bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6506: SOS1 inhibition in combination with HER2 inhibition in models of HER2-driven cancer
Authors: Schenk Robyn L. , Kostyrko Kaja , Popow Johannes , Gewinner Christina , Baum Anke , Albrecht Christoph , Hinkel Melanie , Jacob Robin , Madensky Tom , Ruzicka Regina , Strauss Eva , Lyu Hengyu , Lopez Anastasia M. , Feng Ningping , Vellano Christopher P. , Marszalek Joseph R. , Heffernan Timothy P. , Pearson Mark , Hofmann Marco H. 
Published: March 2024

Abstract
Cancers driven by amplifications or mutations of the gene ERBB2 (coding for the receptor tyrosine kinase (RTK) HER2) have been the focus of HER2-targeting antibodies as well as small molecule inhibitors. Despite initial efficacy, resistance to these HER2-targeted therapies inevitably develops. One strategy to tackle this resistance is to identify rational combinations to address common pathways/factors that contribute to resistance. One such common mechanism of resistance is reactivation of the Mitogen-activated protein kinase (MAPK) pathway. SOS1 is a guanine nucleotide exchange factor (GEF) which regulates the MAPK pathway by catalyzing the exchange of RAS-GDP (inactive) to RAS-GTP (active). SOS1 is activated by multiple different RTKs - upon RTK-ligand binding, autophosphorylation of the RTK recruits the GRB2-SOS1 protein complex to the plasma membrane, enabling the complex to bind and activate RAS-GDP. Given SOS1’s role downstream of RTKs and upstream of the MAPK pathway, we sought to investigate the potential of a SOS1 inhibitor (SOS1i) in combination with a HER2 inhibitor (HER2i) in preclinical models of cancer driven by HER2 mutation or gene amplification. Using in vitro and in vivo models we found evidence of added benefit of SOS1i in combination with HER2i, as well as enhanced inhibition of MAPK signaling, as seen by decrease in ERK activation and expression of MAPK effector genes such as DUSP6. Taken together, we propose that SOS1 inhibition combined with HER2 inhibition may be a rational strategy for deeper and more prolonged responses to HER2 inhibitor treatment by preventing resistance via the MAPK pathway.
Citation Format: Robyn L. Schenk, Kaja Kostyrko, Johannes Popow, Christina Gewinner, Anke Baum, Christoph Albrecht, Melanie Hinkel, Robin Jacob, Tom Madensky, Regina Ruzicka, Eva Strauss, Hengyu Lyu, Anastasia M. Lopez, Ningping Feng, Christopher P. Vellano, Joseph R. Marszalek, Timothy P. Heffernan, Mark Pearson, Marco H. Hofmann. SOS1 inhibition in combination with HER2 inhibition in models of HER2-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6506.
Abstract 6525: Modulating the immune response in cholangiocarcinoma: Targeting sulfatase-2 for therapeutic intervention
Authors: Brooks Tayla R. , Campbell Nellie , Keim Melanie , Roberts Lewis R. 
Published: March 2024

Abstract
Cholangiocarcinoma (CCA) is an aggressive epithelial malignancy of the bile ducts. Recent reports have suggested a rise in the incidence of CCA globally. Current treatments for CCA have limited effectiveness, with only 20-30% response rates in patients with advanced cancer. Thus, there is a growing need to investigate new therapeutic targets for CCA. The tumor microenvironment (TME) is a potential target for novel therapies. The TME plays an important role in progression and metastasis of cancer through facilitating immune escape. Recent studies have demonstrated potential roles for heparan sulfate proteoglycans (HSPGs) in tumorigenesis. Sulfatase 2 (SULF2) is a heparan sulfate editing sulfatase that removes the 6-O sulfate moiety within the heparan sulfate (HS) chains and alters the affinity of HS chains for growth factors and cytokines and their receptors, thus modulating HSPG function in cell signaling pathways. HSPG specific sulfatases have been recently identified as a potential therapeutic target in CCA. We aimed to assess the effects of anti-Sulfatase-2 antibody on immune cells in the tumor microenvironment of syngeneic CCA xenografts in C57BL6 mice. Mice bearing syngeneic CCA xenografts were treated with an anti-sulf2 antibody, and the tumors compared to untreated control xenografts. After treatment, the tumors were harvested and analyzed by Cytometry by time of flight (Cytof) to identify changes in the types and numbers of immune cells in the tumor xenografts. Treatment with anti-sulf2 antibody resulted in a decrease in immunosuppressive cells such as tumor associated macrophages (TAMs) and myeloid derived suppressor cells (MDSC) compared to the control. There was also an increase in anti-tumor cells such as T-cells and NK cells, suggesting that suppressing sulf-2 in the microenvironment can shift the TME toward an anti-tumorigenic rather than a pro-tumorigenic environment. In summary, our work demonstrates the potential to target Sulfatase 2 as a therapeutic mechanism for immunomodulation of the tumor microenvironment. Future experiments to determine the relationship between specific clinical phenotypes and the number, activities and types of immune cells seen in the TME, and experiments in other hepatobiliary cancers models, such as hepatocellular carcinoma and gallbladder cancer, will be conducted.
Citation Format: Tayla R. Brooks, Nellie Campbell, Melanie Keim, Lewis R. Roberts. Modulating the immune response in cholangiocarcinoma: Targeting sulfatase-2 for therapeutic intervention [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6525.
Abstract 6533: Pivotal role of specific LYVE1+ tissue resident macrophages in PDAC progression & immunotherapy resistance
Authors: Li Hong , Yan Jun 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense fibrotic stroma and abundant myeloid cell infiltration, which render it resistant to any therapeutic interventions, including immunocheckpoint blockade (ICB) therapy. Understanding the composition and function of myeloid cells within the PDAC microenvironment may help identify promising targets for PDAC immunotherapy. Tissue resident macrophages (TRMs) contribute to organogenesis and tissue regeneration and metabolism. In this study, we discovered a distinct population of pancreas TRMs that highly express lymphatic vessel hyaluronan receptor 1 (LYVE-1). Single cell RNAseq data reveal that LYVE-1+ TRM cluster in the pancreas expresses high levels of complement activation genes and transcription factors such as c-Maf and Stab1. RNAseq data also confirm that LYVE-1+ TRMs express enriched genes related to mannose binding, endocytosis, and glutathione metabolic process, while LYVE-1 negative macrophages express enriched genes related to antigen processing and presentation, T cell activation, and phagocytosis. Multiparameter flow cytometric analysis demonstrates that LYVE-1+ TRMs express M2-like markers, including increased CD163, CD206 and decreased MHC Class II molecule. During PDAC development and progression, LYVE-1+ TRMs expand and localize around the tumor border, promoting fibrotic stroma formation. Imaging mass cytometry (IMC) also reveals abundant infiltration of LYVE-1+CD14+CD68+ macrophages in human PDAC tumors and colocalized with collagen deposition. This subset of macrophages also highly express c-Maf. Through the use of Lys-Cre-c-Maf f/f mice, we demonstrate that depletion of c-Maf from myeloid cells significantly reduces LYVE-1+ TRMs and polarizes them to resemble an M1-like phenotype. In conclusion, our findings suggest that LYVE-1+ macrophages are a unique subset of myeloid cells within the pancreas and likely play a critical role in PDAC progression and immunotherapeutic resistance. Future work will focus on targeting LYVE1+ TRMs using various approaches, such as conditional knockout mice and small molecule inhibitors, to determine their therapeutic potential for PDAC treatment.
Presented by Dr. Hong Li
Citation Format: Hong Li, Jun Yan. Pivotal role of specific LYVE1+ tissue resident macrophages in PDAC progression & immunotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6533.
Abstract 6567: Affinity and cooperativity modulate ternary complex formation to drive degradation of SMARCA2
Authors: Archibeque Ivonne , Dellamaggiore Ken , Rex Karen , Ghimire-Rijal Sudipa , Choi Kaylee , Kate Smither , Amegadzie Albert , Chen Ning , Li Xiaofen , Wurz Ryan , Vaish Amit , Hughes Paul , Mohl Dane 
Published: March 2024

Abstract
Small molecules that hijack the ubiquitin-proteasome system to degrade target proteins have gained traction as tools for chemical biology and as promising clinical candidates. Targeted degradation strategies encompass relatively large hetero-bifunctional small molecules (hSMs) that are built from target and effector ligands joined by a linker to much smaller molecular glues that have limited affinity for the target or effector proteins outside of a ternary complex. There is good reason for medicinal chemists to move from linkered hSMs toward glue-like scaffolds. Molecular glues can be considerably smaller, e.g., the IMiDs, and thus are less likely to possess atoms and functional motifs that add up to poor permeability and higher protein binding.
Guided by the principle that hSMs with reduced molecular weight will have superior druglike properties, we have used SMARCA2, a potential therapeutic target in patients that have both copies of SMARCA4 inactivated, as a test of our own ability to drive rapid target degradation in relevant models. The hetero-bifunctional degraders that resulted from our work trade conventional linkers for chemical spacers that orient SMARCA2 and VHL to promote fortuitous protein-protein contacts in the ternary complex. Following in the footsteps of previously published works, we employed surface plasmon resonance (SPR), x-ray crystallography, and molecular modeling to understand the relationships between our cell-based metrics of degrader activity and the biophysical parameters that describe the ternary complex. Consequently, we found that cooperativity (α) and ternary complex affinity (KLPT) correlated well with both DC50 and initial rate of degradation. Within our series of novel SMARCA2 degraders, compound 1 exhibited exceptional cooperativity and ternary complex affinity, α = 12.8 and KLPT = 4.7 ± 1. The result of high cooperativity and enhanced affinity was rapid and near complete SMARCA2 degradation. Treatment of a cancer cell line with compound 1 resulted in 50% of SMARCA2 being degraded
in under 30 minutes, and greater than 90% degradation in 2 hours. Most importantly, the near complete degradation of SMARCA2 resulted in potent effects on SWI/SNF dependent transcription in vitro and in inhibition of tumor cell growth both in vitro and in vivo.
Citation Format: Ivonne Archibeque, Ken Dellamaggiore, Karen Rex, Sudipa Ghimire-Rijal, Kaylee Choi, Smither Kate, Albert Amegadzie, Ning Chen, Xiaofen Li, Ryan Wurz, Amit Vaish, Paul Hughes, Dane Mohl. Affinity and cooperativity modulate ternary complex formation to drive degradation of SMARCA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6567.
Abstract 6587: Discovery of molecular glue of FBXW7:MYC interaction using small molecule microarray
Authors: Guo Shenghao , Stilgenbauer Morgan , Wu Bocheng , Mankan Yatin , Koehler Angela N. 
Published: March 2024

Abstract
MYC deregulation is a key driver and feature of many human cancers. Yet, despite its importance in cancer progression, MYC is considered “undruggable” by small molecules due to its disordered conformation. Therefore, interfering with its interactions with protein partners to modulate MYC activity appears viable. FBXW7 is an E3 ligase, which serves as a constituent of the SCF (Skp1-Cul1-F box) ubiquitin ligase complex. It mediates the degradation of both c-Myc and Cyclin E through ubiquitin-dependent proteolysis. FBXW7 mutations are found in various human tumor types, establishing its role as a general human tumor suppressor. Specifically, FBXW7 down-regulation increases MYC level, and its expression correlates to lethal outcomes of breast epithelial cells, poor prognosis in glioblastoma, and T cell acute lymphoblastic leukemia remission. Therefore, our project aims to discover potent small molecule glues that would enhance the interaction between FBXW7 and MYC, leading to MYC degradation through proteolysis and eventually suppression of various cancers. Taking advantage of our high throughput screening technology, Small Molecule Microarrays (SMMs), we successfully identified 29 compounds that potently bind to both c-Myc and FBXW7 after screening our 65,000 ‘drug-like’ small molecule library. We then performed secondary assays using a mCherry-GFP MYC reporter cell line to identify our lead compound, KI-FBX-001, which decreases MYC’s expression:transcription ratio by over 50% compared to control. Additionally, this down-regulation can be rescued by protease inhibitor MG132, indicating that the effect is achieved via proteolysis. In vitro dose-response and time-course treatment revealed an optimal drugging concentration at 15uM in K562 cells, with inhibition reaching its peak at the 4-hour time point at over 60%. Using the Qiagen MYC reporter assay, the in vitro IC50 of KI-FBX-001 is found at 7.42uM. Beyond the protein level, the qPCR result also reveals a decrease in MYC mRNA level at over 70%. Surface Plasmon Resonance (SPR) is used to confirm direct binding between FBXW7 and KI-FBX-001, which showed promising binding with kd=0.17µM. Proximity Ligation Assay further confirms KI-FBX-001’s effect in enhancing FBXW7:MYC interaction in the cell. In summary, our findings proved that KI-FBX-001 is a promising molecular glue in the FBXW7:MYC interaction, and can effectively modulate the MYC level for future therapeutic purposes.
Citation Format: Shenghao Guo, Morgan Stilgenbauer, Bocheng Wu, Yatin Mankan, Angela N. Koehler. Discovery of molecular glue of FBXW7:MYC interaction using small molecule microarray [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6587.
Abstract 6630: Non-cell-autonomous cancer progression from chromosomal instability
Authors: Li Jun , Hubisz Melissa , Earlie Ethan , Duran Mercedes , Hong Christy , Varela Austin , Lettera Emanuele , Deyell Matthew , Tavora Bernardo , Havel Jonathan , Su Phyu , Amin Amit Dipak , Budre Karolina , Kamiya Erina , Cavallo Julie-Ann , Garris Christopher , Powell Simon , Reis-Filho Jorge , Wen Hannah , Bettigole Sarah , Khan Atif , Izar Benjamin , Parkes Eileen , Laughney Ashley , Bakhoum Samuel 
Published: March 2024

Abstract
Chromosomal instability (CIN) is a driver of cancer metastasis, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumor microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signaling abrogates CIN-dependent effects on the tumor microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumor cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signaling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumors spurred by CIN-induced inflammation.
Citation Format: Jun Li, Melissa Hubisz, Ethan Earlie, Mercedes Duran, Christy Hong, Austin Varela, Emanuele Lettera, Matthew Deyell, Bernardo Tavora, Jonathan Havel, Phyu Su, Amit Dipak Amin, Karolina Budre, Erina Kamiya, Julie-Ann Cavallo, Christopher Garris, Simon Powell, Jorge Reis-Filho, Hannah Wen, Sarah Bettigole, Atif Khan, Benjamin Izar, Eileen Parkes, Ashley Laughney, Samuel Bakhoum. Non-cell-autonomous cancer progression from chromosomal instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6630.
Abstract 6651: Compromised TGFβ signaling and DNA repair primes immune poor tumors response to immune checkpoint blockade by activating NK cells
Authors: Moore Jade T. , Gkantalis Jim , Guix Ines , Barcellos-Hoff Mary Helen 
Published: March 2024

Abstract
We investigated the interplay between transforming growth factor beta (TGFβ) regulation of immunosuppressive signaling and immunogenic DNA repair. Loss of TGFβ signaling by cancer cells is accompanied by increased use of error-prone repair. We described a transcriptomic score, βAlt, that reports the TGFβ/DNA repair functional relationship. Pan-cancer analysis showed that high βAlt cancers (i.e., low TGFβ and high error-prone DNA repair) are sensitive to chemoradiation and have a greater fraction of genome altered compared to low βAlt cancers. Defective mismatch repair is associated with T cell infiltration and response to immune checkpoint blockade (ICB), hence we investigated the immune context of bAlt. Unsupervised clustering of RNAseq profiles 12 independent immunocompetent mouse tumor derived transplant (mTDT) tumors based on βAlt score indicated that high βAlt was associated with immune poor phenotype and lack of type I interferon signatures. A similar relationship was evident in the bladder, breast, and lung TCGA data. A high βAlt, immune poor mTDT in which T cells were only 20% of 10% CD45 were treated with monotherapy consisting of single fraction 10 Gy radiation, anti-PD-L1 or TGFβ inhibition, dual or triple treatment. Only monotherapy or combinations with radiation significantly increased survival. However, these ICB resistant tumors responded to triple treatment. Response was accompanied by increased tumor infiltrating CD45+ cells (P=0.02), circulating CD8 T cells (P&lt;0.001) and natural killer (NK) cells (P&lt;0.001). As NK cells tripled and TGFβ broadly impairs NK cell effector function, we depleted NK cells to test whether they were required for the response to triple treatment. NK depletion completely abrogated response (P&lt;0.00001) indicating NK cells can provoke an ICB response in high βAlt immune poor tumors. Both mouse tumors and human cancers show that loss of TGFβ signaling resulting in error-prone DNA damage response is strongly associated with immune poor tumors and suggests that TGFβ inhibition can override NK cell dysfunction to create vulnerability to ICB.
Citation Format: Jade T. Moore, Jim Gkantalis, Ines Guix, Mary Helen Barcellos-Hoff. Compromised TGFβ signaling and DNA repair primes immune poor tumors response to immune checkpoint blockade by activating NK cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6651.
Abstract 6690: Gut microbial metabolite butyrate facilitates antitumor efficacy of telomerase-specific oncolytic adenovirus via MHC-I and cGAS-STING pathway activation
Authors: Sakamoto Masaki 
Published: March 2024

Abstract
Introduction: Gut microbiota has been reported to have a potential to modulate tumor sensitivity to chemo- or immuno-therapies although the underlying mechanism is still unclear. Oncolytic virotherapy is a promising antitumor treatment that selectively induces oncolytic cell death in tumor cells. We have previously developed OBP-702, a telomerase-specific oncolytic adenovirus armed with the p53 tumor suppressor gene, highlighting potent antitumor effects across different cancer types. To explore the potential of gut microbial metabolites, particularly butyrate, in augmenting the antitumor efficacy of oncolytic virotherapy.
Materials and Methods: We assessed the synergistic antitumor effects of butyrate and OBP-702 in cytotoxic assay using two human (HCT116, SW48) and two murine (CT26, MC38) colorectal cancer cell lines in vitro, and the in vivo antitumor effects in subcutaneous tumor models using HCT116 and CT26. We explored underlying mechanisms of the synergistic effects, focusing on the influences of butylate on viral infectivity via Coxsackie-Adenovirus Receptor (CAR) and integrins, and antitumor immunity via tumor MHC-I expression and CD8-positive T cells.
Results: Butyrate and OBP-702 showed potent synergistic effects in all four cell lines in vitro, and the combination suppressed tumor growth significantly in HCT116 and CT26 subcutaneous tumors compared to each monotherapy. These synergistic effects were produced by butyrate increasing the potential of OBP-702 by enhancing viral infection efficiency via upregulating expressions of CAR and integrins on tumor cells. Butyrate also increased MHC-I expression on tumor cells by activating the cGAS-STING pathway, leading to increased CXCL10 expression, which led to activation of antitumor immunity through recruitment of CD8-positive T cells in tumor tissues. The synergistic effects of butyrate and OBP-702 were proved in an orthotopic colorectal tumor model with liver metastases using CT26 cells expressing luciferase, in which this combination not only reduced tumor growth, but also improved survival by activating antitumor immunity via CD8-positive T cells.
Conclusion: Butyrate and OBP-702 showed synergistic antitumor effects via activation of systemic antitumor immunity in addition to direct effects of butyrate on viral cytotoxic potential, which provides valuable insights into the development of innovative cancer treatment strategies.
Citation Format: Masaki Sakamoto. Gut microbial metabolite butyrate facilitates antitumor efficacy of telomerase-specific oncolytic adenovirus via MHC-I and cGAS-STING pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6690.