bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C066: Update on the phase 1 trial of Nelmastobart in patients with advanced solid tumors
Authors: Yoo Stephen , Lee Soohyeon , Shin Sangjoon , LoRusso Particia , Hur Jiwon , Jung Hyunjin , Hong David S 
Published: December 2023

Abstract
Background: Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint that is found to be mutually exclusive with PD-(L)1. BTN1A1 has the potential to broaden the range of immunotherapeutic treatments available for patients who are currently unresponsive to anti-PD-(L)1 therapy. In this phase, 1 clinical trial, the safety and preliminary efficacy of Nelmastobart (hSTC81), a humanized monoclonal antibody targeting BTN1A1, was evaluated in patients with advanced solid tumors.
Methods: This is a first-in-human, phase 1, dose-escalation study evaluating Nelmastobart in pts with advanced solid tumors. Primary objectives are to characterize the safety profile and determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Nelmastobart is administered as monotherapy at increasing dose levels of 0.3, 1, 3, 6, 10, and 15 mg/kg on a Q2W schedule.
Results: As of June 30, 2023, 45 pts are enrolled at dose levels of 0.3 (n=1), 1 (n=9), 3 (n=10), 6 (n=9), 10 (n=9), and 15 mg/kg (n=8). Of note, 3 pts with ovarian cancer at dose levels of 6 (n=1), 10 (n=1), 15 mg/kg (n=1), and 1 pt with thymic cancer at the dose level of 6 mg/kg (n=1) were enrolled. A maximum administered dose of 15 mg/kg was achieved; no DLTs were observed at any dose level. Focusing on the ovarian/thymic cancer subgroup, 2 pts are ongoing: 1 pt with ovarian cancer (10 mg/kg) and 1 pt with thymic cancer (6 mg/kg). The median duration of therapy was 20 weeks (maximum 33 weeks). Only 1 pt with ovarian cancer (6 mg/kg) reported any treatment-related adverse events (TRAE), including grade 1 headache, nausea, myalgia, and decreased appetite. In the evaluable pts, two confirmed stable diseases are observed in thymic cancer (6 mg/kg) and ovarian cancer (10 mg/kg). The median duration of SD pts is 29 weeks. Preliminary pharmacokinetic (PK) analysis revealed consistent exposure with linear PK. Pharmacodynamic analysis measuring cytokines and cell-based markers is pending and will be shared.
Conclusion: Nelmastobart demonstrates excellent tolerability without any DLTs up to the highest administered dose of 15 mg/kg. The available data show promising signs of anti-tumor activity, along with sustained stable disease. Currently, clinical development planning for a phase Ib/II clinical trial is underway, aiming to investigate the optimal therapeutic dose and efficacy of Nelmastobart in multiple types of solid tumors.
Citation Format: Stephen Yoo, Soohyeon Lee, Sangjoon Shin, Particia LoRusso, Jiwon Hur, Hyunjin Jung, David S Hong. Update on the phase 1 trial of Nelmastobart in patients with advanced solid tumors [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 C066.
Abstract C069: Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status
Authors: Wang Xiaoguang , Ravindranathan Sruthi , Chin Daniel , Tseng Su-Yi , Klakamp Scott , Widmann Kate , Kapoor Varun , Vexler Vladimir , Keegan Patricia , Yao Sheng , Khare Sanjay D , LaVallee Theresa , Rajasekaran Narendiran 
Published: December 2023

Abstract
Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have revolutionized cancer treatment favoring prognostic benefits to a broad range of cancer patients. Currently, US Food and Drug Administration (FDA)–approved PD-1 monoclonal antibodies (mAbs) have demonstrated significant clinical benefit, particularly in patients with programmed cell death ligand 1 (PD-L1)-expressing tumors. Toripalimab is a PD-1 targeting humanized IgG4 mAb that is currently pending approval by the FDA as a first-line treatment for patients with recurrent or metastatic nasopharyngeal carcinoma (RM-NPC). In combination with chemotherapy, toripalimab demonstrated significant clinical efficacy irrespective of PD-L1 status in patients in three different clinical trials, namely JUPITER-02 (NPC), JUPITER-06 (esophageal squamous cell carcinoma [ESCC]) and CHOICE-01 (non-small cell lung cancer [NSCLC]). Here we investigated the molecular and functional characteristics of toripalimab and compared it to pembrolizumab, a PD-1 mAb that is approved in the largest number of indications in the PD-1 mAb class. In comparison to pembrolizumab, toripalimab demonstrated a 12-fold higher binding affinity to PD-1 and selectively induced higher Th1 and myeloid derived inflammatory cytokine responses in human peripheral blood mononuclear cells (PBMCs). Upon treating dissociated tumor cells from treatment naïve NSCLC patients, toripalimab demonstrated an enhanced expression of several unique genes in interferon gamma and immune cell pathways compared to pembrolizumab. The binding of toripalimab to PD-1 ectopically expressed in Jurkat T cells, recruited lower levels of SHP1 and SHP2, the negative regulators of T cell activation, compared to pembrolizumab. Overall, our study demonstrates that toripalimab is differentiated from pembrolizumab in terms of stronger PD-1 binding, more potent in-vitro T cell activation and lower agonistic potential. These characteristics of toripalimab present it as a next generation PD-1 checkpoint inhibitor with potential for favorable clinical outcomes in treating cancer patients irrespective of their PD-L1 status.
Citation Format: Xiaoguang Wang, Sruthi Ravindranathan, Daniel Chin, Su-Yi Tseng, Scott Klakamp, Kate Widmann, Varun Kapoor, Vladimir Vexler, Patricia Keegan, Sheng Yao, Sanjay D Khare, Theresa LaVallee, Narendiran Rajasekaran. Toripalimab an anti-PD-1 antibody that demonstrates potent T cell activation and enhanced clinical efficacy irrespective of PD-L1 status [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 C069.
Abstract C084: Metabolomic profiling identifies molecular modifiers contributing to proteasome inhibitor resistance in multiple myeloma
Authors: Gaikwad Snehal M , Hughitt Vincent Keith , Gyabaah-Kessie Nana , Matera-Vatnick Mikaela , Michalowski Aleksandra A , Quintanilla-Arteaga Anaisa , Andresson Thorkell , Mock Beverly A 
Published: December 2023

Abstract
Metabolic reprogramming plays a crucial role in the maintenance and differentiation of various cancers, including multiple myeloma (MM), the second-most common incurable hematological malignancy. Drug resistance poses a significant challenge to conventional proteasome inhibitor (PI) based therapy. A body of literature suggests that several metabolites are significantly deregulated in MM patients, however, their role in driving resistance is unclear. This study aims to identify metabolites modulated during acquired resistance to proteasome inhibitors in relapsed refractory (RR)MM. Two clinically relevant cell line models of PI-resistance (PIR) were developed by dose-escalation of the PI over one year. Cell cytotoxicity assays, immunoblotting, immunofluorescence, and flow cytometric analyses were used to assess the resistance phenotype. Mass spectrometry-based metabolomic profiling was performed to identify altered metabolites in resistant as compared to sensitive cell lines. PIR cells demonstrated pan-resistance to multiple PIs, including a &gt;10-fold increase in IC50 for oprozomib compared to parental cells. PIR cells had higher bioenergetic and glycolytic activity (Seahorse) while gene expression profiling suggested downregulation of oxidative phosphorylation. Mass spectrometry-based metabolomic profiling identified distinct metabolites deregulated in drug-resistant cells. The metabolomic profiles of the drug-resistant cell lines showed that the lipid synthesis and beta-oxidation of fatty acid pathways were highly modulated. Several pathway components demonstrated a negative association with overall survival in multiple myeloma patient datasets (MMRF, GSE31161 & GSE9782). PI resistance led to increased phosphorylation of ACLY involved in fatty acid synthesis and increased expression of CPT1A indicative of activation of the beta-oxidation pathway. Use of ACLY and FASN tool compounds affected proliferation, survival, and response to treatment in PIR cells. Metabolites modulated during acquired resistance to proteasome inhibitor in relapsed refractory (RR)MM were identified and potential mechanisms driving resistance were studied.
Citation Format: Snehal M Gaikwad, Vincent Keith Hughitt, Nana Gyabaah-Kessie, Mikaela Matera-Vatnick, Aleksandra A Michalowski, Anaisa Quintanilla-Arteaga, Thorkell Andresson, Beverly A Mock. Metabolomic profiling identifies molecular modifiers contributing to proteasome inhibitor resistance in multiple myeloma [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 C084.
Abstract C089: PRMT5 as a novel druggable vulnerability for EWSR1-ATF1-driven clear cell sarcoma
Authors: Li Bingbing X , David Larry L , Davis Lara E , Xiao Xiangshu 
Published: December 2023

Abstract
Clear cell sarcoma of soft tissue (CCSST) is a rare and aggressive soft tissue sarcoma. The 5-year survival rate is only 20% for metastatic cases of CCSST. CCSST is insensitive to existing chemotherapies or radiotherapy. New target therapies will have tremendous impact on CCSST patients. The hallmark of CCSST is a chromosome translocation, which generates an oncogene EWSR1-ATF1, where Ewing’s sarcoma gene (EWSR1) is fused with activating transcription factor 1 (ATF1). EWSR1-ATF1 is a constitutively active form of ATF1 and is independent of extracellular cues to drive ATF1-dependent gene transcription. We recently discovered that protein arginine methyltransferase 5 (PRMT5) is involved in EWSR1-ATF1-mediated gene transcription. Genetic silencing of PRMT5 in CCSST cells results in severely inhibited cell growth. We further identified a PRMT5 inhibitor JNJ-64619178 to potently and efficaciously inhibit CCSST cell growth in vitro and in vivo. This becomes clinically very relevant as JNJ-64619178 finished phase I clinical trial (NCT03573310) in advanced solid tumors and non-Hodgkin lymphoma patients and it demonstrated manageable toxicity. Our results presented here provide a strong mechanistic basis for further clinical evaluation of JNJ-64619178 to treat CCSST patients.
Citation Format: Bingbing X Li, Larry L David, Lara E Davis, Xiangshu Xiao. PRMT5 as a novel druggable vulnerability for EWSR1-ATF1-driven clear cell sarcoma [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 C089.
Abstract C099: Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model
Authors: III Armando Diaz , Simonson Alyssa , Flores Johnnie , Holahan Joseph , Papadopoulos Kyriakos P , Lund Jim , Rasco Drew , Patnaik Amita , Wick Michael J 
Published: December 2023

Abstract
Background: Acute myeloid leukemia (AML) with NUP98 fusions is associated with poor prognosis in adults and especially children. Pediatric AML is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations, including the NUP98-KDM5A fusion found in a particular subgroup of patients with complex karyotypes. To better understand this subtype of AML, we established and characterized a XPDX model designated ST1653 representing NUP98-KDM5A-driven disease from a previously treated AML patient. We performed DNA and RNA-based sequencing of the model. Further we evaluated in vivo sensitivity towards cytarabine and inhibitors targeting the JAK and CDK6 pathways, which have been shown to be important in NUP98-KDM5A-driven AML. Methods: ST1653 was established from a bone marrow aspirate collected from a 63-year-old Caucasian male who had AML recurrence following high dose cytarabine. The sample was injected subcutaneously into a triple-deficient mouse and the P0 model passaged after seventy days into CB-17 SCID and athymic nude mice and further developed until stable. WES and RNAseq were then performed. For in vivo studies, ST1653 was evaluated against cytarabine and the JAK inhibitors ruxolitinib, baricitinib and tofacitinib and the CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C&lt;0%) versus Day 0 tumor volume was also reported. Results: Growth of the ST1653 AML XPDX model was similar in CB-17 SCID or athymic nude mice with a median time to endpoint of forty-five days, although the take rate in the SCID strain was superior. Sequencing identified the presence of the NUP98-KDM5A fusion and chimeric protein expression was confirmed. In vivo, ST1653 was insensitive to cytarabine and the JAK inhibitors but demonstrated limited sensitivity to CDK4/6i treatment. Conclusion: We have established and characterized a XPDX model of NUP98-KDM5A-driven AML including sequencing and in vivo evaluation. This model is an important tool for developing novel therapies to this high-risk leukemia subtype.
Citation Format: Armando Diaz III, Alyssa Simonson, Johnnie Flores, Joseph Holahan, Kyriakos P Papadopoulos, Jim Lund, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model [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 C099.
Abstract C110: miR195 - A potential therapeutic molecule for breast cancer: Present and future
Authors: Purohit Paresh , Saini Neeru 
Published: December 2023

Abstract
Breast cancer is the leading cause of death in women worldwide (Globocan 2020). Surgery, chemotherapy as well as radiation therapy are the commonly used modes of treatment and the treatment depends on the tumor type. Patients develop resistance and demonstrate poor prognosis after prolonged treatment. Hence there’s is always a need for new diagnostics and therapeutics. miRNAs are 18-22 nucleotides small RNAs known to play a role in development and disease. Deregulation of miRNAs in diseased conditions can be harnessed as potential therapeutics by miRNA mimics or miRNA inhibition by antimiRs. Till date, several miRNA-targeted therapeutics have reached clinical development. Our laboratory has shown that miR-195 not only down regulates anti-apoptotic protein bcl-2 but also key genes of lipid metabolism (FASN, HMGCR) which are upregulated in breast cancer. The altered calcium signaling is deleterious to cells and is also known to be associated with different hallmarks of cancer. We recently observed that miR-195 perturbs calcium homeostasis in breast cancer cells by down-regulating a major calcium efflux pump present on the plasma membrane. Experimental validation has been performed in breast cancer cells and spheroids using western blotting, qRT-PCR, dual luciferase assay, calcium measurements using flow cytometry and immunofluorescence. MiR-195 alters calcium homeostasis leading to ER stress and autophagy in breast cancer. The current work describes recent advances in our understanding of miRNA-195 in breast cancer.
Citation Format: Paresh Purohit, Neeru Saini. miR195 - A potential therapeutic molecule for breast cancer: Present and future [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 C110.
Abstract C123: Alloferon inhibits migration of pancreatic cancer by regulating the expression of IL-22Rα
Authors: Jo Hyejung , Kim Yejin , Shin Seulgi , Kang Jae Seung 
Published: December 2023

Abstract
Pancreatic cancer frequently metastasizes into one or more organs and tissues located near the pancreas. Metastasis contributes to make curative approach unachievable and bring poor prognosis. Therefore, it is important to develop a strategy to regulate the metastasis of pancreatic cancer. Recent research has reported that IL-22 increases the factors involved in migration and invasion to support the development of pancreatic cancer. The binding of IL-22 to IL-22 receptor exerts its biological effects and, IL-22 receptors are heterodimer receptor complex composed of IL-22Rα and IL-10Rβ. Previously we showed that alloferon, known as the immune modulator, increases chemosensitivity in pancreatic cancer by downregulating the SLC6A14, a transporter of glutamine. In this study, we identified that alloferon is a potential adjuvant therapeutic agent for pancreatic cancer by regulating the expression of IL-22Rα. We found that IL-22 has essential role in migration and invasion of pancreatic cancer by increasing the chemokine receptors such as CXCR3 and CXCR4. In addition, alloferon decreased the expression of IL-22Rα in pancreatic cancer cell line. Therefore, the expression of CXCR3 and CXCR4 decreased in AsPC-1 in presence of alloferon even upon the treatment with recombinant IL-22. To evaluate the effect of alloferon on tumor migration, the migration and invasive capacity were measured in pancreatic cancer cells in absent or present of alloferon. It was observed that alloferon significantly inhibit the migration of AsPC-1 toward ligand of CXCR3 and CXCR4, CXCL10 and CXCL12. These findings established that the expression of IL-22Rα associated with metastasis is likely related to overexpression of CXCR3 and CXCR4 in pancreatic cancer. Taken together, it is suggested that alloferon could be used as an adjuvant therapy to inhibit the metastasis of pancreatic cancer by regulating the expression of IL-22Rα.
Citation Format: Hyejung Jo, Yejin Kim, Seulgi Shin, Jae Seung Kang. Alloferon inhibits migration of pancreatic cancer by regulating the expression of IL-22Rα [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 C123.
Abstract C125: Development of attenuated orf virus as a new generation oncolytic viral vector
Authors: Yamada Yumiko , Hsu Wei-Li , Wang Yu-Chih , Liu Hao-Ping 
Published: December 2023

Abstract
The orf virus (ORFV) possesses remarkable qualities that make it a potential viral vector for cancer therapy. Recently, the cancer-killing properties of ORFV have been demonstrated in a variety of human cancers, including nasopharyngeal carcinoma (NPC). Initially, we found that the ORFV-bearing wild-type genome was successful in eliminating two NPC cell lines derived from patients in Hong Kong and Taiwan, HK-1 and TW02, respectively. To make viral vectors safer for medical use, the oncolytic effects of two live attenuated ORFVs, which were created by removing one of the virulent factors, VEGF or CBP, were further evaluated in these two cell lines. Despite this attenuation, the two recombinant ORFVs were still able to effectively infect and kill NPC cells, particularly HK-1 cells. ORFV infection caused pyroptosis in NPC cells through GSDME cleavage, resulting in significant cell detachment and reduction in FAK and AKT activation during the early stages of infection. The innate immune response is also affected by ORFV infection, as shown by the increased chemotaxis of NK cells and synergistic effect of NK on the cytotoxicity of NPC cells caused by ORFV infection. Infection with both wild-type and CBP-deleted ORFVs significantly reduced HK-1 tumor growth in a xenograft mouse model, suggesting its potential as a therapeutic agent for NPC treatment. To maximize its therapeutic use, it is essential to comprehensively understand the mechanisms that drive the oncolytic activity of ORFV.
Citation Format: Yumiko Yamada, Wei-Li Hsu, Yu-Chih Wang, Hao-Ping Liu. Development of attenuated orf virus as a new generation oncolytic viral vector [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 C125.
Abstract C133: BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors
Authors: Revollo Leila , Brenneman Jehrod , Paudyal Sharad , Nguyen Toan , Lee Yong-Hee , Jin Taiguang Jimmy 
Published: December 2023

Abstract
The Hippo pathway regulates several cellular functions including cell lineage fate, proliferation, migration, apoptosis, maintenance of cell stemness and dedifferentiation, and organ size. TEA domain family members 1-4 (TEAD1-4) are evolutionarily conserved transcription factors and core components of the Hippo pathway. TEADs are functional partners of the oncoproteins YAP (Yes-associated protein) and its paralog TAZ (transcriptional co-activator with PDZ-binding motif). Mutations in components of the Hippo pathway have been implicated in several diseases, including cancer. YAP/TEAD activation has also been associated with resistance to targeted therapies by EGFR TKIs in EGFR-mutant NSCLC. Targeting TEAD transcription activity has emerged as a promising approach to addressing cancers with abnormalities in the Hippo pathway. BBT-4437 is a novel, brain-penetrable, reversible pan-TEAD inhibitor that exhibits excellent selectivity in blocking TEAD transcriptional activity in the TEAD reporter gene assay. It demonstrates nanomolar potency in inhibiting cell proliferation in NF2-deficient mesothelioma cells in vitro. BBT-4437 also inhibits the expression of downstream YAP-TEAD target genes (CCN1/CYR61, CCN2/CTGF and IGFBP3) in a concentration-dependent manner in vitro. Moreover, BBT-4437 shows synergistic effect in combination with osimertinib in the H1975 NSCLC cell line. Furthermore, daily oral administration of BBT-4437 leads to significant tumor regression in NF2-deficient H226 and H2373 mesothelioma xenograft models. BBT-4437 demonstrates favorable pharmacokinetic and ADME profiles, including excellent brain penetration. Therefore, BBT-4437 has the potential to be a best-in-class TEAD inhibitor for targeting tumors with aberrant Hippo signaling and overcoming drug resistance caused by upregulation of the Hippo pathway in the clinic.
Citation Format: Leila Revollo, Jehrod Brenneman, Sharad Paudyal, Toan Nguyen, Yong-Hee Lee, Taiguang Jimmy Jin. BBT-4437, a novel, brain-penetrable, reversible pan-TEAD inhibitor targeting the Hippo signaling pathway in solid tumors [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 C133.