment was terminated. A preliminary toxicology study in Cynomolgus monkeys with multiple doses was also carried out. Although moderate anemia was observed at the dose of 30 mg/kg, no other abnormalities were observed, indicating a tolerable safety profile. Taken together, these results indicate that PPMX-T003 could be a potent therapeutic antibody for the treatment of hematologic malignancies. Citation Format: Lilin Zhang, Fumiko Nomura, Yoichi Aikawa, Yoshikazu Kurosawa, Kazuhiro Morishita, Yukio Sudo. PPMX-T003, a fully human anti-TfR1 antibody with potent efficacy against hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5586. doi:10.1158/1538-7445.AM2017-5586
Abstract 2173: Targeting CDK1 and MEK/ERK overcome mutantBRAF-mediated apoptosis resistance in human colorectal cancer cells
Authors: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope
Journal: Cancer Research (2017)

Abstract BRAFV600E mutation occurs in ~10% of human colorectal cancers (CRC) where it is associated with treatment resistance and poor prognosis. Data from TCGA and a clinical trial cohort identified a distinct subset of BRAF mutant colon cancers with deregulation of the cell cycle and overexpression of CDK1 (Barras D, et al, Clin Cancer Res. 2016). We tested the hypothesis that CDK1 inhibition can enhance apoptosis in BRAFV600E CRC cells. Since BRAF mutant cells show p-ERK activation, combined inhibition of CDK1 and MEK/ERK was evaluated. Using isogenic colon cancer cells, BRAF mutant alleles were shown to confer resistance to the CDK1 inhibitor, R0-3306, in a gene dose-dependent manner that was associated with reduced cleavage of caspase-3 and downstream PARP, and decreased pH2AX (DNA fragmentation marker). Ectopic BRAFV600E or constitutively active MEK mutant also conferred resistance to R0-3306. CDK1 siRNA was shown to increase cobimetinib-induced apoptosis, including annexin V labeling, and increased pH2AX. Furthermore, ERK siRNA or cobimetinib treatment attenuated CDK1 protein expression and increased R0-3306-induced pH2Ax. Moreover, treatment with R0-3306 plus cobimetinib significantly enhanced a caspase-dependent apoptosis and markedly reduced colony formation vs either drug alone in two CRC cell lines. Caspase-3 cleavage by R0-3306 + cobimetinib was dependent upon caspase-8. Mechanistically, CDK1 inhibition by R0-3306 suppressed the phosphorylation of procaspase-8 at Ser-387 shown by R0-3306 withdrawal which restored p-C8-S387 coincident with expression of the mitotic marker, pH3S10. In conclusion, inhibition of CDK1 can significantly augment apoptosis induction by MEK/ERK inhibition in BRAFV600E CRC cells, suggesting a novel therapeutic strategy to overcome mutant BRAF-mediated resistance. Apoptosis induction by CDK1 inhibitor (R0-3306) ± MEK/ERK inhibitor cobimetinibTreatmentTreatmentTreatementTreatmentCRC cell linesDMSOR0-3306 (5 µM)cobimetinib (5 µM)combinationAnnexin V+ (%)RKO13.43 ± 1.4132.55 ± 2.9315.04 ± 0.2652.72 ± 3.16Annexin V+ (%)HT-2911.22 ± 1.8442.44 ± 2.7025.29 ± 0.1665.62 ± 4.11 Citation Format: Hisato Kawakami, Shengbing Huang, Frank A. Sinicrope. Targeting CDK1 and MEK/ERK overcome mutant BRAF-mediated apoptosis resistance in human colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2173. doi:10.1158/1538-7445.AM2017-2173
Pediatric Phase I Trial and Pharmacokinetic Study of Trebananib in Relapsed Solid Tumors, Including Primary Tumors of the Central Nervous System ADVL1115: A Children's Oncology Group Phase I Consortium Report
Authors: Sarah E.S. Leary, Julie R. Park, Joel M. Reid, Andrew T. Ralya, Sylvain Baruchel, Bing Wu, Timothy P.L. Roberts, Xiaowei Liu, Charles G. Minard, Elizabeth Fox, Brenda Weigel, Susan Blaney
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide–Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia (n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension (n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062–9. ©2017 AACR.
Abstract 1803: Combining anti-Ang-2/VEGF-A therapy with radio- and chemotherapy in glioma
Authors: Gergely Solecki, Matthias Osswald, Weber Daniel, Malte Glock, Miriam Ratliff, Hans-Joachim Müller, Oliver Krieter, Yvonne Kienast, Wolfgang Wick, Frank Winkler
Journal: Cancer Research (2017)

Abstract Angiogenesis is a biological hallmark of malignant gliomas, but antiangiogenic strategies especially targeting the VEGF axis did not show striking antitumor activities in the majority of patients so far. Other pathways may be more relevant in selected tumor entities or patients. Further, it remains unresolved which antiangiogenic combination regimen with standard radio- and/or chemotherapy is most effective. Therefore, we compared the therapeutic effects of anti-VEGF-A, anti-Ang-2, and bispecific anti-Ang-2/VEGF-A antibodies, alone and in combination with radio- or temozolomide (TMZ) chemotherapy in a malignant glioma model using multi-parameter two-photon in vivo microscopy in mice. We demonstrate that anti-Ang-2/VEGF-A leads to strongest vascular changes including vascular normalization, both as monotherapy and when combined with chemotherapy. The latter combination regimen was accompanied by most effective chemotherapy-induced death of cancer cells independent of blood vessel proximity, indicative of a better distribution of TMZ throughout the tumor. Furthermore, the combination of anti-Ang-2/VEGF-A plus TMZ consistently resulted in decreased tumor cell motility, and decreased formation of resistance-associated tumor microtubes (TMs), which finally lead to best tumor growth inhibition. Remarkably, all these parameters were just reverted when radiotherapy was chosen as combination partner. In contrast, when anti-VEGF-A was combined with radiotherapy, vascular normalization was highest, and TM length, nuclear motility and tumor growth were concordantly reduced. In conclusion, while TMZ chemotherapy benefits most from combination with anti-Ang-2/VEGF-A, radiotherapy does from anti-VEGF-A. The findings imply that unexpected, even divergent effects can occur when a specific antiangiogenic therapy is added to chemo- or radiotherapy in glioma, and that uninformed combination regimens should be avoided. Note: This abstract was not presented at the meeting. Citation Format: Gergely Solecki, Matthias Osswald, Weber Daniel, Malte Glock, Miriam Ratliff, Hans-Joachim Müller, Oliver Krieter, Yvonne Kienast, Wolfgang Wick, Frank Winkler. Combining anti-Ang-2/VEGF-A therapy with radio- and chemotherapy in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1803. doi:10.1158/1538-7445.AM2017-1803
Interferon alpha receptor-2c on cell membrane is important in antiproliferative effect of interferon-α against human hepatocellular carcinoma cells
Authors: Bazarragchaa Damdinsuren, Hiroaki Nagano, Masato Nakamura, Hiroshi Wada, Takehiro Noda, Shigeru Marubashi, Atsushi Miyamoto, Yutaka Takeda, Koji Umeshita, Keizo Dono, Morito Monden
Journal: Cancer Research (2006)

4677   Both clinical and preclinical data suggest efficacy of combination chemotherapies with interferon (IFN) in treatment of hepatocellular carcinoma (HCC). We reported previously that the efficacy of IFN-α/5-fluorouracil therapy was observed in 43.6% of the patients with advanced HCC, and the response was correlated with the expression of IFN alpha receptor (IFNAR)2. However, the gain of diverse sensitivities of HCC to IFN-based therapy is not yet clear. We performed this mechanistic study in order to clarify the role of IFN signal transduction components, specifically pointing on IFNAR2, in anti-tumor effect of IFN-α in HCC cells.  Experimental procedure:  We studied the expression of IFN signaling components [IFNAR1, 2 and signal transducer and activator of transcription (STAT)1, 2, 3, 5] and their functional properties in association with IFN-α sensitivity using Western blot, growth-inhibitory assays in six HCC cell lines (HuH7, PLC/PRF/5, HLE, HLF, HepG2 and Hep3B). To study the impact of IFNAR2 in the IFN-α’s effect, we investigated the IFN’s effect and signaling on the following models; knockdown of IFNAR2 using siRNA, and blocking the receptor with neutralizing antibody designed to target extracellular part of IFNAR2.  Results:  Among the studied cell lines, the PLC/PRF/5 cells were the most sensitive to growth-inhibitory effect of IFN-α, while other cells were more resistant. On Western blot analysis, the expression of IFNAR2c (long subunit), especially on cell membrane, was significantly higher in IFN-sensitive PLC/PRF/5 cells than in resistant cell lines. The cell lines expressed various levels of STAT proteins, and no difference was observed between sensitive and resistant cell lines. However, when the cells were treated with IFN-α, phosphorylation of STAT1 and 3 was higher in PLC/PRF/5 compared with the other cells, and it was dependent to the IFN dose. We hypothesized that high expression of IFNAR2c on membrane resulted in intensive IFN signal transduction and further strong growth-inhibitory effect. To clarify this speculation we performed the knockdown and/or the neutralizing experiments. The knockdown of the receptor with siRNA decreased the IFN signal transduction and growth-inhibitory effect of IFN-α. Moreover, the antibody to extracellular IFNAR2 also blocked both, IFN signaling and antiproliferative effect in the IFN-sensitive cells.  Conclusion:  Our results suggest that the membrane expression of IFNAR2c with subsequent activation of STAT1 and 3 is important for antiproliferative effect of IFN-α in HCC cells. Increase of IFNAR2c expression on membrane may improve the efficacy of IFN-α and/or IFN based chemotherapy for HCC.
Abstract 5594: High throughput combinatorial profiling of checkpoint inhibitor antibodies on the iQue® Screener PLUS
Authors: Tom Hasaka
Journal: Cancer Research (2017)

Abstract Checkpoint inhibitors have become valuable immuno-modulatory targets in the advancement of cancer treatment. Looking for the synergy between new checkpoint inhibitor antibodies and known inhibitors is an important aspect of this research. The iQue Screener PLUS platform is a powerful tool to simultaneously assess these interactions in a single well of a microtiter plate. ForeCyt® software provides plate-level analytics and high content visualization to generate deep insight rapidly. Using a mixed lymphocyte reaction (MLR) model, we profiled potential synergies of several known checkpoint inhibitors antibodies. Responses of PD-1, PD-L1, and CD73 inhibitors both individually, and in combination with CTLA-4 inhibitors, were assessed for proliferation, viability and cytokine secretion simultaneously in the same well. MultiCyt® cell-based and bead-based reagents were used for this analysis. Synergies ranging from 2-10 fold increase over CTLA-4 alone were observed in the secretion of TNFα and IL-1β. Results were obtained and analysis completed in a 384-well plate in 30 minutes. In conclusion, this study highlights the power of the iQue Screener PLUS platform to rapidly characterize multiple endpoints and the ForeCyt software to provide high content visualization that reveals actionable insights. Citation Format: Tom Hasaka. High throughput combinatorial profiling of checkpoint inhibitor antibodies on the iQue® Screener PLUS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5594. doi:10.1158/1538-7445.AM2017-5594
Abstract 2453: Chromatin remodeling genes are frequently somatically altered in cervical carcinomas
Authors: Akinyemi Ojesina, Aishwarya Sundaresan, Vinodh Srinivasasainagendra, Hemant Tiwari, Warner Huh
Journal: Cancer Research (2017)

Abstract Introduction: Cervical cancer is responsible for 15% of all deaths due to cancer in women worldwide. There is a need to identify somatic mutations driving this cancer in order to facilitate development of novel therapeutic strategies. Experimental procedures: We analyzed whole exome sequencing data from 430 cervical carcinomas. The data were derived from a combination of our previously published work (Ojesina et al. Nature 2014; Chung et al, Int J Cancer 2015), and publicly available data generated by the Cancer Genome Atlas (TCGA). The Mutect2.0 and MutSig2CV algorithms were used to identify somatic mutations and significantly mutated genes (SMGs) respectively. Copy number alterations were analyzed using the GISTIC algorithm. Findings: Based on MutSig2CV false discovery rate threshold of 0.1, we identified MLL3 (19%) and MLL2 (13%) as novel significantly mutated genes (SMGs) in cervical cancer. In addition, other chromatin modifying genes including EP300 (12%) and ARID1A (7%) were confirmed as SMGs. Further investigation of genes that did not meet the threshold revealed that 228 of 430 (53%) of cervical tumors harbored at least one somatic mutation in a chromatin modifying gene. These include genes in the myeloid/lymphoid or mixed-lineage leukemia (MLL) family (28%), lysine (K)-specific demethylase (KDM) family (23%), AT rich interactive domain (ARID) family (13%), SWI/SNF related, matrix associated, actin dependent regulator of chromatin (SMARC) family (8%) and histone cluster 1 (HIST1) family (4%). Conclusions: We have demonstrated that a majority of cervical cancers harbor somatic mutations in chromatin remodeling genes. This novel finding was facilitated by the larger sample size derived from combining multiple datasets, and may have diagnostic and therapeutic implications in cervical cancer. Citation Format: Akinyemi Ojesina, Aishwarya Sundaresan, Vinodh Srinivasasainagendra, Hemant Tiwari, Warner Huh. Chromatin remodeling genes are frequently somatically altered in cervical carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2453. doi:10.1158/1538-7445.AM2017-2453