bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C125: Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins
Authors: Ohoka Nobumichi , Tsuji Genichiro , Shoda Takuji , Fujisato Takuma , Kurihara Masaaki , Demizu Yosuke , Naito Mikihiko 
Published: March 2020

Abstract
Targeted protein degradation using chimeric small molecules is an emerging modality in drug discovery. These compounds termed proteolysis-targeting chimeras (PROTACs) and specific and nongenetic inhibitors of apoptosis protein [IAP]-dependent protein erasers (SNIPERs) contain two ligands connected with a linker: one ligand is specific for an E3 ubiquitin ligase, and the other ligand is specific for the target protein, and cross-link the E3 ligase and the target protein within the cell, thereby inducing the poly-ubiquitylation and proteasomal degradation of the target. Currently only a limited number of the E3 ligases, including IAPs, VHL and CRBN, can be recruited to the target proteins by this technology. Here, we expand the repertoire of E3 ligases capable of ubiquitylating target proteins using this system. By incorporating β-naphthoflavone (β-NF) as a ligand for E3 ubiquitin ligase, we developed a novel class of chimeric molecules that recruit the aryl-hydrocarbon receptor (AhR) E3 ligase complex. β-NF-ATRA, a chimeric degrader directed against cellular retinoic acid binding proteins (CRABPs), induced the AhR-dependent degradation of CRABP-1 and CRABP-2 via the ubiquitin-proteasome pathway. A similar compound ITE-ATRA, in which an alternative AhR ligand was used, also degraded CRABP proteins. We also developed a chimeric compound b-NF-JQ1 that is directed against bromodomain-containing (BRD) proteins using b-NF as an AhR ligand. β-NF-JQ1 induced the interaction of AhR and BRD proteins and displayed effective anticancer activity that correlated with protein knockdown activity. These results demonstrate a novel class of chimeric degrader molecules based on the ability to recruit AhR E3 ligase to the target proteins.
Citation Format: Nobumichi Ohoka, Genichiro Tsuji, Takuji Shoda, Takuma Fujisato, Masaaki Kurihara, Yosuke Demizu, Mikihiko Naito. Development of small molecule chimeras that recruit aryl-hydrocarbon receptor (AhR) E3 ligase to induce degradation of target proteins [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 C125. doi:10.1158/1535-7163.TARG-19-C125
Abstract CN05-03: Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction
Authors: Bader Benjamin 
Published: March 2020

Abstract
Mutants of RAS are major oncogenes and occur in many human cancers, but efforts to develop drugs that directly inhibit the corresponding constitutively active RAS proteins failed so far. We therefore focused on SOS1, the guanine nucleotide exchange factor (GEF) and activator of RAS. A combination of high-throughput and fragment screening resulted in the discovery of the first nanomolar SOS1 inhibitors, which effectively downregulate active RAS in tumor cells. The identification of novel potent and cellular active small molecule inhibitors will be presented which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action and selectivity were elucidated using crystal structures of KRASG12C–SOS1, SOS1 and SOS2. By preventing formation of the KRAS–SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. Compound BAY-293 selectively inhibits the KRAS–SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations. In cells with wild-type KRAS, we observed complete inhibition of the RAS–RAF–MEK–ERK pathway. In a mutant KRAS cell line, SOS1 inhibition resulted in a reduction of pERK activity by 50%. In preventing the reloading of with GTP the SOS-inhibitors strongly synergize with covalent inhibitors like ARS-853 or ARS-1620 targeting the mutant KRASG12C in its GDP-state. Together, the data indicate that inhibition of GEFs may represent a new viable approach for targeting RAS-driven tumors. Reference Hillig RC, et al. (2019) Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS–SOS1 interaction. Proceedings of the National Academy of Sciences 116(7):2551-2560
Citation Format: Benjamin Bader. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction [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 CN05-03. doi:10.1158/1535-7163.TARG-19-CN05-03
Abstract LB-A21: Decouple the toxicity and efficacy of BJ-001, an integrin targeting IL-15
Authors: Wang Yanlan , Zhu Ziyan , Zhang Meng 
Published: March 2020

Abstract
IL-15 has been actively investigated for its potential in tumor immunotherapy. To enhance the anti-tumor activity of IL-15, BJ-001, an integrin targeting IL-15 was designed and studied. B-J001 showed tumor cell targeting without compromising IL-15 activity in vivo. In xenograft models, BJ-001 had potent anti-tumor activities. For majority of immunotherapies, increased efficacy is associated with increased toxicity. Interestingly, by monitoring the changes of immune cells and cytokines in vivo, the toxicity and efficacy of BJ-001 can be uncoupled. Increased efficacy of BJ-001 can be achieved without increasing toxicity. These studies may provide guidance for the therapeutic use of BJ-001, which is currently in Phase I human trial.
Citation Format: Yanlan Wang, Ziyan Zhu, Meng Zhang. Decouple the toxicity and efficacy of BJ-001, an integrin targeting IL-15 [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-A21. doi:10.1158/1535-7163.TARG-19-LB-A21
Abstract LB-B09: ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma cells
Authors: Gerosa Luca , Chidley Christopher , Froehlich Fabian , Sanchez Gabriela , Lim Sang Kyun , Muhlich Jeremy , Chen Jia-Yun , Baker Gregory J. , Schapiro Denis , Shi Tujin , Yi Lian , Nicora Carrie D. , Qian Wei-Jun , Wiley H. Steven , Sorger Peter 
Published: March 2020

Abstract
Anti-cancer drugs commonly target signal transduction proteins activated by mutation. In patients with BRAFV600E melanoma, small molecule RAF and MEK kinase inhibitors cause dramatic but often transient tumor regression. Emerging evidence suggests that cancer cells adapting by non-genetic mechanisms constitute a reservoir for the development of drug-resistant tumors. Here, we show that few hours after exposure to RAF/MEK inhibitors, BRAFV600E melanomas undergo adaptive changes involving disruption of negative feedback and sporadic pulsatile reactivation of the MAPK pathway, so that MAPK activity is transiently high enough in some cells to drive proliferation. ERK pulses are locally triggered by autocrine/paracrine factors in the local microenvironment so that ERK activity levels are low on average, but transiently high enough in patches of cells to explain the infrequent division characteristic of persister cells. Quantitative proteomics and computational modeling show that pulsatile MAPK reactivation is possible due to the co-existence in cells of two MAPK cascades: one driven by BRAFV600E that is drug-sensitive and a second driven by receptors that is drug-resistant. Paradoxically, this may account both for the frequent emergence of drug resistance and for the tolerability of RAF/MEK therapy in patients.
Citation Format: Luca Gerosa, Christopher Chidley, Fabian Froehlich, Gabriela Sanchez, Sang Kyun Lim, Jeremy Muhlich, Jia-Yun Chen, Gregory J. Baker, Denis Schapiro, Tujin Shi, Lian Yi, Carrie D. Nicora, Wei-Jun Qian, H. Steven Wiley, Peter Sorger. ERK pulses drive non-genetic resistance in drug-adapted BRAFV600E melanoma 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 LB-B09. doi:10.1158/1535-7163.TARG-19-LB-B09
Abstract LB-B11: Myeloid p38 MAPK promotes tumorigenesis by suppressing cytotoxic T cell recruitment
Authors: Choo Min-Kyung , Park Jin Mo 
Published: March 2020

Abstract
The last decade has seen explosive progress in understanding how tumor-associated macrophages (TAM) contribute to the development, metastasis, and therapy resistance of cancer. TAM and their molecular components are investigated as targets for cancer therapy. However, the precise mechanisms for their function remain to be fully elucidated. The p38 MAP kinase is known to play a pivotal role in cellular responses to stress, mitogenic stimuli, and immune signaling. Evidence from clinical observations and cell culture experiments reveals a role for p38 in many aspects of cancer and immunity. However, little is known about the functions of p38alpha, the most abundant and ubiquitously expressed p38 isoform, in TAM. Here we found that myeloid-specific p38alpha ablation resulted in a decrease in tumor incidence and multiplicity in a DMBA-TPA carcinogenesis model. Tumors from these mutant mice displayed markedly reduced proliferation and poorly developed blood vessels compared to those from control WT mice. Genome-wide expression analysis revealed that p38alpha ablation in macrophages resulted in enhanced CXCL9 expression, a chemokine crucial for cytotoxic T cell recruitment. Indeed, we observed greater number of tumor-infiltrating CD8+ T cells in myeloid-specific p38alpha-knockout mice. p38alpha indel mutations in THP-1 cells also led to elevated CXCL9 induction. TCGA data analysis revealed that higher intratumoral expression of CXCL9 was associated with prolonged survival of cancer patients, suggesting a beneficial effect of CXCL9 in human cancers. Next, we sought to identify the molecular mechanism linking p38alpha to the regulation of CXCL9 expression, and found that p38alpha directly phosphorylates and enables the induction of ATF3, a transcription factor that represses CXCL9 expression. Consistent with this finding, ATF3-deficient macrophages exhibited higher CXCL9 expression similar to p38alpha-deficient macrophages. Therefore, macrophage-specific targeting of p38alpha signaling may promote cytotoxic T cell recruitment to the tumor microenvironment and maximize the potential of checkpoint inhibitor and CAR T cell therapies and other therapeutic modalities that rely on tumor-killing CD8+ T cells.
Citation Format: Min-Kyung Choo, Jin Mo Park. Myeloid p38 MAPK promotes tumorigenesis by suppressing cytotoxic T cell recruitment [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-B11. doi:10.1158/1535-7163.TARG-19-LB-B11
Abstract PL03-03: Navigating gene-gene and drug-gene interaction landscapes underpinning the DNA damage response
Authors: Durocher Daniel 
Published: March 2020

Abstract
Loss of genome maintenance is a hallmark of cancers and targeting DNA and DNA repair processes have been mainstays of cancer therapy for decades. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells. I will highlight how these screens can be used to identify new genome stability factors, characterize drug responses and provide new insights into the genetic architecture of the genome stability network by identifying potentially actionable synthetic lethal genetic interactions. Given the focus of the conference, I will highlight how these screens can reveal new synthetic lethal interactions of therapeutic potential.
Citation Format: Daniel Durocher. Navigating gene-gene and drug-gene interaction landscapes underpinning the DNA damage 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 PL03-03. doi:10.1158/1535-7163.TARG-19-PL03-03
Abstract B15: Therapeutic potential of targeting amino acid metabolism in pancreatic cancer
Authors: Fernandez-Zapico Martin , Kim Dae Won , Philip Philip , Vandell Alexander , Eckard Jonathan , Korn Ron , Priore Giuseppe Del , Simeone Diane 
Published: March 2020

Abstract
Background: A wide range of cancers, including pancreatic cancer, display altered expression of amino acid transporter LAT-1. LAT-1 overexpression has been shown to be an important prognostic factor and predicts chemo resistance in pancreatic cancer (Kaira K, 2012; Altan B, 2018). Radiolabeled amino acids for PET imaging, including 3-18F-l-α-methyl-tyrosine ([18F] FAMT), have successfully leveraged cancer’s aberrant LAT1 expression and amino acid uptake for decades. SM-88 is a denatured D/L racemic form of α-methyl-tyrosine designed for selective uptake and disruption of protein synthesis in cancer cells, as well as disruption of catecholamine production via inhibition of tyrosine hydroxylase. Catecholamines have been reported to potentially have a role in driving pancreatic cancer progression and changes in the tumor immune status (Renz B, Cancer Cell 2018; Calvani M, Oncotarget 2014). Initial clinical and preclinical results with SM-88 indicate that this agent could pose a novel approach in the treatment of pancreatic cancer.
Methods and Results: Initial xenograft models of human gastrointestinal cancers using monotherapy SM-88 showed a &gt;50% decrease in tumor growth at three weeks of treatment (p&lt;0.05). Ongoing preclinical experiments are testing the full pharmacodynamic effects of SM-88 on pancreatic cancer cells, as well as potential effects on the tumor microenvironment due to catecholamine interruption. In results from the ongoing phase 2 trial of SM-88 in heavily pretreated metastatic pancreatic cancer patients, SM-88 has shown monotherapy antitumor activity based on RECIST 1.1 criteria. Additionally, 16/24 patients demonstrated a reduction in circulating tumor cells, with the median nadir decline of 63%. LAT1 has been reported to be important in EMT transition and mesenchymal cell survival (Holldorsson S, Cancer letters 2017); examination of the impact of SM-88 on this important emerging biomarker is ongoing.
Conclusion: Altered amino acid (LAT1) metabolism has been shown to be a negative prognosticator in pancreatic cancer outcomes and progression. Targeting LAT1 and amino acid pathways has been identified as a therapeutic approach in multiple cancers (Fuchs BC, Semin Ca Biol 2005). Initial and ongoing studies of SM-88 may clarify the potential utility of this approach in the treatment of pancreatic cancer.
Citation Format: Martin Fernandez-Zapico, Dae Won Kim, Philip Philip, Alexander Vandell, Jonathan Eckard, Ron Korn, Giuseppe Del Priore, Diane Simeone. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B15.
Abstract C18: TGF-beta blockade paradoxically activates non-SMAD signaling
Authors: Husain S. Mazher , Kansal Rita , Alvarez Marcus A. , Glazer Evan S. 
Published: March 2020

Abstract
Transforming growth factor-beta (TGF-B) activates a receptor leading to a critical signaling cascade in pancreatic ductal adenocarcinoma (PDAC) that results in cancer progression through epithelial-to-mesenchymal transition (EMT) and therapeutic resistance. This signaling is through both the canonical SMAD and non-SMAD proteins. Clinically, there exists a TGF-B paradox where TGF-B is a tumor suppressor in nonmetastatic PDAC but a tumor promotor in metastatic PDAC. We hypothesized that TGF-B receptor blockade helps explain the paradox leading to EMT and therapeutic resistance due to non-SMAD signaling. We investigated expression of proteins involved in non-SMAD TGF-B signaling in human PDAC cell lines with Western blot and in patient-derived organoids with immunofluorescence. Inhibition of the TGF-B receptor type 1 with galunisertib resulted in increased phospho-MAPK14 and phospho-Akt compared to controls. In metastatic PDAC, we also demonstrated that this results in increased levels of the activate beta-catenin complex. There were no changes to SMAD2 or SMAD3 phosphorylation. Our work demonstrates that despite blocking of the TGF-B receptor 1, phosphorylation of MAPK14 increases leading to non-SMAD signaling through Akt. Our data demonstrate that beta-catenin is the effector molecule for cancer progression. Our results also demonstrate a possible mechanism for the development of therapeutic resistance in patients with PDAC who undergo TGF-B receptor inhibition therapy.
Citation Format: S. Mazher Husain, Rita Kansal, Marcus A. Alvarez, Evan S. Glazer. TGF-beta blockade paradoxically activates non-SMAD signaling [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C18.
Abstract C63: The analysis of microbiota composition between tumor and normal tissues in pancreatic cancer and the comparison with the public data of NCBI
Authors: Choi Hwi Wan , Kim Jinju , Kim Eo Jin , Jun Eunsung 
Published: March 2020

Abstract
Purpose: The translocation of gut bacteria and its derivatives may be an essential factor contributing to the various diseases of the pancreas. However, microbial function on the development and progression of pancreatic cancer is not clear and the research is still lacking. The aim of this study is to analyze the composition of microbiota in pancreatic cancer tissue and to compare the result with the existing public data.
Methods: We obtained the cancer and normal tissues from patients who underwent pancreatic cancer surgery in Korea (IRB: 2018-0710), and total bacterial genomic DNA was purified from tissue. Through the gene sequencing of 16S rRNA (V3-V4 lesion), we analyzed the quantitative and qualitative composition of microbiome. Then we compared the microbiome composition with public data of NCBI (SRP132007).
Results: We successfully performed the gene sequencing of 16s rRNA from 12 tumor tissues and 6 normal tissues. Based on the results obtained from the tumor and normal tissues, we compared the composition from the phylum to the species levels. We confirmed that there were significant differences in the microbiome composition of the tumor and normal tissues and identified various strains of 20 or more species with a high specificity in tumor or normal tissues. In addition, through the comparison with SRP132007 data, we confirmed a distinct difference between the two groups.
Conclusions: We have analyzed the patterns and characteristics of tumor or normal specific microbiomes through pancreatic cancer tissues. There is a clear difference between the two groups with environmental differences, even in the microbiomes of patients with the same disease. We expect to further clarify the importance of microbiomes in pancreatic cancer and point to the development of new therapies through further studies.
Citation Format: Hwi Wan Choi, Jinju Kim, Eo Jin Kim, Eunsung Jun. The analysis of microbiota composition between tumor and normal tissues in pancreatic cancer and the comparison with the public data of NCBI [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C63.
Abstract ES2-2: Evolving opportunities to personalize radiation decisions - Guiding decisions to omit radiation after breast conserving surgery for invasive breast cancer
Authors: Speers C 
Published: March 2020

Abstract
Much as the development of molecularly based signatures (OncotypeDx®, MammaPrint®, ProSigna™, etc.) has revolutionized the decision-making process surrounding the need for adjuvant chemotherapy in women with early stage breast cancer, the development of prognostic and predictive signatures to determine the need and efficacy of radiation for women with breast cancer holds similar promise. While preliminary efforts to develop these signatures has been encouraging, much work remains in order to successfully translate these signatures into the clinic. In this educational session, we will review the current status of genomic-based signatures for radiation decision making. We will also review the barriers to clinical adoption and the molecularly stratified trials testing these signatures for treatment omission. Ultimately, for any of these tests to be translated into the clinic it will require demonstration of their accuracy and reproducibility as a test and perhaps more importantly, demonstration of clinical utility and an ability to improve outcomes for women with breast cancer. While not yet realized, the ongoing development of these signatures holds much promise as the field seeks to finally realize “personalized medicine” as it relates to radiation treatment for women with breast cancer.
Citation Format: C Speers. Evolving opportunities to personalize radiation decisions - Guiding decisions to omit radiation after breast conserving surgery for invasive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES2-2.
Abstract ES2-3: Guiding selection of RT approach after lumpectomy
Authors: Shaitelman SF 
Published: March 2020

Abstract
Level I evidence supports the usage of adjuvant radiation therapy following breast conserving surgery for early stage breast cancer. Historically, this was typically delivered using standard fractionation whole breast irradiation. We will review multicenter, randomized controlled trials that support the use of hypofractionation in this setting. More recent level I data has also demonstrated excellent local control with partial breast irradiation for select, early stage breast cancers. In this educational talk we will review the local control and toxicity data for partial breast irradiation. International guidelines on the use of hypofractionated whole breast irradiation and partial breast irradiation will be discussed. We will aim to provide a framework for decision making when electing radiation technique in this setting.
Citation Format: SF Shaitelman. Guiding selection of RT approach after lumpectomy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES2-3.