bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A165: FGFR alterations in pediatric cancers: Opportunity for targeted therapy
Authors: Li Ivan , Huo Yuchen , Li Gary , Zage Peter 
Published: December 2023

Abstract
Introduction: The Fibroblast Growth Factor Receptor (FGFR) family consists of four members, FGFR1–4, and is involved in regulating cell proliferation, survival, and differentiation. FGFR alterations, such as fusions, mutations and amplification, have been found in multiple adult cancers, for which several FGFR inhibitors are in clinical development. Although cancer is a leading cause of death in children, the understanding of genetic causes of pediatric cancers is urgently lacking and the progress in developing targeted therapy in children significantly lags that in adults. This study aimed to uncover the FGFR alterations in pediatric cancers and provide preclinical rationale for FGFR inhibitors as potential therapy in children with cancer.
Methods: The prevalence of FGFR alterations in pediatric cancers such as neuroblastoma (NB) , gliomas and sarcomas was calculated based on systematic queries of multiple cancer databases that house real-world molecular profiling data. A pan-FGFR inhibitor, BGJ398, was used as a tool compound for FGFR inhibition. Effect of BGJ398 on cell proliferation was tested by Incucyte in a panel of 12 NB cell lines. Cell migration, survival and signaling pathway modulation were carried out in a subset of NB lines.
Results: The overall rates of genomic alterations (fusions, mutations and amplification) of FGFR1, 2, 3 and 4 in pediatric cancers are 0.5%, 0.1%, 1.1% and 0.8%, respectively, with pediatric gliomas exhibiting higher rates in all subtypes. Although FGFR genomic alterations are rare (&lt;0.1%) in neuroblastoma and rhabdoid sarcoma, overexpression of FGFR1-4 is observed in subsets of these tumors. In pediatric glioma, FGFR1, 2, 3 and 4 alterations are found in 1%, 1.6%, 2.1% and 0.9% tumor samples, respectively, and the mutation profile substantially differs from that of adult glioma. Dose-dependent inhibition of cell proliferation and migration, as well as induction of cell death, were achieved with BGJ398 treatment in a panel of NB cells, accompanied by inhibition of MAPK pathway and induction of apoptosis.
Conclusions: Adult and pediatric cancers share common mechanisms of FGFR activation, but differ in overall alteration rates and in relative abundance of specific aberrations. Preliminary preclinical data indicates the therapeutic potential of FGFR inhibitors in the treatment of certain pediatric cancers.
Citation Format: Ivan Li, Yuchen Huo, Gary Li, Peter Zage. FGFR alterations in pediatric cancers: Opportunity for targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A165.
Abstract A178: Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer
Authors: Grobelny Anna L , Maggi Leonard B , Weber Jason D 
Published: December 2023

Abstract
Many current therapeutic efforts in cancer biology focus on inhibiting the function of aberrant oncogenes whose activities are known to increase proliferation and cell growth. Unfortunately, these efforts have had limited success in lung cancer, where the five-year survival rate remains unchanged. We sought a novel approach; rather than inhibiting oncogenes, we worked to reestablish the function of the p14ARF tumor suppressor in non-small cell lung cancer (NSCLC) to block tumor growth and proliferation. The p14ARF tumor suppressor is encoded by the CDKN2A gene and is the second most commonly mutated gene in NSCLC. p14ARF is known to play a fundamental role in preventing cancer progression by regulating senescence, apoptosis, and proliferation. Here, to determine the minimal functional domain of p14ARF, we generated a panel of p14ARF expression mutants, deleting various amino acids within the known functional and conserved domains of p14ARF. These mutants were then evaluated for their ability to function as wild type p14ARF. Through proliferative and transformative studies, we identified a 10-amino acid domain that is required for p14ARF function. New cell-penetrating peptide technology was employed to determine if these resides were sufficient to elicit antiproliferative effects on their own. We now show that this small region of ARF is capable of entering tumor cells when linked to a cell penetrating peptide. Moreover, this small cell penetrating ARF peptide retains all of ARF’s known tumor suppressor functions. Our findings provide evidence that small cell penetrating peptides are capable of inhibiting tumor cell growth and proliferation. These experiments also lay the foundation for more precise therapeutic peptide cancer treatments, ones that could be used to restore p14ARF tumor suppressor function.
Citation Format: Anna L Grobelny, Leonard B Maggi, Jason D Weber. Therapeutic potential of a p14ARF minimal domain peptide in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A178.
Abstract B013: Identification of a Notch transcriptomic signature for breast cancer
Authors: Braune Eike-Benjamin , Geist Felix , Tang Xiaojia , Kalari Krishna , Boughey Judy , Wang Liewei , Leon-Ferre Roberto A. , D’Assoro Antonino B. , Ingle James N. , Goetz Matthew P. , Wang Kang , Foukakis Theodoros , Seshire Anita , Wienke Dirk , Lendahl Urban 
Published: December 2023

Abstract
Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would thus be warranted, and in this report, we have established such a classifier.
Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated and reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by g-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent data sets.
Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2) and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome.
Conclusions: The 20-gene transcriptional signature has the potential to better stratify patients and to evaluate the response of future Notch-based therapies for breast cancer.
Citation Format: Eike-Benjamin Braune, Felix Geist, Xiaojia Tang, Krishna Kalari, Judy Boughey, Liewei Wang, Roberto A. Leon-Ferre, Antonino B. D’Assoro, James N. Ingle, Matthew P. Goetz, Kang Wang, Theodoros Foukakis, Anita Seshire, Dirk Wienke, Urban Lendahl. Identification of a Notch transcriptomic signature for breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B013.
Abstract B015: Tumor fraction as a predictive factor of outcome of patients referred for oncology early phase clinical trials: Analysis of the STING precision medicine study
Authors: Belcaid Laila , Bayle Arnaud , Trin Kilian , Aldea Mihaela , Vasseur Damien , Sakkal Madona , Loriot Yohann , Hollebecque Antoine , Ponce Santiago , Italiano Antoine 
Published: December 2023

Abstract
Background The quantification of ctDNA shed by measuring tumor fraction (TF) has been associated with prognosis in solid tumors pts. However, whether TF can be also predictive of clinical benefit of systemic treatments in patients referred for early phase studies remain unknown.
Methods: All consecutive adult pts with an advanced solid tumor referred to the Early Phase Trials Department of Gustave Roussy( Villejuif France) between December 2020 and December 2021 and enrolled in the precision medicine study STING (NCT04932525, sponsor: Institut Gustave Roussy, Villejuif, France) were analyzed. All pts underwent comprehensive genomic profiling with the 324-gene FoundationOne. TF was analyzed as a binary variable, indicating whether a specimen had TF ≥10% or TF &lt;10%. Response to treatment was assessed as per RECIST criteria. Multivariate analysis included previously validated prognostic scores: the Royal Marsden Hospital (albumin, LDH, number of metastatic sites) and the GRIm (LDH, neutrophil/lymphocyte ratio (NLR), albumin) scores as well as their individual components.
Results: 947 patients entered the study. High TF was associated with significantly worse overall survival (OS) (HR:2.52 [CI95%: 2.06 - 3.08, p&lt;0.001] independently of the RMH and GRIM scores as well as their individual components. 409 pts received a systemic treatment following ctDNA profiling (Immuno-oncology agent: 146 patients, non-IO: 254 patients)The treatment was investigational for 200 patients. The most frequent tumor types were non-small cell lung cancer (n=85), prostate cancer (n=49), colorectal cancer (n=33). High TF was significantly associated with worse objective response/stable disease rate (37.8% vs 53.8%, p=0.006), PFS (2.1 vs 3.9 months, p&lt;0.001) and OS (7.1 vs 18.6 months, p&lt;0.001) .
Conclusions: Besides its prognostic value, TF is predictive of outcome on systemic therapy in patients referred for early phase studies. This parameter can be used for informed decision making for patients before participating in phase 1 trials.
Citation Format: Laila Belcaid, Arnaud Bayle, Kilian Trin, Mihaela Aldea, Damien Vasseur, Madona Sakkal, Yohann Loriot, Antoine Hollebecque, Santiago Ponce, Antoine Italiano. Tumor fraction as a predictive factor of outcome of patients referred for oncology early phase clinical trials: Analysis of the STING precision medicine study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B015.
Abstract B022: Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial
Authors: Messier Terri , Scotland Molly , Naumov George , Dulloo Sean , Fennell Dean , Cunniff Brian 
Published: December 2023

Abstract
Tumor cells generate increased levels of reactive oxygen species (ROS) that promote growth and survival through activation of redox dependent signaling pathways. To survive under increased ROS levels tumor cells, including mesotheliomas, must increase antioxidant expression, activity and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical ROS scavenging enzyme localized to the mitochondrial matrix. Our group has characterized the mechanism of action of the PRX3 inhibitor and pro-oxidant therapeutic thiostrepton (TS). TS covalently crosslinks the peroxidatic and resolving cysteines of PRX3, leading to increased levels of mitochondrial ROS, resulting in tumor cell death. TS is the active pharmaceutical ingredient of RSO-021, a new covalent inhibitor of PRX3 currently being tested in the MITOPE phase 1/2 clinical trial in patients with malignant pleural effusion (MPE) due to advanced solid tumors or mesothelioma (NCT05278975). RSO-021 is administered locally to patients through an indwelling pleural catheter (IPC) weekly. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner when tested ex vivo. Using MPE drainages from patients enrolled in the MITOPE trial we evaluated cytokine levels pre and 24 and 168 - hours (7 days) post initial administration of RSO-021. Cytokines were measured in decellularized MPE drainages using Human Cytokine ELISA plates manufactured by Signosis, Inc.Adiponectin and ICACM-1 where elevated in all patients pre and post treatment. Cytokines found to be increased in patients treated with RSO-021 included IL-1B, IL-8, and Resistin. Cytokines found to be decreased following treatment included IL-13, IL-31, and IP-10. Together, these data provide the first evidence for the molecular activity of TS in patients and the resulting changes to cytokine profiles. The downstream effects of these changes to cytokine levels on cellular composition and patient responses is an ongoing focus of our research teams.
Citation Format: Terri Messier, Molly Scotland, George Naumov, Sean Dulloo, Dean Fennell, Brian Cunniff. Effects of RSO-021 on cytokine profiles of malignant pleural effusions from patients enrolled in the MITOPE phase 1/2 clinical trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B022.
Abstract B027: Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma
Authors: Chen Josephine , George Andrew , Zhou Lanlan , El-Deiry Wafik 
Published: December 2023

Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults with a median survival time of 15 months. The standard of care involves surgical resection followed by chemoradiotherapy. Even with the full course of treatment, GBM is uncurable, and patients eventually relapse. Although temozolomide (TMZ) is the first-choice chemotherapeutic for GBM, tumor drug resistance limits the effects of the treatment. There is a growing need for new therapies with enhanced efficacy on GBM tumors. ONC201 is a TNF-related apoptosis-inducing ligand (TRAIL)-inducing compound that is increasingly being studied for GBM treatment. This small molecule induces apoptosis by activating the integrated stress response, which involves transcription factors ATF4 and CHOP. Subsequently, these transcription factors upregulate proapoptotic protein TRAIL and its receptor, Death Receptor 5 (DR5). This study aims to investigate the combinatory effects of chemotherapeutics ONC201 and TMZ on GBM. Preliminary studies examined the cell viability of GBM cell line U251MG using ONC201 concentrations up to 40uM and TMZ concentrations up to 200uM. Additionally, western blots performed with 0, 2, and 4uM of ONC201 in combination with 0 and 120uM of TMZ demonstrated greater ATF4 expression when both drugs were administered concurrently than when either drug was administered alone. Subsequent western blots were conducted using three GBM cell lines (U251MG, T98G, and SNB19-GFP) at three time points (8, 24, and 48 hours). All cell lines were treated with 0 and 4uM of ONC201 in combination with 0 and 120uM of TMZ. At all three time points and for all three cell lines, ATF4 expression increased in the combined presence of TMZ and ONC201. However, the effects of TMZ on ONC201-induced ATF4 expression were most pronounced in U251MG. These observations suggest synergy between chemotherapeutics ONC201 and TMZ in the ATF4 integrated stress response pathway in GBM. By exploring the effects of this dual treatment on upstream and downstream factors in the integrated stress response pathway, we can identify, characterize, and potentially target the root cause of this synergy.
Citation Format: Josephine Chen, Andrew George, Lanlan Zhou, Wafik El-Deiry. Synergy between ONC201 and temozolomide on ATF4 integrated stress response in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B027.
Abstract B028: Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors
Authors: Toivanen Kirsi L. J. , Murumägi Astrid , Arjama Mariliina A. , Merikoski Nanna J. , Salmikangas Sami I. , Kallioniemi Olli P. , Böhling Tom O. , Sihto Harri J. 
Published: December 2023

Abstract
Phosphodiesterase 3A (PDE3A) modulators are promising anticancer agents for tumors that coexpress PDE3A and Schlafen 12 (SLFN12), including sarcomas. The cytotoxic effect of these modulators is based on their ability to form a complex between PDE3A and SLFN12, and correlates with the expression levels of the two proteins. In cases where the two proteins are only moderately expressed, PDE3A modulator efficacy may remain poor and additional therapeutic options are needed. In this study, we investigated the combinatorial effects of a PDE3A modulator, anagrelide, with 526 other oncological compounds in two PDE3A and SLFN12 expressing liposarcoma cell lines (SA4 and GOT3). Both cell lines were responsive to PDE3A modulators, as expected. Interestingly, we found synergy with seven different drug classes that can be grouped based on their protein and protein family targets: Bcl-2l/Bcl-xL, HDAC, integrin α2 (ITGA2), mTOR, NEDD-activating enzyme E1 regulatory subunit proteins, and PAK. Additional detailed drug combination synergy studies in PDE3A modulator –sensitive liposarcoma, gastrointestinal stromal tumor, melanoma, and astrocytoma cell lines indicated a sensitizing effect of PDE3A modulators to Bcl-2/Bcl-xL inhibitors. These cell lines, excluding GOT3, showed no response to Bcl-2/Bcl-xL inhibitors otherwise. Furthermore, we discovered that the sensitization effect depends on the coexpression of PDE3A and SLFN12, and that cotreatment resulted in stronger activation of programmed cell death. Our findings suggest additional combinatorial opportunities between PDE3A modulators and inhibitors of key cancer pathways that could be explored for their therapeutic value.
Citation Format: Kirsi L. J. Toivanen, Astrid Murumägi, Mariliina A. Arjama, Nanna J. Merikoski, Sami I. Salmikangas, Olli P. Kallioniemi, Tom O. Böhling, Harri J. Sihto. Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B028.
Abstract B090: Partially open conformation of the G323E mutated HIF-2α PASB domain captured by X-ray crystallography
Authors: Shia Steven , Malgapo Ian , Chen Jeffrey , Pham Amber , Meleza Cesar A , Shen Lunda , Morar Mariya , Lawson Kenneth V , Gauthier Kelsey E Sivick , Kwon Hyock J 
Published: December 2023

Abstract
Under hypoxic conditions, vital cell processes such as angiogenesis, erythropoiesis, cell proliferation and metabolism are regulated by a group of transcription factors known as hypoxia-inducible factors (HIFs). These proteins belong to the helix-loop-helix family of transcription factors and require heterodimerization to function. Constitutively expressed HIF-1β protein forms a heterodimer with one of the oxygen-labile counterparts: HIF-1α, HIF-2α, or HIF-3α. The HIF-αs are degraded under normoxic conditions via ubiquitination by the von Hippel Lindau (VHL) E3 ubiquitin ligase and become available for dimerization under either hypoxia or VHL dysfunction. Certain cancer types take advantage of this HIF-regulated transcription for survival and growth, as exemplified by VHL-deficient clear cell renal cell carcinoma (ccRCC). Inhibitors aimed at disruption of the HIF-1β:HIF-2α heterodimer have been advanced into clinical development, including belzutifan (approved by the Food and Drug Administration for adult patients with VHL disease who require therapy for RCC among other indications) and AB521 (Arcus Biosciences). This class of small molecules functions by binding to and causing a conformational change in the internal cavity of the PasB domain of HIF-2α. A mutation within this internal cavity, G323E, was reported in a patient undergoing treatment with HIF-2α inhibitor. This mutation restored the ability of HIF-1β to heterodimerize with HIF-2α in presence of the inhibitor. To better understand this potential resistance mechanism and how the G323E mutation affects inhibitor binding, we used X-ray crystallography to examine the structure of the mutant HIF-2α PasB domain in complex with a novel small molecule inhibitor active in vitro against the G323E mutant form. We report a co-crystal structure that reveals a partially disordered open conformation of the HIF-2α PasB domain. This structure strengthens existing hypotheses regarding the route of compound entry into the HIF-2α PasB cavity and lays the foundation for structure-based design of HIF-2α PasB G323E-active inhibitors.
Citation Format: Steven Shia, Ian Malgapo, Jeffrey Chen, Amber Pham, Cesar A Meleza, Lunda Shen, Mariya Morar, Kenneth V Lawson, Kelsey E Sivick Gauthier, Hyock J Kwon. Partially open conformation of the G323E mutated HIF-2α PASB domain captured by X-ray crystallography [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B090.