bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5025: Reduced level of protein kinase C iota renders human glioblastoma less invasive and induces apoptosis via modulating Tak1/NF-κB pathway
Authors: Khalid Khandker Mohammad , Ratnayake Wishrawana S. , Dey Avijit , Oishee Nuzhat N. , Marzan Mahfuza , Acevedo-Duncan Mildred 
Published: April 2023

Abstract
Glioblastoma (GBM) is characterized by poor therapeutic response and overall survival. It is the most aggressive form of primary brain tumor with a tendency to invade surrounding healthy brain tissues, rendering them largely incurable. In this study, small-interference RNA was used to knock down the expression of protein kinase C PKC-ι. The reduced PKC-ι expression impaired the phosphorylation of LIM kinase 1/2 (LIMK), which is a critical step in cofilin recycling and actin polymerization. Additionally, there was a down-regulation of matrix metalloprotease-9 expression in LN-229 and U87G cells, which coincided with decreased invasion. Therefore, PKC-ι regulates both cytoskeleton rearrangement and cell adhesion, which contributed to cell migration. Silencing of PKC-ι also dampened Transforming growth factor-β (TGF-β)-activated kinase 1 (Tak1) level. TAK1 is an essential component in genotoxic stresses-induced NF-κB-activation and mitogen-activated protein kinase (MAPK)-pathways in GBM. TAK1, when activated, forms a complex with TAB1-3 (Tak1 binding proteins). Our data reveal, reduced Tak1 level after silencing PKC-ι interferes with complex formation and reduces NF-κB-activation. Diminished PKC-ι level also reduces activation of Tak1/JNK axis. This deactivation exerts an anti-oncogenic effect on glioblastoma via suppression of Akt1, c-Myc, and STAT3. This implies PKC-ι may have a crucial role in the activation of Tak1. Reduced migration and invasion in glioblastoma cells upon inhibition of PKC-ι was further confirmed by Scratch assay and Boyden assay. These results indicate that PKC-ι is involved in the control of glioblastoma cell migration and invasion. PKC-ι is a central component of multiple converging and bifurcating pathways and is a potential therapeutic target against GBM survival and infiltration.
Citation Format: Khandker Mohammad Khalid, Wishrawana S. Ratnayake, Avijit Dey, Nuzhat N. Oishee, Mahfuza Marzan, Mildred Acevedo-Duncan. Reduced level of protein kinase C iota renders human glioblastoma less invasive and induces apoptosis via modulating Tak1/NF-κB pathway. [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 5025.
Abstract 5029: Determining the biological function of TNK1
Authors: Kohler Emmalee , Lopez-Palacios Tania , Chan Tsz-Yin , Egbert Christina , Truman Jacob , Ashworth Spencer , Vaughan Alec , Andersen Joshua , Madhusanka D. 
Published: April 2023

Abstract
Thirty-eight-negative kinase 1 (TNK1) is a poorly characterized member of the ACK family of non-receptor tyrosine kinases, which we recently identified as a driver of cell survival in a subset of primary hematological malignancies. However, the biological function of TNK1 is not well understood. We also found that TNK1 is unusual among kinases for the presence of a functional ubiquitin association (UBA) domain on its C-terminus. We discovered that the TNK1 UBA domain binds to poly-ubiquitin with high affinity and has no apparent preference for ubiquitin chain length or linkage type. Interestingly, the UBA domain is important for TNK1 function, given that deletion of the UBA domain (TNK1 ΔUBA) alters its localization and phospho-substrate network, while also weakening the oncogenic activity of TNK1 in cell transformation assays. Based on these data, we hypothesized that the UBA domain tethers TNK1 to its substrates. To test this hypothesis, we performed quantitative phospho-tyrosine proteomics using murine pro-B cells transformed with either TNK1 full length or TNK1 ΔUBA and identified TANK-binding kinase 1 (TBK1) as a putative UBA-dependent TNK1 substrate. TBK1 is a serine/threonine kinase involved in the regulation of inflammation, autophagy, and NF-ĸB signaling. During the selective autophagic degradation of misfolded proteins (aggrephagy), TBK1 phosphorylates p62 at S403 to increase its affinity to ubiquitin, and thereby increases p62-mediated recruitment of misfolded proteins into the condensate. Unchecked growth of ubiquitin condensates can overwhelm the size capacity of autophagosomes, potentially causing misfolded proteins to become proteotoxic aggregates. Our preliminary data suggest a model in which active TNK1 accumulates at ubiquitin condensates to phosphorylate and inhibit TBK1. Based on these data, we propose that TNK1 acts as a kinase sensor of poly-ubiquitin to control the TBK1-mediated growth of ubiquitin condensates.
Citation Format: Emmalee Kohler, Tania Lopez-Palacios, Tsz-Yin Chan, Christina Egbert, Jacob Truman, Spencer Ashworth, Alec Vaughan, Joshua Andersen, D. Madhusanka. Determining the biological function of TNK1. [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 5029.
Abstract 504: BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy
Authors: Han Han , Yang Xiaofeng , Zhao Ying , Wang Jin , Yang Xiang , Ju Xuepeng , Zhao Jiayu , Zou Zhengyao , Chen Haibo , Liu Xiaoyun , Guo Jing , Yang Cheng , Lan Hong , Wu Hao , Ding Lieming , Wang Jiabing 
Published: April 2023

Abstract
CD73, also known as ecto-5'-nucleotidase, plays a major role in converting extracellular adenosine monophosphate (AMP) to immunosuppressive adenosine. It is frequently overexpressed across a variety of cancers. High adenosine level in the tumor microenvironment, predominantly signaling through the A2a/A2b receptors, suppresses innate and adaptive immune responses and mediates tumor immune evasion. CD73 overexpression is correlated with poor prognosis in several tumor types. Inhibition of CD73 to reduce adenosine production is a promising therapeutic approach for the treatment of cancer. Both monoclonal antibodies and small molecule inhibitors are being explored to target CD73. Small molecule CD73 inhibitor with good balance of activity and ADME properties are rare. Here we present BPI-472372, a potent, selective, and orally bioavailable small molecule CD73 inhibitor. It strongly inhibits both soluble and cell-bound CD73, with no off-target activity on other related nucleotidases (NTPDases 1/2/3/5), nor on a large panel of enzymes, receptors, and ion channels. BPI-472372 reversed AMP-induced CD4+ T cell suppression in a dose-dependent manner. In vivo, BPI-472372 exhibited anti-tumor effect in MC38 syngeneic mouse model with no visible adverse effect. Moreover, enhanced tumor growth inhibition activity was observed when BPI-472372 was combined with durvalumab (anti-PD-L1) in humanized PD-L1 syngeneic MC38 model. BPI-472372 exhibited desirable drug-like properties including high permeability, low hepatocytes clearance, and adequate oral exposure across multiple pre-clinical species. GLP toxicity study indicated that BPI-472372 was well tolerated at high dose following 4 weeks repeated administration in both mouse and dog. Taken together, BPI-472372 is a potent and orally bioavailable small molecule CD73 inhibitor with single agent anti-tumor efficacy, favorable ADME properties, and a wide therapeutic index.
Citation Format: Han Han, Xiaofeng Yang, Ying Zhao, Jin Wang, Xiang Yang, Xuepeng Ju, Jiayu Zhao, Zhengyao Zou, Haibo Chen, Xiaoyun Liu, Jing Guo, Cheng Yang, Hong Lan, Hao Wu, Lieming Ding, Jiabing Wang. BPI-472372: a potent and orally bioavailable small molecule inhibitor of CD73 for cancer immunotherapy [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 504.
Abstract 5044: Antitumor activity comparison of two somatostatin receptor ligands radiolabeled with Lutetium-177 (SSO110 and DOTA-TATE) alone or combined with chemotherapy in mice bearing AR42J SST2-positive tumors
Authors: Raguin Olivier , Krüger Marcel , Provent Peggy , Cay Funda , Marie dit chatel Elodie , Lux Marie , Lezmi Stéphane , Meyer-Losic Florence , Plas Pascale , Pais Ben , Berthet Cyril 
Published: April 2023

Abstract
Only a limited number of studies have compared the therapeutic effects of repetitive cycles of radiolabeled somatostatin (SST) analogues or assessed potential synergy of these analogues with chemotherapy agents.
Hence, a comparison was conducted in an in vivo AR42J tumor model with an SST2 antagonist, [177Lu]Lu-satoreotide tetraxetan ([177Lu]LuSSO110), and a SST2 agonist, [177Lu]Lu-DOTA-TATE. The efficacy of treatment combining [177Lu]Lu-satoreotide tetraxetan with capecitabine plus temozolomide was also assessed.
Swiss Nude mice were xenografted with AR42J tumor cells. For the evaluation of the tumor response to radiation therapy, animals received one weekly dose of [177Lu]LuSSO110 or [177Lu]Lu-DOTA-TATE for four consecutive weeks. For combined treatments, animals received one weekly dose of [177Lu]LuSSO110 at 20 MBq for four consecutive weeks in association with daily doses of capecitabine and temozolomide (CAPTEM).
Weekly treatment for four consecutive weeks with [177Lu]LuSSO110 at 15 MBq revealed a significantly reduced tumor growth, with 68 days to reach a tumor volume of 850 mm3, compared to [177Lu]Lu-DOTA-TATE at 15 MBq or 30 MBq, with, respectively, 43 days and 48 days. This was associated with a 3.5 fold higher tumor uptake of [177Lu]LuSSO110 (15 MBq) compared to [177Lu]Lu-DOTA-TATE, with no or mild effects on body weight, hematological toxicity, or renal toxicity.
In AR42J tumor-bearing mice treated once a week for four consecutive weeks, [177Lu]LuSSO110 (15 MBq) associated with CAPTEM regimen did
not significantly increase the median time to reach a tumor volume of 1000 mm3 as compared to treatment with [177Lu]Lu-satoreotide alone: 50.7 vs 42.2 days, respectively. The association of the two treatments only led to mild weight losses.
Repeated administrations of [177Lu]LuSSO110 were able to potentiate peptide receptor radionuclide therapy with a higher tumor uptake and longer median survival compared to [177Lu]Lu-DOTA-TATE. The The combination of [177Lu]Lu-satoreotide with capecitabine and temozolomide did not show any synergy, but no antagonism was observed either.
Citation Format: Olivier Raguin, Marcel Krüger, Peggy Provent, Funda Cay, Elodie Marie dit chatel, Marie Lux, Stéphane Lezmi, Florence Meyer-Losic, Pascale Plas, Ben Pais, Cyril Berthet. Antitumor activity comparison of two somatostatin receptor ligands radiolabeled with Lutetium-177 (SSO110 and DOTA-TATE) alone or combined with chemotherapy in mice bearing AR42J SST2-positive tumors. [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 5044.
Abstract 5050: Case report: A 17-year-old patient developed glioblastoma secondary to intracranial germ cell tumor and was stabilized with chemoradiotherapy combined with Tumor Treating Fields
Authors: Li Shaoqun , Lai Mingyao , Li Hainan , Li Juan , Zhou Jiangfen , Hu Qingjun , Ye Minting , Ai Ruyu , Zhu Junqiao , Huang Lijun , Cai Linbo 
Published: April 2023

Abstract
Background: Germ Cell Tumor (GCT) is a rare intracranial tumor occurring in children and young adults. Some patients with GCT are curable with radiotherapy and chemotherapy. Due to long-term survival, the tumor secondary to radiotherapy is of concern. The treatment of the secondary tumor is less elaborated and worth exploring.
Case Presentation: Here we report a patient with GCT who developed radiotherapy-induced glioblastoma. He was diagnosed as pineal gland GCT at the age of 12. Afterwards, he underwent a set of treatments, including chemotherapy, radiotherapy, and surgery. Unfortunately, after 5 years of tumor-free survival, he developed an intracranial mass involved the right thalamus and brainstem, around pineal region. The GCT recurrence was firstly considered, however, the failure of 7 cycles of chemotherapy drew attention. Then brain biopsy underwent by ROSA robot showed high-grade glioma. Next Generation Sequencing showed IDH-wildtype, MGMT methylation, CDKN2A/B homozygous deletion, EGFR amplification, the +7/−10 signature, which supported the diagnosis of glioblastoma. Resection operation is not applicable for this patient as the involvement of thalamus and brainstem. Considering the difficulty of treatment and poor prognosis of glioblastoma, re-radiotherapy is a feasible choice. Chemoradiotherapy with Tumor Treating Fields (TTFields) is a innovative try for secondary glioblastoma in a 17-year-old patient. After the combination therapy, the intracranial mass went regression and the patient has lived for more than 1 years.
Conclusions: For the patients with brain tumor who anticipate long-term survival, the secondary tumor after radiotherapy is of concern. Secondary Glioblastoma is rare and difficult to treat. Chemoradiotherapy with TTFields is a feasible and safe treatment option for some patients, but we need more evidence to support.
Citation Format: Shaoqun Li, Mingyao Lai, Hainan Li, Juan Li, Jiangfen Zhou, Qingjun Hu, Minting Ye, Ruyu Ai, Junqiao Zhu, Lijun Huang, Linbo Cai. Case report: A 17-year-old patient developed glioblastoma secondary to intracranial germ cell tumor and was stabilized with chemoradiotherapy combined with Tumor Treating Fields. [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 5050.
Abstract 5068: Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment
Authors: Suzuki Ryo , Watanabe Satoshi , Shono Kunihiro , Masuda Takaaki , Sekiya Tomoki , Goto Yuka , Fujisaki Toshiya , Arita Masashi , Ohtsubo Aya , Shoji Satoshi , Tanaka Tomohiro , Nozaki Koichiro , Kondo Rie , Saida Yu , Hokari Satoshi , Ohashi Riuko , Shima Kenjiro , Kimura Yosuke , Aoki Nobumasa , Ohshima Yasuyoshi , Koya Toshiyuki , Kikuchi Toshiaki 
Published: April 2023

Abstract
Background: Although programmed cell death-1 (PD-1) inhibitors have achieved promising and durable responses in patients with several types of cancer, many patients show intrinsic resistance to PD-1 inhibitors. Extensive studies have demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit antitumor effects of PD-1 inhibitors. The aim of current study is to investigate whether nintedanib, which targets multi-tyrosine kinase including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor, reduced immunosuppressive cells in tumor microenvironment and augments antitumor effects of PD-1 inhibitors.
Method: Mice were inoculated subcutaneously with CT26 murine colon carcinoma or MC38 murine colon carcinoma and were treated with nintedanib (50 mg/kg), αPD-1mAbs (10 mg/kg) or nintedanib plus αPD-1mAbs. The tumor size was measured in 2 perpendicular dimensions 3 times per week. Types of cells infiltrating into tumors and immune status of tumor-draining lymph nodes were assessed using flow cytometry and immunohistochemistry (IHC).
Results: RNA sequencing data revealed that nintedanib decreased gene expression related to endothelial mesenchymal transition, angiogenesis and coagulation. Flow cytometry showed that nintedanib significantly decreased the percentage of myeloid-derived suppressor cells and cancer-associated fibroblast in tumor tissues. Both of flow cytometry and IHC analysis showed that nintedanib significantly increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating in tumors. In addition, nintedanib plus αPD-1mAbs significantly retarded tumor progression.
Conclusion: Nintedanib decreased immunosuppressive cells, increased effector T cells, and enhanced anti-tumor effects of αPD-1mAbs. Based on these findings, there are possibility that nintedanib improves clinical outcomes of cancer patients treated with PD-1 inhibitors.
Citation Format: Ryo Suzuki, Satoshi Watanabe, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Yuka Goto, Toshiya Fujisaki, Masashi Arita, Aya Ohtsubo, Satoshi Shoji, Tomohiro Tanaka, Koichiro Nozaki, Rie Kondo, Yu Saida, Satoshi Hokari, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. Nintedanib enhances antitumor effects of anti-PD-1 therapies through inhibition of immunosuppressive cells in tumor microenvironment. [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 5068.
Abstract 5184: Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors
Authors: GORVEL Laurent , Demerle Clemence , Mello Marielle , Pastor Sonia , Degos Clara , Zarubica Ana , Angelis Fabien , Fiore Frederic , Nunes Jacques , Malissen Bernard , Greillier Laurent , Guittard Geoffrey , Luche Herve , Barlesi Fabrice , Olive Daniel 
Published: April 2023

Abstract
TNFRF-14/HVEM is the ligand for BTLA and CD160 negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis. We developed C57BL/6 mouse models co-expressing human huBTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands. Here, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with anti-PD-L1 mAb to activate T cells in the presence of PDL-1 positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1 negative cells. In order to better understand HVEM18-10 effect in vivo and especially disentangle its CIS and TRANS effects, we developed a knock-in (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both human BTLA and human HVEM (huBTLA+/+/huHVEM+/+ (DKI)). In vivo pre-clinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+ tumor growth. In the DKI model, anti-HVEM 18-10 treatment induces a decrease of exhausted CD8+ T cells and regulatory T cells and an increase of Effector memory CD4+ T cells within the tumor. Interestingly, mice which completely rejected tumors (± 20%) did not develop tumors upon re-challenge in both settings, therefore showing a marked T cell-memory phenotype effect. Altogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (anti-PD1/anti-PDL-1/anti-CTLA-4).
Citation Format: Laurent GORVEL, Clemence Demerle, Marielle Mello, Sonia Pastor, Clara Degos, Ana Zarubica, Fabien Angelis, Frederic Fiore, Jacques Nunes, Bernard Malissen, Laurent Greillier, Geoffrey Guittard, Herve Luche, Fabrice Barlesi, Daniel Olive. Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors. [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 5184.
Abstract 5200: Novel Immuno-Oncology drugs evaluation by humanised immune cells and cancer co-inoculated models
Authors: Xie Bin , Hou Xin , Chen Hanglu , Yang Pengfei , Zhou Yanbin , Wen Danyi 
Published: April 2023

Abstract
Currently more and more immunotherapeutic drugs and engineered cells have been developed to use human immune system against cancer. While humanized peripheral blood mononuclear cell reconstitution in immune deficient mice is a forward-straight model for evaluating therapeutic antibodies, this conventional model has several drawbacks to hinder its widespread use, including the graft-versus-host-disease happened after one month of reconstitution, insufficient immune cell infiltration from reconstituted circulatory system and hardly retention of functional innate immune cells, such as macrophages and nature killer cells. To overcome this, LIDE has developed a specific human immune cell and cancer cell co-inoculation model. Cancer-priming PBMC and/or its derivates were well mixed with the fresh cancer cells in MatriGel, co-transferring into NCG mice to form a relatively “hot tumor” tissue for immunotherapy, including drugs targeting T cells, dendritic cells and macrophages. Additionally, we also take advantage of human IL15 transgenic mice to study the function of ex vivo expanded NK cells. This novel method has successfully helped evaluate biological function of immune checkpoint blockers and immune agonists in multiple cancers, such as melanoma, breast cancer, lung cancer, hepatocellular carcinoma and ovarian cancer.
Citation Format: Bin Xie, Xin Hou, Hanglu Chen, Pengfei Yang, Yanbin Zhou, Danyi Wen. Novel Immuno-Oncology drugs evaluation by humanised immune cells and cancer co-inoculated models. [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 5200.