bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C053: NP-G2-044, a novel fascin inhibitor, blocks tumor metastasis and increases antitumor immune response
Authors: Chung Vincent , Tsai Frank , Jhaveri Komal , Wang Yufeng , Hoff Daniel D Von , Garmey Edward G , Zhang J. Jillian , Huang Xin-Yun 
Published: March 2020

Abstract
Filopodia are finger-like plasma membrane protrusions that are formed upon remodeling of the actin cytoskeleton beneath the plasma membrane. Fascin protein is the main actin-bundling protein in filopodia and invadopodia which are fundamental to cell shape and motility events. Human fascin expression is low or absent in normal adult epithelial cells but highly expressed in metastatic tumors and in antigen-presenting dendritic cells within the tumor microenvironment. Elevated levels of fascin are correlated with poor prognosis and short survival due to aggressive phenotypes with increased lymph node and distant metastases. Mouse genetic studies demonstrate that deletion of fascin gene delays tumor development, slows tumor growth, reduces metastatic colonization, and increases overall survival. These mouse genetic studies provide strong evidence for fascin’s role in tumor initiation, tumor progression and tumor metastasis, making it an attractive target for drug development. Chemical libraries were screened to identify small-molecule compounds that specifically inhibit the biochemical function of fascin to bundle actin filaments. The inhibitors were optimized to produce the lead compound, NP-G2-044. Preclinical studies showed that fascin inhibitors increase the overall survival of tumor-bearing mice and reinvigorate anti-tumor immune response in syngeneic mouse models of breast, lung, pancreatic and prostate tumors. Fascin protein levels are increased in conventional dendritic cells (cDCs) in the immunosuppressive tumor microenvironment. The number of intra-tumoral activated cDCs is increased following fascin inhibitor treatment. Moreover, together with anti-PD-1 antibody, fascin inhibition markedly increases the number of Ki67+ proliferating and Granzyme-B+ activated CD8+ killer T-cells in tumor tissue. These data demonstrate that fascin inhibitors simultaneously act on tumor cells to block tumor metastasis and on intratumoral DCs to reinvigorate anti-tumor immune response. We are currently conducting a first-in-human phase 1 trial of NP-G2-044 in patients with advanced or metastatic solid tumor malignancies.
Citation Format: Vincent Chung, Frank Tsai, Komal Jhaveri, Yufeng Wang, Daniel D Von Hoff, Edward G Garmey, J. Jillian Zhang, Xin-Yun Huang. NP-G2-044, a novel fascin inhibitor, blocks tumor metastasis and increases antitumor immune response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C053. doi:10.1158/1535-7163.TARG-19-C053
Abstract C089: Adaptive responses of low-grade ovarian cancer cell lines to MEK inhibitor
Authors: Wong Kwong-Kwok , Tsang Yvonne T , Chen Michelle , Kun Eucharist H , Gershenson David M 
Published: March 2020

Abstract
Low-grade ovarian serous carcinomas (OSC) account for more than 70% epithelial ovarian cancers in young women. The exact biological pathways that underlie this disease are elusive. Moreover, chemotherapy and hormonal therapy are relatively ineffective and have generally failed to reduce the high morbidity and mortality associated with this disease. Because the Ras/Raf/MEK/ERK pathway is frequently activated in low-grade OSC, targeting this pathway has been examined as a potential avenue for treatment. Results from a phase II Gynecologic Oncology Group (GOG) trial for patients with recurrent low-grade OSC indicated a majority of the patients had developed resistance to Selumetinib (a MEK inhibitor). There were one complete responder, seven partial responders and 34 patients with stable disease out of the 52 patients treated with the MEK inhibitor. In order to understand the MEK inhibitor adaptive response, we have generated two MEK inhibitor (MEKi) adaptive resistant low-grade OSC cell lines. Using functional proteomic analysis by reverse phase protein array (RPPA), we identified several signaling pathways affected by MEKi (trametinib). Our data indicated pAKT was the most up-regulated protein by MEKi. In addition, other proteins in the mTOR, NF-kB, RTK and immune suppressive pathways were up-regulated. We further validated the result by western blot analysis, phospho-ERK, CHK1, MSH2, pRB and DUSP6 were down-regulated, while pAKT, B7-H4, BIM, and p27 were significantly up-regulated. More interestingly, SERPINE1 was the only highly expressed protein in both MEKi adaptive resistance low-grade OSC cell lines, and its expression was not affected by MEKi treatment. Knocking down the expression of SERPINE1 by siRNA targeting SERPINE1 in the MEKi-resistant low-grade OSC cell line was able to attenuate its resistance to trametinib. In summary, we have deciphered several adaptive responses of low-grade ovarian cancer cell lines to MEK inhibitor and the up-regulation of the SERPINE1 pathway is partly responsible for the development of adaptive resistance.
Citation Format: Kwong-Kwok Wong, Yvonne T Tsang, Michelle Chen, Eucharist H Kun, David M Gershenson. Adaptive responses of low-grade ovarian cancer cell lines to MEK inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C089. doi:10.1158/1535-7163.TARG-19-C089
Abstract C090: Systematic review of neurotrophic tyrosine receptor kinase inhibition as a tumor-agnostic management strategy
Authors: Chu Paula , Batson Sarah , Mitchell Catherine , Hodgson Matt 
Published: March 2020

Abstract
NTRK mutations occur in up to 1% of all solid tumours and are observed in more than 20 different malignancies over diverse tissue/cell lineages. The potential clinical effectiveness of TRK inhibitors is being assessed in phase I and II trials. A systematic review was conducted to provide a summary of published evidence for the currently available NTRK-targeted agents; a meta-analysis feasibility was also conducted to assess whether quantitative comparisons could be made on their relative efficacy and safety. The electronic databases Medline®, Medline® Epub Ahead of Print (In-Process & Other Non-Indexed Citations), Embase, and EBM Reviews were interrogated. Eligibility criteria included clinical studies, economic evaluations, utility studies, or cost/resource use studies conducted in patients (adults or paediatric patients) with NTRK+ solid tumours. 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Data from a pooled analysis of three trials reported an objective response rate (ORR) for larotrectinib of 75% (95% confidence interval [CI] 61–85). After one year, 71% of responses were ongoing, 55% of patients remained progression free, and 90% of patients were still alive. An integrated analysis of entrectinib-treated patients reported an ORR of 57.4% (95% CI 43.2–70.8) and a complete response in 4 patients (7.4%). The median duration of response was 10.4 months (95% CI 7.1– not reported [NR]), median overall survival was 20.9 months (95% CI 14.9–NR) and progression-free survival was 11.2 months (95% CI 8.0–14.9). Both larotrectinib and entrectinib were well tolerated with the majority of adverse events being grade 1 or 2. No relevant economic or humanistic studies were identified. A meta-analysis feasibility assessment was conducted to compare the relative efficacy of entrectinib and larotrectinib for outcomes of interest. However, a robust meta-analysis was not feasible due to the single-arm design of eligible studies, heterogeneity of patient population and outcome data, and small sample sizes. Available evidence to date demonstrates that the currently available NTRK-targeted agents are generally well tolerated and are associated with an impressive clinical benefit (as assessed by ORR). Further corroboration from the expansion of existing studies and real-world data would strengthen the evidence base and further elucidate the optimum positioning of NTRK-targeted agents in the treatment pathway.
Citation Format: Paula Chu, Sarah Batson, Catherine Mitchell, Matt Hodgson. Systematic review of neurotrophic tyrosine receptor kinase inhibition as a tumor-agnostic management strategy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C090. doi:10.1158/1535-7163.TARG-19-C090
Abstract C120: The tumor suppressor role of STXBP6 in triple negative breast cancer
Authors: Lenka Govinda , Shan Jingxuan , Abuaqel Sirin , Chouchane Lotfi 
Published: March 2020

Abstract
Triple negative breast cancer (TNBC) is a subtype of breast cancer (BC) that accounts for approximately 15–20% of all BCs. Additionally, TNBC presents with a poor prognosis mainly due to the lack of effective therapeutic options. For this reason, numerous studies have focused to find the potential molecular targets. Syntaxin binding protein 6, encoded by STXBP6, was initially identified in regulating the formation of the SNARE complex and cytogenesis. It has been reported to be associated with many diseases, such as diabetes, autism and systemic lupus erythematosus. However, there are no studies revealing its biological role and its epigenetic regulation in TNBC. Thus, herein we aim to demonstrate antitumor implications of STXBP6 in TNBC. In this study first, we explored the clinical significance of STXBP6 in cancer. Pan-cancer profiling using TCGA data sets identified aberrant expression of STXBP6 in different cancer types. Importantly, we identified significant down regulation of STXBP6 in TNBC samples. Moreover, significantly improved survival rates were observed in patients when STXBP6 expression levels high. The concurrent analysis between gene expression and methylation of STXBP6 highlighted a clear negative correlation. When the luminal subtype and TNBC subtype of BC cells were treated with demethylating agent 5-aza-2’-deoxycytidine, we observed an increase in the expression of STXBP6 in TNBC cells only which further support the regulatory role of DNA methylation in the control of STXBP6 expression in TNBC. Next, we elucidated the function of STXBP6 in TNBC cells. Overexpression of STXBP6 in TNBC cells significantly decreased cell proliferation, colony formation and increased apoptosis. In summary, these findings highlight the suppression effect of STXBP6 on TNBC progression and could be a novel prognostic and therapeutic target for TNBC in the future. Key Words: STXBP6, Gene Expression, Methylation, Tumor Suppressor, Triple Negative Breast Cancer.
Citation Format: Govinda Lenka, Jingxuan Shan, Sirin Abuaqel, Lotfi Chouchane. The tumor suppressor role of STXBP6 in triple negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C120. doi:10.1158/1535-7163.TARG-19-C120
Abstract C124: HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species
Authors: Nicholson Hilary , Housden Benjamin , Perrimon Norbert , Kaelin William G 
Published: March 2020

Abstract
Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene and its protein product, pVHL, occurs in ~90% of clear cell renal cell carcinoma (ccRCC) cases. pVHL is part of the ubiquitin ligase complex that targets the HIF2α transcription factor, an oncoprotein in ccRCC, for proteasomal degradation. Without functional pVHL, HIF2α accumulates and induces inappropriate transcription of angiogenic, invasive, and growth-promoting genes. Drugs inhibiting HIF2α or its downstream target VEGF are active against ccRCC, but both de novo and acquired resistance are common and no current therapies are curative. We hypothesized that loss of pVHL might create context-specific dependencies that could then be targeted therapeutically. To look for such synthetic lethal targets, we generated human and Drosophila cell pairs that were isogenic for pVHL (or its Drosophila ortholog) and screened using RNAi and chemical compound libraries. The overlap of the hits from these screens identified a hyperdependence on CDK4/6 activity in pVHL-defective cells compared to their pVHL-proficient counterparts. In secondary assays we confirmed that pharmacologic inhibition of CDK4/6 by either Abemaciclib or Palbociclib preferentially reduced viability of VHL-/-cells as compared to VHL+/+cells across a variety of human ccRCC cell lines. Importantly, inhibition of VHL-/-ccRCC cells by Palbociclib was abrogated by expressing a Palbociclib-resistant CDK6 cDNA or by knockout of the canonical CDK4/6 target pRB. Sensitivity to Palbociclib could be reversed by expressing exogenous pVHL, but not a pVHL mutant lacking its known substrate docking site. HIF2aknockout in VHL-/-cells did not eliminate the effect of CDK4/6 inhibition, thus HIF2ais not necessary for the synthetic lethal relationship between VHLand CDK4/6. Moreover, the combination of the HIF2ainhibitor PT2399 and the CDK4/6 inhibitor Palbociclib synergistically suppressed proliferation of VHL-/-ccRCC in vitro in HIF2a-sensitive cell lines. Both Palbociclib and Abemaciclib suppress VHL-/-ccRCC tumor growth in nude mice, including tumors that are PT2399-resistant. My future work will aim to identify the mechanism that underlies the synthetic lethality between VHLand CDK4/6 activity.
Citation Format: Hilary Nicholson, Benjamin Housden, Norbert Perrimon, William G Kaelin. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C124. doi:10.1158/1535-7163.TARG-19-C124
Abstract CN03-01: Functional genomics approaches to the discovery of paralog dependencies in cancer
Authors: Sellers William 
Published: March 2020

Abstract
Advances in next-generation sequencing and projects including the Cancer Genome Anatomy project and the International Cancer Genome Consortium have given us a detailed description of the genetic alterations across a broad spectrum of cancer. This however, does not immediately lead to a detailed functional understanding of those genes whose protein products are necessary for the maintenance of cancer viability. In order to more deeply understand the genes and pathways critical to the survival of cancer cells previous and ongoing efforts have provided functional annotation of the Cancer Cell Line Encyclopedia through the use of deep pooled shRNA or sgRNA libraries. For example, Project DRIVE (Deep RNAi-screening for Viablity Effects in cancer) characterized the viability effects of knockdown of 7,837 genes using 20 shRNAs per gene across 398 cancer cell lines. The DepMap project targeted 18,333 genes in 625 cell lines using CRISPR/CAS9. The data from these efforts are highly robust identifying all known oncogenes mutated in the set of interrogated cell lines, along with multiple new cancer dependent features not previously described. Notably, very few synthetic lethal nodes have emerged from these analyses downstream or within the critical oncogenic pathways that dominate the landscape of human cancer. We hypothesize that this is due to functionally redundant paralogous genes that, while potentially targetable by single therapeutics, are not targeted in current knockdown/knockout screens. This is exemplified by discordance between certain therapeutics and shRNA or sgRNA gene inactivation. For example, the cell line sensitivity profiles of MEK inhibitors which target MEK1 and MEK2, or CDK4/6 inhibitors do not robustly correlate with single gene knockout data. Based on prior work using dual S. pyogenes and S. aureus CAS9 systems, we have built a pairwise sgRNA library targeting roughly 3000 genes and the resulting 5,000 paralog pairs. Initial screening data has demonstrated robustness of the methods. More importantly, new paralog dependencies relevant to NRAS mutant cancers have emerged.
Citation Format: William Sellers. Functional genomics approaches to the discovery of paralog dependencies in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN03-01. doi:10.1158/1535-7163.TARG-19-CN03-01
Abstract CN03-02: Functional genomics approaches to identify targetable dependencies in cancer cells
Authors: Garnett Mathew 
Published: March 2020

Abstract
The next-generation sequencing of tumors is providing an increasingly detailed description of the molecular alterations that occur across the diversity of human cancers. An important and challenging next step is to convert this wealth of information into new therapeutic hypotheses to guide patient care. My laboratory integrates cancer genomics, experimental functional genomics and mechanistic studies to elucidate vulnerabilities operative in cancer cells. These efforts are part of our Cancer Dependency Map initiative which aims to assign a dependency to every cancer cell in a patient and which could be exploited to develop new therapies (https://depmap.sanger.ac.uk/). In my presentation, I will discuss recent results from my laboratory and how these are shaping our understanding of the landscape of targetable dependencies in cancer cells.
Citation Format: Mathew Garnett. Functional genomics approaches to identify targetable dependencies in cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN03-02. doi:10.1158/1535-7163.TARG-19-CN03-02
Abstract CN08-03: LIF in cancer
Authors: Seoane Joan 
Published: March 2020

Abstract
The tumor microenvironment has a critical role in cancer progression. We have identified LIF as a regulator of the tumor stroma, specifically of the tumor immune response. LIF is a cytokine with a crucial role in embryogenesis and previous work has identified LIF as an oncogenic factor that regulates cancer-initiating cells, cancer-associated fibroblasts and chemo- and radioresistance. We have observed that in tumors expressing high levels of LIF, the blockade of LIF inhibited tumor growth and caused tumor regression through the engagement of an immune response. The anti-tumor effect of LIF neutralization was mediated by the tumor-associated macrophages through the regulation of a set of cytokines that impacted on the T cell response. The LIF-mediated immune suppression was observed in several tumor types with an important incidence in glioblastoma. Our results identify LIF as a critical cytokine in the immune response to cancer and a promising therapeutic target.
Citation Format: Joan Seoane. LIF in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr CN08-03. doi:10.1158/1535-7163.TARG-19-CN08-03
Abstract LB-A10: ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer
Authors: Zhou Haiying , Barkund Shravani , Pankov Aleksandr , Sinha Sharvani , Sutimantanapi Dena , Friedman Lori S. , Kabbarah Omar 
Published: March 2020

Abstract
Prostate cancer is the second leading cause of cancer-related death in men. Androgen deprivation is commonly used to treat hormone-sensitive prostate cancer, while second-generation antiandrogens, including enzalutamide and abiraterone, benefit patients with castration-resistant prostate cancer (CRPC). New therapeutic strategies are needed for patients who relapse with metastatic CRPC. The glucocorticoid receptor (GR) has been implicated as a major bypass mechanism to escape androgen blockade in patients with CRPC, indicating that GR-targeted therapies may provide an avenue to overcome therapeutic resistance in this clinical setting. We discovered a novel, selective, oral GR antagonist, ORIC-101, which fully reverses GR-driven resistance to enzalutamide in a dose-dependent manner in preclinical models. Specifically, we show that GR is widely expressed in prostate cancer cell lines, organoids, and tumor tissue, and that GR levels are upregulated upon enzalutamide treatment. We demonstrate in preclinical studies that physiological levels of glucocorticoids promote tumor cell growth, stimulate androgen-regulated gene expression, and drive resistance to enzalutamide. Importantly, these effects were completely reversed by ORIC-101, suggesting ORIC-101 overcomes GR-driven resistance to enzalutamide. To inform the clinical development of ORIC-101 in combination with enzalutamide, we identified FKBP5 and KLK3 as direct transcriptional targets of both androgen receptor and GR. We subsequently validated that secreted PSA, a product of the KLK3 gene, can be induced by glucocorticoids and this induction is fully inhibited by ORIC-101. These findings confirm that targeting GR may help overcome resistance to enzalutamide in CRPC, and that FKBP5 and KLK3 are rational PD biomarkers that may be used in clinical trials of ORIC-101, along with PSA.
Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Sharvani Sinha, Dena Sutimantanapi, Lori S. Friedman, Omar Kabbarah. ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A10. doi:10.1158/1535-7163.TARG-19-LB-A10