bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1451: AN3025: A novel anti-human TNFR2 antibody that exhibits immune activation and strong anti-tumor activity in vivo
Authors: Chen Yonglin , Jia Manxue , Xu Sherry , Zhao Yanhui , Chan Eric , Zhang Meng , Chen Emma , Zhang Yi 
Published: July 2021

Abstract
Background:
The unique biology and expression pattern of tumor necrosis factor receptor-2 (TNFR2) make it an attractive therapeutic target for immuno-oncology. TNFR2 highly expresses on a subset of regulatory T cells (Tregs) and MDSCs within tumor microenvironment that can activate these cells through nuclear factor kappa B (NF-kB) pathway. TNFR2+ Treg has been shown to be most suppressive among all Treg populations in tumor. On the other hand, TNFR2 is also abundantly expressed on the surface of many human tumors. TNFR2 blocking antibody is expected to relieve TNFR2-mediated immunosuppression and inhibit TNFR2-expressing tumor cell survival. AN3025 is a novel humanized IgG1 (variant) anti-hTNFR2 antibody under preclinical development. The immunomodulatory and anti-tumor activity of AN3025 were evaluated both in vitro and in vivo.
Materials and methods:
AN3025 was generated through rabbit immunization followed by phage display, then humanized by CDRs grafting. The binding affinity and specificity were studied by ELISA and FACS. The ability of AN3025 to mitigate TNF/TNFR2 signaling pathway was characterized using TNFR2 overexpressing Jurkat cell line in vitro. The in vivo anti-tumor activity was evaluated in TNFR2 humanized mouse model bearing MC38 tumor. The tumor samples from control and AN3025 treated mice were taken for further FACS and RNA seq analysis.
Results:
AN3025 binds to the extracellular domain of human TNFR2 with sub-nanomolar affinity and specificity. It cross-reacts with cynomolgus TNFR2 with similar affinity, but not with mouse or rat TNFR2. Mechanistically, AN3025 partially competes with TNFα for binding to TNFR2 receptor and inhibits TNFα induced hTNFR2 overexpressing Jurkat cell death, however it lacks of agonist activity towards TNFR2 even in the presence of hFC crosslinking. In vivo AN3025 significantly inhibits MC38 tumor growth as a monotherapy in hTNFR2 mouse model, while no impact on body weight. Subsequent FACS analysis suggests decreased Tregs% in AN3025 treated tumor. RNA seq suggests immune activation such as increased IFN-gamma and Granzyme expression. In addition, AN3025 enhances anti-tumor efficacy of mPD-1 antibody in a combination study.
Conclusions:
AN3025 is a novel anti-hTNFR2 antibody and demonstrates immunomodulatory activity and potent anti-tumor efficacy in vivo, supporting its clinical development for the treatment of human cancers.
Citation Format: Yonglin Chen, Manxue Jia, Sherry Xu, Yanhui Zhao, Eric Chan, Meng Zhang, Emma Chen, Yi Zhang. AN3025: A novel anti-human TNFR2 antibody that exhibits immune activation and strong anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1451.
Abstract 1461: PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells
Authors: Han June H-J , Kim Kyu-Tae , Im Jeejin , Park Sojung , Choi Min Kyung , Kim Inki , Nam Ky-Youb , Yoon JeongHyeok 
Published: July 2021

Abstract
Purpose: Development of the potent and selective checkpoint kinase 2 (CHK2) inhibitor to overcome limiting clinical utility of poly(ADP-ribose) polymerase 1 (PARP1) inhibitors.
Experimental Procedure: Preclinical evaluation of PHI-101 for cellular and molecular potency in ovarian and breast cancer cell lines and patient derived primary cells; it includes biochemical binding assay, cellular assays, animal efficacy studies, combination study, signaling pathway effect examination, and cell cycle analysis.
Summary: CHK2 is a serine/threonine kinase and a cell cycle checkpoint regulator involved in the ATM-mediated DNA repair upon replication blocks and DNA damage. It has been proposed that Chk2 functions as a barrier to tumorigenesis by maintaining genomic stability, and this DNA damage induction is thought to prevent or delay genetic instability and tumorigenesis. The inhibition of CHK2 is a promising approach to achieve synthetic lethality of cancer cells when combined with PARP1 inhibitors. Solid cancer indications of PHI-101 was identified by the Chemiverse Network module which is an AI and Big data-based in-house drug discovery platform. Biochemical kinase assays for PHI-101 showed stronger affinity to CHK2 over CHK1 more than 5-fold. PHI-101 treatment of ovarian and breast cancer cells for 72 hrs elicit a synergistic lethal response in combination with PARP1 inhibitor Olaparib regardless of functional BRCA and P53 in the cells. PHI-101 also potentiates a countermeasure to dose-limiting toxicity triggered by genotoxic agents such as cisplatin and topotecan. The present results from in vivo and in vitro preclinical testing do demonstrate that PHI-101 is a highly potent inhibitor of CHK2 and may exert mono- and combinational therapeutic activity in ovarian and breast cancer model.
Conclusion: The preclinical evaluation of PHI-101, a novel CHK2 inhibitor, showed clear evidence of anticancer activity for refractory ovarian and breast cancer cells and improved efficacy in both in vitro and in vivo models. Consequently, PHI-101 is currently under investigation in Phase 1 clinical trials for relapsed or refractory ovarian cancer patients.
Citation Format: June H-J Han, Kyu-Tae Kim, Jeejin Im, Sojung Park, Min Kyung Choi, Inki Kim, Ky-Youb Nam, JeongHyeok Yoon. PHI-101, a potent and novel inhibitor of CHK2 in ovarian and breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1461.
Abstract 1731: EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy
Authors: Payne Andrew , Fons Pierre , Alt Isabella , van Ham Joost , Taubert Christina , Bell Andy , Versluys Stephanie , Bertrand Florie , Visentin Virgile , Mirey Emilie , Pelissier Emilie , Paillasse Michael , Pagliarusco Sabrina , Vladimer Gregory , Whittaker Mark 
Published: July 2021

Abstract
Elevated levels of adenosine found in the tumor microenvironment have been highlighted as a potential mechanism contributing to the restricted efficacy of immune checkpoint inhibitors. While the advent of these inhibitors has brought significant benefit to patients with cancer, there is still significant unmet need even in disease indications for which these agents are approved. Adenosine has an immune-suppressive effect in tumors, and pre-clinical and early clinical evidence indicates that antagonists of the GPCR family of adenosine receptors are able to relieve that suppression and restore anti-tumor immune cell activity. EXS21546 is a non-furan, selective antagonist of the A2A receptor with low brain penetration. Using EXS21546, we show that activity at the A2A receptor is sufficient for complete restoration of T-cell function in the presence of high concentrations of adenosine analogue. Translational studies with EXS21546 have been undertaken using patient samples to better understand its activity in signaling and disease-relevant endpoints. We will present data characterizing the activity of EXS21546 ex vivo in patient-derived whole blood samples. Interrogation of primary cancer cells from pancreatic and lung cancer patients treated with EXS21546 ex vivo by phenotypic image-based screening, demonstrated that EXS21546 reduces the relative fraction of viable cancer cells while inducing an expansion of the viable CD8+ T cell fraction in the presence of high concentrations of an adenosine analogue. Together, these data indicate the potential for EXS21546 may have a role in cancer therapy. EXS21546 has completed pre-IND studies in preparation for initiation of first-in-human clinical studies.
Citation Format: Andrew Payne, Pierre Fons, Isabella Alt, Joost van Ham, Christina Taubert, Andy Bell, Stephanie Versluys, Florie Bertrand, Virgile Visentin, Emilie Mirey, Emilie Pelissier, Michael Paillasse, Sabrina Pagliarusco, Gregory Vladimer, Mark Whittaker. EXS21546, a non-CNS penetrant A2AR-selective antagonist for anti-cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1731.
Abstract 1807: T cell conditional knockout mouse model of the mitochondrial branched chain aminotransferase (BCATm) responds with delayed tumor growth to a lymphoma challenge
Authors: Adam Christie , Martin Alexander , Betar Rebekah , Foster Mercedes , Boyer Michael , Ananieva Elitsa 
Published: July 2021

Abstract
Enzymes in amino acid catabolism are emerging as attractive targets for cancer therapies. The mitochondrial branched-chain amino transferase (BCATm), an enzyme catalyzing the first step in leucine, valine, and isoleucine degradation, has been recently implicated in cancer growth but its role in T cell driven anti-cancer immunity has never been explored. To fulfill the gap in current scientific knowledge and address some of the challenges with lymphoma immunotherapies, we used the CD4-Cre-Lox recombination to create a conditional knockout mouse (T-BCATmKO) with CD4+ and CD8+ T cells deficient in the Bcat2 gene that encodes BCATm. Based on initial studies showing that a deletion of BCATm from T cells leads to increased glycolytic and oxygen metabolism and up-regulation of complex 1 of the mammalian target of rapamycin (mTORC1) signaling, we hypothesized that if BCATm is absent from T cells, this would stimulate T cell activation leading to improved T cell function in mice challenged with lymphoma. For this purpose, T-BCATmKO and T-BCATmfl/fl male mice (15-16 weeks old) were subcutaneously injected with 2.5x105 mouse lymphoma EG7-OVA cells. Tumor growth, animal weight, and food intake were recorded daily for a period of 20 days. Mice developed tumors around day 10 and this was not associated with weight loss or poor feeding of the mice as no changes in body weights or food intake between the different mouse groups were observed. Statistical analysis via one-way ANOVA revealed that T-BCATmKO mice had significantly delayed tumor growth compared to T-BCATmfl/fl mice (P= 0.05). In addition, CD4+ T cells isolated from T-BCATmKO mice released significantly more IFNγ after 48-72 hours of activation suggesting that CD4+ T cells from T-BCATmKO mice were more active than T cells from T-BCATmfl/fl mice. This study revealed that targeting BCATm in T cells may offer an advantage in mice to better fight lymphoma cancer and represents an attractive target for future immunotherapeutic anti-cancer approaches.
Citation Format: Christie Adam, Alexander Martin, Rebekah Betar, Mercedes Foster, Michael Boyer, Elitsa Ananieva. T cell conditional knockout mouse model of the mitochondrial branched chain aminotransferase (BCATm) responds with delayed tumor growth to a lymphoma challenge [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1807.
Abstract 1873: GlycoConnect™ ADCs based on topoisomerase 1 inhibitor exatecan (SYNtecan E™) show excellent in vivo efficacy and tolerability
Authors: van Delft Floris 
Published: July 2021

Abstract
Camptothecins form a powerful class of chemotherapy drugs (e.g. irinotecan, topotecan, belotecan), based on their ability to inhibit topoisomerase I. Some camptothecins, such as DXd and SN-38, have also proven powerful payloads for antibody-drug conjugates (ADCs), as exemplified by the recent market approval of Enhertu® and Trodelvy®, respectively. We have reported earlier that the native glycan of monoclonal antibodies is a priviliged conjugation site for ADCs (GlycoConnect™)1, while the highly polar spacer technology (HydraSpace™)2 enables the conjugation of any cytotoxic payload, providing ADCs with significantly expanded therapeutic index (TI) versus mainstream ADC technologies.
We here show that exatecan (DX-8951f), a clinically validated and potent campothecin, is readily combined with HydraSpace™ technology to provide linker-payload (SYNtecan E™). Homogeneous and stable GlycoConnect™ADCs were generated from trastuzumab and SYNtecan E™ and compared head-to-head with DXd or SN-38payload, as well as deruxtecan, the linker-payload applied in Enhertu®. Complete tumor regression was observed in a mouse xenograft study (BT-474) after a single dose, while safety studies in mouse corroborated the high tolerability of SYNtecan E™ ADCs. Taken together, these studies demonstrate the potential of SYNtecan E™ for application in stable and site-specific ADCs with excellent therapeutic index.
1 van Geel et al. Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of NativemAbs Provides Homogeneous and Highly Efficacious Antibody−Drug Conjugates. Bioconj. Chem. 2015, 26, 2233-2242.
2 Verkade et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody-Drug Conjugates. Antibodies 2018, 7, 12, doi:10.3390/antib7010012.
Citation Format: Floris van Delft. GlycoConnect™ ADCs based on topoisomerase 1 inhibitor exatecan (SYNtecan E™) show excellent in vivo efficacy and tolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1873.
Abstract 1910: Augmented secretion of IL-1α from mouse oral squamous cell carcinoma (OSCC) cells caused by the serum deprivation and hypoxia promotes immune-suppressive activity of mesenchymal stromal cells
Authors: Kondoh Nobuo , Matsunami Akihiro , Mizuno-Kamiya Masako , Umemura Naoki , Takayama Eiji , Kawaki Harumi , Ueno Kyouhei , Morimoto-Ito Hiroe , Muramatsu Yasunori , Sumitomo Shinichiro 
Published: July 2021

Abstract
Objectives; We have already reported that mouse oral squamous carcinoma (OSCC), Sq-1979-1, cells produce IL-1α which specifically enhances the immunosuppressive activity of co-cultured mesenchymal stromal, 10T1/2, cells (Morimoto-Ito, Open Dent J. 2019). In this report, we evaluated conditions promoting the expression of IL-1α of Sq-1979-1 cells to further enhance immunosuppressive function of the 10T1/2 cells, and also examined the expression in OSCC tissues.
Methods; Expression of IL-1α in Sq-1979-1 cells was evaluated by RT-PCR, western blots and enzyme-linked immune sorbent assay (ELISA). Conditioned mediums (CMs) from Sq-1979-1 cells were co-cultured with 10T1/2 cells and anti-CD3 antibody-stimulated mouse spleen cells. The production of interferon (IFN)- γ and IL-1α was evaluated using ELISA. The function of IL-1α in CM was examined by anti- IL-1α antibody. Immunohistochemical analysis of OSCC tissues was performed.
Results; The production of IL-1α from Sq-1979-1 cells was specifically enhanced in lower serum (0.5% or 1.0%FBS), or under hypoxia (1.0% oxygen) compared to that in the standard growth condition supplemented with 10% FBS under normoxia. Compared to standard CM, the CMs prepared in 0.5% and 1.0% FBS, or under hypoxia significantly reduced IFN-γ production from stimulated spleen cells co-cultured with 10T1/2 cells. These functions of the CMs completely abolished by anti- IL-1α antibody. Expression of IL-1α in OSCC tissues was prominent in the midst of carcinomatous cellular lesion, or nearby necrotic lesion, where the supply deficiency could be occurred.
Conclusions; The promotion of immunosuppressive activity of mesenchymal cells by Sq-1979-1 cells was specifically augmented in lower serum and hypoxic conditions, mediated by increased IL-1α production.
Citation Format: Nobuo Kondoh, Akihiro Matsunami, Masako Mizuno-Kamiya, Naoki Umemura, Eiji Takayama, Harumi Kawaki, Kyouhei Ueno, Hiroe Morimoto-Ito, Yasunori Muramatsu, Shinichiro Sumitomo. Augmented secretion of IL-1α from mouse oral squamous cell carcinoma (OSCC) cells caused by the serum deprivation and hypoxia promotes immune-suppressive activity of mesenchymal stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1910.
Abstract 1929: Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro
Authors: Mcglorthan Latoya , Paucarmayta Ana , Casablanca Yovanni , Maxwell George L. , Syed Viqar 
Published: July 2021

Abstract
Previously we have shown that progesterone and calcitriol induce apoptosis of cancer cells. However, the apoptotic mechanisms of the two agents have not been well characterized yet. Herein, we investigated the molecular mechanisms of how progesterone and calcitriol induce apoptosis in cancer cells. DNA fragmentation was upregulated by progesterone and calcitriol in ovarian and endometrial cancer cells. Time-dependent treatment of ovarian cancer cells, ES-2, and TOV-21G with progesterone enhanced caspase -8 activity after 12 h, whereas OV-90, TOV-112D, HEC-1A, and HEC-59 cells showed increased activity after 24h. Caspase 9 activity was increased in all cell lines after 24h treatment with calcitriol. Pretreatment of cancer cells with a caspase-8 inhibitor (z-IETD-fmk) or caspase-9 inhibitor (Z-LEHD-fmk) significantly attenuated progesterone and calcitriol induced caspase-8 and caspase-9 expression, respectively. The expression of FasL, Fas, FAD, and pro-caspase-8, which constitute the death-inducing signaling complex (DISC), was upregulated in progesterone treated cancer cells. Knockdown of FAS or FADD with specific siRNAs significantly blocked progesterone-induced caspase-8. Cleavage of the BID was not affected by caspase-8 activation suggesting the absence of cross-talk between caspase-8 and caspase-9 pathways. Calcitriol treatment decreased mitochondrial membrane potential and increased the release of cancer cytochrome C. These findings indicate that progesterone induces apoptosis through activation of caspase-8 and calcitriol through caspase-9 activation in cancer cells. A combination of progesterone-calcitriol activates both extrinsic and intrinsic apoptotic pathways in cancer cells.
Citation Format: Latoya Mcglorthan, Ana Paucarmayta, Yovanni Casablanca, George L. Maxwell, Viqar Syed. Progesterone induces apoptosis by activation of caspase-8 and calcitriol via activation of caspase-9 pathways in ovarian and endometrial cancer cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1929.
Abstract 1945: Modulation of intracellular redox milieu regulates Mcl-1 levels and sensitizes venetoclax resistant cancer cells
Authors: Lai Jolin Xiao , Pervaiz Shazib 
Published: July 2021

Abstract
Mcl-1, a member of the Bcl-2 family of anti-apoptotic proteins is commonly amplified in malignant cancers and has been implicated in chemotherapy resistance. More recently, it has been reported to mediate resistance to the Bcl-2 specific BH3 mimetic, venetoclax (ABT199). The protein stability of Mcl-1 is regulated largely by post-translational modifications (PTMs) such as phosphorylation and ubiquitination. Where phosphorylation of Thr163 residue at the PEST domain region by kinases result in Mcl-1 stability and extended protein half-life, phosphorylation of Ser159 residue leads to protein degradation via proteasome pathway. Given the importance of PTMs in regulating Mcl-1, identification of signaling pathways that could modulate PTMs of Mcl-1 to thereby sensitize tumors to chemotherapy have been explored extensively. The intracellular redox milieu has been widely reported to modulate protein-protein signaling as well as inducing PTMs, where different reactive oxygen species (ROS) have also been shown to mediate differential effects. For example, enhanced production of O2- (by either inhibition or downregulation of SOD1/SOD2) could mediate tumorigenicity and chemoresistance. To that end, our group and others have also previously reported the oncogenicity of superoxide (O2-), where an elevated O2- level mediates enhanced anti-apoptotic activity against chemotherapeutic agents through sustained Bcl-2 phosphorylation and the inhibition of O2- production conversely sensitized cells to chemotherapy. Nonetheless, the exact mechanisms of how O2- exerts its pro-survival effects remain elusive. Our preliminary findings now suggest that elevated intracellular O2- levels induces Mcl-1 stability in cancer cells through PTMs as a potential mechanism of chemotherapy resistance. Increased intracellular O2- levels induced Mcl-1 through phosphorylation of Thr163 residue of Mcl-1, which in turn reduced ubiquitination dependent degradation of Mcl-1. Importantly, increased O2- level increased resistance to cell death induced by Mcl-1 specific BH3 mimetic, S63845 and conversely, reducing O2- levels resulted in sensitization of intrinsically venetoclax resistant leukemia cells to venetoclax induced cell death. These results provide a novel insight into how the intracellular redox state could impact upon cancer cell viability and therapy resistance.
Citation Format: Jolin Xiao Lai, Shazib Pervaiz. Modulation of intracellular redox milieu regulates Mcl-1 levels and sensitizes venetoclax resistant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1945.