bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 141: Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma
Authors: Church Isabella , Gruen Charli , Sassano Antonella , Valencia Julio , Wu Emily , Yang Howard , Needle Gabe , Smith Cari , Chin Sung , Ebersole Jessica , Marcelus Christina , Fon Anyen , Liu Huaitian , Day Chi-Ping , Young Howard , Lee Maxwell , Merlino Glenn , Pérez-Guijarro Eva 
Published: June 2023

Abstract
Immune checkpoint blockade (ICB) therapies are the current first-line melanoma treatments within the clinic; however, their specific mechanisms for combatting tumor progression remain unclear and determinants for efficacious and durable responses within patients remain unknown. Intratumor heterogeneity (ITH) provides cancers with significant adaptability, leading to metastatic progression and resistance to treatment, but its complexity often complicates its study. To understand how ITH contributes to ICB response, we derived 24 clonal sublines from single cells of an ICB-sensitive and genetically and phenotypically heterogenous mouse model of melanoma. Genomic and transcriptomic analyses uncovered the diversity of these sublines and their plasticity while in vivo studies demonstrated a wide range of responses to ICB therapy including resistant, partially sensitive, and fully responsive. Distinct responses to anti-CTLA-4 monotherapy compared to combination (anti-CTLA-4 plus anti-PD-L1) therapy were also observed, and further exploration of untreated tumors revealed correlations between highly inflamed and differentiated phenotypes with response to anti-CTLA-4. To better understand changes in plasticity and immune profile throughout the course of treatment, tumors were harvested from the parental cell line prior to treatment and at several timepoints after treatment with anti-CTLA-4 monotherapy. These samples are undergoing high throughput spatial transcriptomics analysis to map the melanoma phenotypes characterized in the clonal sublines with changes in the immune compartment. Furthermore, blood samples were collected to investigate inflammatory profiles of cytokines and chemokines to describe the evolution of the tumor microenvironment throughout the course of immunotherapy. Further studies will allow us to identify predictive and prognostic biomarkers of resistance and relapse upon ICB therapy, respectively. Overall, the 24 clonal sublines serve as a valuable tool to model tumor dynamics associated with ICB efficacy and understand the complex role melanoma plasticity plays in immune evasion mechanisms.
Citation Format: Isabella Church, Charli Gruen, Antonella Sassano, Julio Valencia, Emily Wu, Howard Yang, Gabe Needle, Cari Smith, Sung Chin, Jessica Ebersole, Christina Marcelus, Anyen Fon, Huaitian Liu, Chi-Ping Day, Howard Young, Maxwell Lee, Glenn Merlino, Eva Pérez-Guijarro. Interrogating subclonal mechanisms of immune evasion and immunotherapy resistance in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 141.
Abstract 1439: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Authors: Fischer John , Bouhana Karyn , Chicarelli Mark , Fell Brad , Fulton Jennifer , Guarnieri Anna , Haygood Leyla , Jalluri Ravi , Johnson Amber , Mclean Brent , Mejia Max , Rieger Rob , Robinson John , Rodriguez Mareli , Sullivan Francis , Wang Yang , Winski Shannon , Zhou YeYun 
Published: June 2023

Abstract
Fibroblast growth factor receptor (FGFR) mutations, fusions, and rearrangements have been linked to the pathogenesis of multiple tumor types. FGFR2 alterations have emerged as oncogenic drivers across a variety of tumor types, including cholangiocarcinoma, lung, endometrial, and uterine cancer. Approved FGFR inhibitors have demonstrated responses in patients that harbor FGFR genetic alterations but show reduced activity in patients with gatekeeper and molecular brake mutations. In addition, pan-FGFR inhibitors are associated with dose-limiting hyperphosphatemia linked to the inhibition of FGFR1. To address these issues, a novel series of reversible FGFR2 inhibitors with activity against clinically relevant mutations and selectivity over FGFR1 has been identified. The inhibition of FGFR2 phosphorylation in engineered cell lines demonstrated activity toward wild-type FGFR2, molecular brake mutations N549H/K, and gatekeeper mutations V564I/F/L. Selectivity of these inhibitors against FGFR1 and the broader kinome could lead to fewer dose limiting toxicities compared to approved FGFR inhibitors. Additionally, maintaining potency against molecular brake and gatekeeper mutations may result in significantly improved clinical response. In vivo characterization to be presented includes dose escalating rodent pharmacokinetics (PK), second species PK, and pharmacodynamics (PD) in tumor bearing mice. Most importantly, efficacy in a mouse tumor xenograft model at a dose that does not show elevated plasma phosphorus levels in the rat hyperphosphatemia model will be presented. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described.
Citation Format: John Fischer, Karyn Bouhana, Mark Chicarelli, Brad Fell, Jennifer Fulton, Anna Guarnieri, Leyla Haygood, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, YeYun Zhou. In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1439.
Abstract 1661: Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers
Authors: Miller Andrew T. , Jin Qihui , Plouffe David , Corpuz Manny , Rodrigo Evelyn , Wu Tom Y.- 
Published: June 2023

Abstract
Transforming growth factor beta (TGFβ) signaling has been implicated in many cancers and fibrotic diseases. Recent pharmacological intervention has shown promising activities in preclinical models and early clinical trials. There are over 15 investigational agents targeting this pathway currently in the clinic, but none have been approved. In particular, small molecule TGFβ inhibitors targeting ALK5 (TGFβ type 1 receptor) have been limited by mechanism-based heart valve toxicity to low dose and intermittent dosing regimens. NEX002 is an oral liver-targeted ALK5 inhibitor with low heart exposure for the treatment of liver cancer and other gastrointestinal cancers with liver metastases. The compound was designed following drug design principles from known liver-specific drugs, such as the statins. In animals, NEX002 exerts preferential distribution (pharmacokinetic) and target inhibition (pharmacodynamic) in liver over the heart. NEX002 has demonstrated activity in several intrahepatic and subcutaneous tumor models, and significantly enhanced the durability of anti-tumor efficacy in combination with lenvatinib, a VEGFR inhibitor approved for the treatment of hepatocellular carcinoma. No heart valve toxicity was observed when benchmarked against galunisertib (systemic ALK5 inhibitor) in toxicity studies with repeated daily dosing. These data suggest that our liver-targeted/heart-sparing approach may allow more robust target engagement compared to systemic ALK5 inhibitors through higher dose or more frequent dosing.
Citation Format: Andrew T. Miller, Qihui Jin, David Plouffe, Manny Corpuz, Evelyn Rodrigo, Tom Y.- Wu. Heart-sparing ALK5 inhibitor for treatment of gastrointestinal and liver cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1661.
Abstract 1715: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer
Authors: Sale Matthew J. , Mukherjee Neal , Ruzicka Regina , Jacob Robin , Albrecht Christoph , Zanin Teresa , Madensky Tom , Kostyrko Kaja , Schenk Robyn L. , Baum Anke , Gerlach Daniel , Hofmann Marco H. , McCormick Frank 
Published: June 2023

Abstract
SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in 3-5% of non-small cell lung cancers (NSCLC), colorectal cancers (CRC) and melanomas. The recent development of novel SOS1 inhibitors, including BI-3406 and BI-1701963, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. Of the 11 available SOS1-mutant cancer cell lines without RAS co-mutation, 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture, while cells with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. Treatment with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of SOS1-mutant cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain settings, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a rebound in RAS signaling after treatment with SOS1i that was dependent on SOS2. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. In addition, we show that, as with SOS1, SOS2 is a target for ERK1/2-dependent feedback phosphorylation. Thus, relief of ERK1/2-dependent negative regulation of SOS2, following SOS1 inhibition, likely contributes to receptor tyrosine kinase (RTK)-SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i inhibited tumor growth in xenograft models of SOS1-mutant AML and NSCLC. Tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations.
Citation Format: Matthew J. Sale, Neal Mukherjee, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Tom Madensky, Kaja Kostyrko, Robyn L. Schenk, Anke Baum, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1715.
Abstract 1842: The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates
Authors: Li Wei , Xu Yixuan , Zhou Xin , Zhu Dan , Xiao Meng , Zhou Yulin , Yang Zhijie , Li Haodong , Pang Bo , Song Xinghai , Xiao Yan , Shi Wenting , Qian Qian , Gu Qingyang 
Published: June 2023

Abstract
Cytokines are indispensable regulators of innate and adaptive immunity that transfer signals between cells over short distances. Given their abilities to initiate and activate immune responses, cytokines have long been utilized in cancer therapy, whereas there are limitations, short half-life, pleiotropism, functional redundancy, and side effects, slow down the wide application of cytokine therapy. Thus, evaluating the pharmaceutical properties of cytokines or their translated forms, such as supercytokines, immunocytokines, engager cytokines, and synthetic cytokines, in non-human primates shall be a substantial approach to guide and define clinical trial strategies of cytokine-based therapies. In this study, Interleukin-15 (IL-15) is preferably focused due to its potential in proliferating natural killer cells and cytotoxic T lymphocytes by which host’s immunity was boosted to fight against tumor progression. To evaluate the safety and pharmacodynamics of IL-15 in vivo, rhesus macaques were administered intravenously with recombinant human IL-15 (rhIL-15). We revealed that intravenous administration of rhIL-15 to rhesus macaques caused a slightly weight loss and neutropenia, while no other abnormalities were observed during the whole study. Moreover, the level of C-reactive protein (CRP) was found significantly elevated which was consistent with the increased abundance of MCP1, CCL4, and IL-RA chemokines in serum, suggesting that IL-15 treatment induces acute inflammatory response. Furthermore, flow cytometry analysis showed the activation, proliferation and expansion of memory T and NK cells after receiving IL-15. In conclusion, our study deepens the understanding of T and NK cell homeostasis after IL-15 administration in NHPs and may offer critical clinical strategies for human trials.
Citation Format: Wei Li, Yixuan Xu, Xin Zhou, Dan Zhu, Meng Xiao, Yulin Zhou, Zhijie Yang, Haodong Li, Bo Pang, Xinghai Song, Yan Xiao, Wenting Shi, Qian Qian, Qingyang Gu. The safety assessment and the pharmacodynamics evaluation of therapeutic cytokine in non-human primates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1842.
Abstract 1849: Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2
Authors: Lotz-Jenne Carina , Cren Sylvaine , Joesch Christoph , Ackerknecht Sabine , Brandes Jennifer , Moebs Claire , Hartl Dominik , Hartrampf Felix , Guerry Philippe , Pothier Julien , Chavanton-Arpel Alexia 
Published: June 2023

Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2) catalyze the oxidation of L-Tryptophan (TRP) leading to the formation of immunosuppressive kynurenine (KYN) pathway metabolites. According to TCGA, a substantial fraction of different tumor types expresses both IDO1 and TDO2. In 82 tumor samples (GBM, hepatocellular carcinoma, NSCLC, and ovarian cancer) analyzed for IDO1/TDO2 RNA expression (RNA sequencing) and TRP metabolite content (LC-MS/MS), we found TDO2 highly expressed in hepatocellular carcinoma and to lower levels in NSCLC and ovarian cancer. IDO1 was found to be expressed in NSCLC and ovarian cancer but at higher levels and its expression was correlating with KYN levels. Immunosuppressive properties of KYN and downstream metabolites are mediated through T cell apoptosis and regulatory T cell (Treg) induction. In our hands, KYN at concentrations ≥ 50uM was shown to be immunosuppressive, notably inducing T cell apoptosis. According to our and published data, such high KYN concentrations (≥ 50uM) can be found in a subset of human tumors. As outlined, both IDO1 and TDO2 can contribute to high KYN levels in tumors. Hence, dual IDO1/TDO2 inhibition should be superior in decreasing tumor KYN levels and levering immunosuppression as compared to IDO1 selective inhibition. In this regard, we have generated potent dual IDO1/TDO2 inhibitors inhibiting IDO1 and TDO2 enzyme activity in cellular assays in vitro. To prove the concept of superiority in vivo, we established a dual IDO1/TDO2 expressing human tumor model (LOVO+IFNg) in the mouse and showed that the oral administration of a dual IDO1/TDO2 inhibitor as compared to an IDO1 selective inhibitor showed enhanced KYN/TRP modulation in the tumor. Lead compounds with favorable drug-like properties are currently investigated for pre-clinical development.
Citation Format: Carina Lotz-Jenne, Sylvaine Cren, Christoph Joesch, Sabine Ackerknecht, Jennifer Brandes, Claire Moebs, Dominik Hartl, Felix Hartrampf, Philippe Guerry, Julien Pothier, Alexia Chavanton-Arpel. Superiority of dual IDO1/TDO2 inhibition versus IDO1 selective inhibition in reducing immunosuppressive KYN levels in tumors co-expressing IDO1 and TDO2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1849.
Abstract 1851: Mechanisms underlying focused ultrasound-induced immunogenicity in melanoma
Authors: Pelka Sandra , Bandyopadhyay Sanmay , Pandey Sanjay , Guha Chandan , Macian Fernando 
Published: June 2023

Abstract
Advanced melanoma is an aggressive skin cancer characterized by low survival rates. The generation of a robust anti-tumor response relies on dendritic cells (DCs) to process tumor antigens, migrate to draining lymph nodes, and activate T-cells. Within the tumor microenvironment, immunosuppressive factors impede DC differentiation and activation, and the subsequent immature DC phenotype is a major mechanism underlying the ineffective T-cell response in melanoma patients. We have shown that low-intensity focused ultrasound (LOFU), a novel therapy that delivers mechanical and thermal stresses locally at the tumor site, may enhance DC function in a B16 murine melanoma model. We hypothesize that LOFU enhances the dendritic cell-mediated anti-tumor response by inducing changes in tumor cell and dendritic cell autophagy and increasing pro-immunogenic factors in the TME.
Autophagy is a lysosome-dependent process of cellular content degradation that has previously been implicated in the regulation of multivesicular body formation/degradation, and thus in the secretion of extracellular vesicles. Autophagy may subsequently modify the cargo of tumor-derived extracellular vesicles, such as exosomes, in a pro-immunogenic manner. We have found that LOFU treatment is associated with an increase in autophagic flux in melanoma cells and have identified at least 82 proteins within melanoma-derived extracellular vesicles that are significantly enriched or reduced with LOFU treatment, with enriched proteins partaking in essential processes including antigen processing, intracellular trafficking, and cellular metabolism. DCs pulsed with vesicles from LOFU-treated melanoma cells have shown enhanced activation of both CD4+ and CD8+ T-cell activation, suggesting that the LOFU-induced increase in tumor cell autophagy and modification of vesicular cargo may promote a DC-activated anti-tumor antigen activation response. Characterization of other mechanisms by which LOFU may enhance DC function, such as direct changes in DC autophagy, is critical to elucidate DC-mediated pathways involved in the anti-tumor response. Further understanding of DC involvement in the anti-tumor response will provide novel targets for the development of immunotherapies to improve survival and quality of life in advanced melanoma patients.
Citation Format: Sandra Pelka, Sanmay Bandyopadhyay, Sanjay Pandey, Chandan Guha, Fernando Macian. Mechanisms underlying focused ultrasound-induced immunogenicity in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1851.
Abstract 2013: Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs
Authors: Hamilton Joseph Z. , Klussman Kerry , Mahzereh Rebecca , Simmons Jessica , Ulrich Michelle , Gardai Shyra J. , Senter Peter D. , Burke Patrick J. 
Published: June 2023

Abstract
Novel payloads with orthogonal mechanisms of action (MOAs) to established ADC technologies are important for expanding the utility of antibody-drug conjugates (ADCs) in cancer treatment. Anthracyclines, a class of cytotoxic small molecules that include important clinical chemotherapeutics such as doxorubicin, have long been of interest to the ADC field due to their high potency and unique MOA. Interest in anthracyclines has increased in recent years due to their status as canonical inducers of immunogenic-cell death (ICD), a feature that may lead to more durable tumor regressions and increased synergy with immune checkpoint blockade. In this work, we investigate several drug-linkers based on oxidized derivatives of the highly potent anthracycline analogue PNU-159682. Resultant ADCs are potent and immunologically specific with linker-dependent bystander activity in co-culture cytotoxicity assays displaying heterogeneous antigen (Ag+/Ag-) expression. Rodent in vivo anti-tumor activity and tolerability are shown with significant differences emerging between the toxicity profile of the cleavable and non-cleavable analogues. In vitro, tumor cells treated with anthracycline ADCs showed key hallmarks of ICD including markers of endoplasmic reticulum (ER) stress and the induction of ICD damage-associated molecular patterns (DAMPs) such as HMGB1 and ATP. In vivo mouse xenograft studies show increased tumoral F4/80+ macrophage infiltration by IHC in anthracycline ADC treated animals relative to controls. ADCs delivering monomethyl auristatin E (MMAE) show comparable activity in ICD assays, confirming MMAE as an ICD inducing ADC payload alongside canonical inducers such as anthracyclines. Our results indicate there is a therapeutic window in rodents alongside ICD induction by anthracycline ADCs, positioning anthracyclines as a potentially impactful class of ADC payloads.
Citation Format: Joseph Z. Hamilton, Kerry Klussman, Rebecca Mahzereh, Jessica Simmons, Michelle Ulrich, Shyra J. Gardai, Peter D. Senter, Patrick J. Burke. Oxidized anthracycline payloads induce anti-tumor immunogenic cell-death and show linker-dependent tolerability when delivered as ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2013.