tbuckley/cabot-search huggingface dataset:
Abstract 5651: A LAG-3/PD-L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models
Authors: Matthew Kraman, Katarzyna Kmiecik, Carlo Zimarino, Katy Everett, Mustapha Faroudi, Mateusz Wydro, Jacqueline Doody
Journal: Cancer Research (2017)

Abstract Combining immunotherapeutic antibodies in cancer treatment has shown benefits over single agents. An alternative to combining two antibodies is the development of bispecific antibodies that not only bring two biologies together but may result in novel mechanisms of action that are impossible to attain with combinations. Lymphocyte Activation Gene-3 (LAG-3) is a member of the Ig superfamily expressed on activated T cells, NK cells, pDCs, B cells, γδ T cells and participates in immune suppression. Programmed Cell Death receptor (PD-1) binds to its ligand PD-L1, expressed not only on activated immune cells to inhibit cellular immune responses but also on tumor cells. Expression of both these surface molecules therefore leads to T cell exhaustion allowing the tumor to escape immune surveillance. A mAb² TM (bispecific antibody) was engineered which binds murine LAG-3 and PD-L1 simultaneously and with nanomolar affinities. The anti-LAG-3/PD-L1 mAb² inhibits LAG-3 binding to MHCII and PD-L1 binding to PD-1 and CD80, resulting in T cell activation in vitro. This translates into in vivo efficacy, where the mAb² decreased tumor burden in the MC38 colon carcinoma tumor model. At the end of the study tumor-free animals were more numerous in the LAG-3/PD-L1 bispecific group than in the group given a combination of individual anti-LAG-3 and PD-L1 antibodies. The results were recapitulated in the CT26 murine colon cancer model, where the mAb² showed an increase of antitumor activity as compared to the antibodies given in combination. Thus, the preclinical data supports developing an anti-human LAG-3/PD-L1 mAb² for the treatment of cancer patients. Citation Format: Matthew Kraman, Katarzyna Kmiecik, Carlo Zimarino, Katy Everett, Mustapha Faroudi, Mateusz Wydro, Jacqueline Doody. A LAG-3/PD-L1 bispecific antibody inhibits tumor growth in two syngeneic colon carcinoma models [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 5651. doi:10.1158/1538-7445.AM2017-5651
Abstract LB-125: Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1
Authors: Jun Wang, Qing Ye, Yubin Guo, Yanan Cao, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, B. Mark Evers, Qing-Bai She
Journal: Cancer Research (2017)

Abstract The mTOR inhibitors, including the second generation of mTOR kinase inhibitors, for cancer treatment have been evaluated in clinical trials, but their overall activity as monotherapy is limited. The cap-dependent translation repressor, 4E-BP1, is an important effector of the mTOR kinase in controlling cell proliferation and tumor growth. Loss of 4E-BP1 expression in cancer has been linked to malignant progression and poor prognosis. However, the molecular mechanism(s) by which 4E-BP1 is downregulated in cancer remain largely unknown. Here, we identify Snail as a novel repressor of 4E-BP1 expression that can be exploited to alter mTOR-targeted therapies. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Mechanistically, we show that Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly inhibits 4E-BP1 expression, and promotes cap-dependent translation and resistance to the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic depletion of Snail restores 4E-BP1 expression and sensitizes cancer cells to mTOR inhibition by enhancing the translation-repressive function of 4E-BP1 on cell proliferation and tumor growth. Thus, our findings reveal a critical role for Snail in determining the therapeutic response to mTOR kinase inhibitors, and suggest that Snail may be a potential marker for predicting the efficacy of mTOR-target therapies in the clinic. Moreover, our work highlights the importance of combining Snail inhibition with mTOR kinase inhibitors for the treatment of tumors in which Snail overexpression occurs with reduced 4E-BP1 expression. Citation Format: Jun Wang, Qing Ye, Yubin Guo, Yanan Cao, Xiuping Huang, Wenting Mi, Side Liu, Chi Wang, B. Mark Evers, Qing-Bai She. Snail determines the efficacy of mTOR-targeted therapies by transcriptional repression of 4E-BP1 [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 LB-125. doi:10.1158/1538-7445.AM2017-LB-125
Abstract 640: Subsets of HLA alleles are capable of binding neoantigens derived from mutations within cancer driving genes such as KRAS and EGFR
Authors: Andrew Nguyen, J Zachary Sanborn, Charles J. Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong, Steve Benz
Journal: Cancer Research (2017)

Abstract Background: Immunoncology has shown great promise as a low toxicity tool to combat several cancers. Use of checkpoint inhibitors against PD1 or CTLA4 unlocks the immune system’s ability to recognize tumor antigens and, more specifically, neoantigens caused by random mutations within cancers. The vast majority of neoantigens consist of private mutations unique to a patient’s tumor genome, but several cancers harbor recurrent mutations. Mutations in the KRAS gene, such as p.G12V, occur in roughly 25% of colorectal cancers. Mutations in EGFR occur in 10% and 35% of patients with non-small cell lung cancer in the US and East Asia, respectively. Even more prevalent are mutations within the TP53 tumor suppressor gene, with roughly 23000 unique protein variants reported to date. If these mutations in cancer driving genes are so prevalent in cancers, why are neoantigens against these targets not more readily available? Results: We collected recurrent mutations across a variety of cancer driving genes such as KRAS, EGFR, TP53 and MYC and performed binding analysis using netMHC 3.4 to see which HLA alleles are capable of binding specific cancer mutations such as KRAS p.G12V. Using this method, we report all possible HLA alleles capable of binding these recurrent mutations within cancer genes. We further performed 3-dimensional modeling to determine whether complexes created by the HLA alleles and cancer neoepitopes are stable. Conclusions: Several HLA alleles are capable of binding recurrent cancer mutations. These include both MHC Class 1 and Class 2 alleles. The variation in alleles capable of binding commonly mutated genes such as EGFR may explain the difference in prevalence of these mutations between geographic populations. Determining whether a certain HLA allele confers resistance to common cancer gene mutations may lead to identification of immune cells within these populations that can recognize neoantigens from commonly mutated cancer genes. Citation Format: Andrew Nguyen, J Zachary Sanborn, Charles J. Vaske, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong, Steve Benz. Subsets of HLA alleles are capable of binding neoantigens derived from mutations within cancer driving genes such as KRAS and EGFR [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 640. doi:10.1158/1538-7445.AM2017-640
Abstract 4873: Shedding light on the unknown of Ewing sarcoma: Single cell study shows a co-expression pattern between TAPA-1 and EWSR1-FLI1
Authors: Roxane Khoogar, Doris Phelps, Peter Houghton
Journal: Cancer Research (2017)

Abstract Introduction: Ewing Sarcoma (ES) is the second most frequent bone cancer found in children, and has the highest rate of recurrence among all childhood cancers. This suggests the need for a better understanding of heterogeneous cancer populations and rare cells that survive intensive cytotoxic therapy and cause recurrence in patients. It is widely accepted that ‘EWSR1-FLI1’ has a major role in determining ES survival and proliferation, but the mechanism is unknown. Most studies in which expression of ‘EWSR1-FLI1’ is correlated with the level of expression of ‘EWSR1-FLI1’ regulated genes have been conducted on bulk populations that ignore potential heterogeneity of ‘EWSR1-FLI1’ in the cell population. To address this we have used single cell RNA-Seq approaches. Methods: The WaferGen iCell8 system was used to perform SMART whole transcriptome amplification using EW-8 ES cells.We sequenced single-cell RNA-Seq libraries prepared from over 1260 ES parental cells. We combined computational analysis with stringent quality control filters to profile candidate ES cells.We used EWSR1 expression profile to partition the entire population into two clusters. A population of cells with TAPA-1 expression was distinguished and studied for their co-expression patterns with EWSR1. Results: Results revealed that ES cells show considerable heterogeneity at the transcriptome level between seemingly identical EW-8 cells. We identified a subpopulation of EW-8 ES cells with a positive correlation between the expression of EWSR1 and Target of the antiproliferative antibody 1 and tetraspanin-28 (TAPA-1/CD81). Our preliminary data from 200 cells indicate that EWSR1 (0-18 unique transcripts, median 1) and TAPA-1/Cd81 (0-8 unique transcripts, median 0) were correlated (r= 0.32, P&amp;lt;0.10). TAPA-1, a surface membrane protein, most frequently associated with hematopoetic cells, that regulates cell development, activation, growth and motility and has been implicated in proliferation of many cancers. Conclusions: Taken together, our results suggest that there are two classes of cells with respect to the expression of TAPA-1 in EW-8 cells. We also show the relationship between TAPA-1 with EWSR1-FLI1 expression in a single cell level. This type of classification may lead us to identify a rare population with a poor response rate to cytotoxic treatments. Future studies will determine if EW-8 ES cells having elevated TAPA-1 have differential sensitivity to cytotoxic agents compared with populations with low level expression. Citation Format: Roxane Khoogar, Doris Phelps, Peter Houghton. Shedding light on the unknown of Ewing sarcoma: Single cell study shows a co-expression pattern between TAPA-1 and EWSR1-FLI1 [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 4873. doi:10.1158/1538-7445.AM2017-4873
Abstract LB-143: Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness
Authors: Luz Elisa Tavera, Karen Simon, Juying Li, Katherine Geromini, Zhuo Zhang, Sarah Keates, Harry A. Rogoff, Chiang J. Li
Journal: Cancer Research (2017)

Abstract Signal transducer and activator of transcription 3 (STAT3) is a transcription factor constitutively activated in many cancer types, and has been identified as a major mediator of cancer stemness (Li et.al., PNAS 2015). The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2) is the reactive oxygen species (ROS) sensor and a master regulator of antioxidant gene expression. NRF2 has recently been implicated in contributing to cancer stem cell phenotypes, chemoresistance, and is associated with poor clinical prognosis. Hypoxia is considered a major feature of the tumor microenvironment as it can promote tumor progression, increased stemness characteristic, and resistance to conventional therapeutic intervention. Hypoxia can regulate a series of stress-sensor transcription factors, notably, the reactive oxygen species (ROS) sensor and response modulator NRF2. We studied NRF2 transcript and protein levels in breast cancer cell lines MCF7 and AU565 cells under both hypoxic and normoxic conditions. Our data shows that in response to STAT3 pathway activators, NRF2 is upregulated at both mRNA and protein levels under hypoxia and this upregulation is STAT3 dependent. NRF2 ChIP-Seq experiments demonstrate that both hypoxia and STAT3 stimulation can modulate NRF2 binding in MCF-7 breast cancer cells. Surprisingly, under hypoxic conditions, STAT3 activation dramatically enhances (10 fold) NRF2 binding sites across the genome. Downstream analysis of NRF2 target genes revealed a significant change from stress response to activation of gene signaling pathways involved in stemness-high cancer cells and metastatic cells under both hypoxic and STAT3 stimulation. Finally, we investigated whether the stemness inhibitor BBI-608 (Napabucasin) could reduce chemotherapy-induced NRF2 upregulation. Our results indicate that STAT3 modulates NRF2 levels and transcriptional activity, and that stemness inhibitor BBI-608 can prevent this upregulation. Our data revealed STAT3-NRF2-Hypoxia as a novel reinforcing regulatory mechanism for promoting cancer stemness and chemoresistance. Citation Format: Luz Elisa Tavera, Karen Simon, Juying Li, Katherine Geromini, Zhuo Zhang, Sarah Keates, Harry A. Rogoff, Chiang J. Li. Identification of STAT3-NRF2-hypoxia as a novel reinforcing mechanism for promoting cancer stemness [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 LB-143. doi:10.1158/1538-7445.AM2017-LB-143
Abstract 1386: Effects of histone deacetylase inhibitors on differentiation markers and growth of colon and bladder cancer cells
Authors: Michael A. Lea, Lauren Cué, Elizabeth Batista, Erik Lew, Charles desBordes
Journal: Cancer Research (2017)

Abstract Alkaline phosphatase and dipeptidyl peptidase are markers of differentiation in colon cancer cells. In colon cancer cells differentiation can often be induced by treatment with inhibitors of histone deacetylase (HDAC) activity. In some colon cancer cells butyrate causes a several-fold induction of alkaline phosphatase but only modest effects on dipeptidyl peptidase. There is relatively little information on changes in activity of cell surface hydrolases in bladder cancer. However, there is some evidence for decreased alkaline phosphatase activity in bladder cancer. We tested the hypothesis that there may be retention of activity in more slowly growing cancer cells and the activity will be regulated by HDAC inhibitors in a manner similar to that in colon cancer. In our initial studies we screened seven human bladder cancer cell lines for alkaline phosphatase activity. We identified three cell lines (5637, HT1197 and HT1376) with activity comparable to that in more differentiated colon cancer cell lines. The response to incubation with the HDAC inhibitors butyrate and valproate was compared with effects in three colon cancer cell lines Caco-2, HT29 and SW1116. In all six cell lines there were growth inhibitory effects that tended to be a little greater with butyrate than with valproate. Induction of alkaline phosphatase activity was generally greater with butyrate than with valproate and was apparent even without normalizing the activity on a protein basis. After determining the activity per unit protein there were increases in dipeptidyl peptidase activity after treatment with the HDAC inhibitors that were smaller than for alkaline phosphatase. Growth inhibition was observed with all the HDAC inhibitors examined including LMK235, nicotinamide, RGFP966, romidepsin and tubacin but increased activity of alkaline phosphatase was not always seen. Activities of the enzymes were very low in CRL1790 human colonocytes of fetal origin and there was little or no induction with HDAC inhibitors. Although pyruvate and carnitine have been reported to be HDAC inhibitors, incubation with colon and bladder cancer cells did not cause induction of alkaline phosphatase activity. It was concluded that regulation of alkaline phosphatase and dipeptidyl peptidase by HDAC inhibitors can be similar in bladder and colon cancer cells. Citation Format: Michael A. Lea, Lauren Cué, Elizabeth Batista, Erik Lew, Charles desBordes. Effects of histone deacetylase inhibitors on differentiation markers and growth of colon and bladder 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 1386. doi:10.1158/1538-7445.AM2017-1386
Impact of KIR/KIR ligand genotype for neuroblastoma patients in a phase III COG immunotherapy trial.
Authors: Amy K Erbe, Wei Wang, Lakeesha Carmichael, KyungMann Kim, Eneida A Mendonca, Yiqiang Song, Dustin Hess, Wendy B. London, Jacquelyn A Hank, Mitchell B Dicciani, Ralph A Reisfeld, Stephen D Gillies, Michael D. Hogarty, John M. Maris, Julie R. Park, Mehmet Fevzi Ozkaynak, Andrew Lee Gilman, Alice L. Yu, Paul M. Sondel
Journal: Journal of Clinical Oncology (2016)

e14014 Background: High-risk neuroblastoma (NBL) patients (pts) enrolled in a COG phase III clinical trial (ANBL0032) were randomized to isotretinoin (RA) alone or RA + immunotherapy (IM): dinutuximab (anti-GD2 mAb) + IL2 + GMCSF (Yu et al., NEJM363:1324, 2010). Dinutuximab acts via antibody-dependent cell-mediated cytotoxicity by innate immune cells, including NK cells. NK cells express Killer Immunoglobulin-like Receptors (KIRs) that bind KIR-Ligands (KIR-Ls), MHC Class I molecules. Prior studies suggest that KIR/KIR-L status impacts outcome for pts with NBL. We investigated whether KIR/KIR-L genotype was associated with event-free survival (EFS) and overall survival (OS) in this trial. Methods: Of the 226 pts randomized, 174 pts had DNA allowing evaluation of genotype correlations with outcome (IM: n=88; RA: n=86; >5yr follow-up if no event). For the inhibitory KIRs, we assessed the impact of all KIR-Ls present vs. missing at least one KIR-L (KIR-L missing) on outcome. Cox regression models and log-rank tests were used to evaluate EFS/OS with genotypes. Results: In contrast to prior reports, outcome for IM pts was not associated with KIR-L present vs. KIR-L missing genotypes (EFS p=0.35; OS p=0.33; Table). Interestingly, we found that IM therapy benefited those pts with KIR-L present as opposed to those with KIR-L missing (OS: p=0.01 vs. p=0.77; Table). Conclusions: IM (vs. RA) treatment resulted in improved outcome (Yu et al., 2010), but IM can have toxic side effects. Our data suggest that KIR/KIR-L genotype could be used prospectively to identify pts most likely to benefit from this therapy. We are continuing to evaluate KIR/KIR-L genotypes in this study to determine if there are certain genotypes that are likely to respond to IM (eg. KIR-L present, Table), and identify KIR/KIR-L genotypes that might benefit from alternate treatment regimens (eg. KIR-L Missing, Table). Clinical trial information: NCT00026312.Treatment EFS OS KIR-L present KIR-L missing Genotype p-value KIR-L present KIR-L missing Genotype p-value RA 5 yr % 39 48 0.24 42 66 0.06 [95% CI] [22-55] [34-61] [24-58] [52-78] Events/n 19/31 27/55 18/31 21/55 RA + IM 5 yr % 72 52 0.35 80 71 0.33 [95% CI] [50-86] [39-64] [58-91] [59-81] Events/n 9/25 30/63 7/25 25/63 Treatment p-value 0.03 0.54 0.01 0.77
Abstract 4793: TRAF2 is required for the survival of ErbB2-transfored mammary tumor cells
Authors: Hasem Habelhah, Yumei Fan, Laiqun Zhang
Journal: Cancer Research (2017)

Abstract TRAF2 regulates signaling pathways downstream of many members of the TNF receptor superfamily, such as TNFR1 and CD40. Recently, we found that TRAF2 also plays an important role in breast cancer cell survival under conditions of endoplasmic reticulum (ER) stress. It is known that TRAF2 knockout (KO) mice die within a week of birth and this lethality can be rescued by KO of TNFα or TNFR1. In order to determine the role of TRAF2 in mammary tumor development and progression, we crossed MMTV-ErbB2 mice (FVB) with TNF-/-/TRAF2-/+ mice (B6), and generated MMTV-ErbB2 (ErbB2), MMTV-ErbB2-TNF-/- (ErbB2/T-KO) and MMTV-ErbB2-TNF-/-/TRAF2-/- (ErbB2/T/T2-DKO) mice all in FVB/B6 mixed background. In 43 weeks, only 1 of 10 ErbB2/T/T2-DKO mice developed a mammary tumor, while 50% of ErbB2 and ErbB2/T-KO mice developed multiple and larger tumors in 30-32 weeks. Interestingly, the tumor derived from the ErbB2/T/T2-DKO mice did not show decreased cyclin D1 expression, nor the tumor cells cultured in vitro show decreased NF-κB activation in response to RANKL. In addition, ErbB2/T/T2-DKO cells formed mammospheres of similar appearance with that of ErbB2 cells in HEMA-coated plates. However, after dispersion of the mammospheres into single cells, ErbB2/T/T2-DKO cells formed dead cell aggregates, while ErbB2 and ErbB2/T-KO cells formed secondary mammospheres, suggesting that the self-renewal capacity of ErbB2/T/T2-DKO cells is impaired. Mechanistic studies reveal that ErbB2/T/T2-DKO cells are sensitive to death caused by ER stress but not by TRAIL or DNA damage, and that this sensitivity is significantly inhibited by knockdown of RIP1. Collectively, these findings suggest that TRAF2 plays a critical role in mammary tumor development and progression by suppressing the pro-death activity of RIP1, and that TRAF2 and RIP1 interaction could be an attractive target for development of new anti-breast cancer drugs. Citation Format: Hasem Habelhah, Yumei Fan, Laiqun Zhang. TRAF2 is required for the survival of ErbB2-transfored mammary tumor 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 4793. doi:10.1158/1538-7445.AM2017-4793
Abstract 496: Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination
Authors: Mayank Singh, Amy C. Burrows, Andrew Dickson, Komal Komal, Debjani Pal, Matthew K. Summers
Journal: Cancer Research (2017)

Abstract Protein deubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction. Ubiquitin specific peptidases (USPs) remove ubiqiuitin tags from target proteins to control both protein fate and function. USP37 (Ubiquitin specific peptidase 37) has been implicated in cancer and we have previously shown that antagonizes the tumor suppressor APCCDH1and promotes S phase entry. However, the role of USP37 during S-phase was unknown. Here, we report that in cells experiencing replication stress USP37 overexpression confers survival advantage while its depletion enhances sensitivity. USP37 overexpressing cells were able to resolve different DNA damage markers much more effectively then the control cells or cells in which USP37 was depleted. Mechanistically, our data indicate that USP37 binds and stabilizes the active form of CHK1 and deubiquitinates Chk1 to increase its stability and promote the checkpoint response. USP37 overexpression results in constitutive replication fork movement and long tract DNA synthesis while USP37 depleted cells were unable to carry out long tract DNA synthesis. Notably, expression of low level of Chk1 in USP37 depleted cells rescues cell survival and DNA damage response. Overall our data suggest that inhibition of USP37 may represent a novel mechanism to modulate Chk1 activity. Note: This abstract was not presented at the meeting. Citation Format: Mayank Singh, Amy C. Burrows, Andrew Dickson, Komal Komal, Debjani Pal, Matthew K. Summers. Ubiquitin specific peptidases 37 promotes constitutive replication fork movement by stabilizing Chk1 via its deubiquitination [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 496. doi:10.1158/1538-7445.AM2017-496