bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4828: Therapeutic targeting of P2 × 4 receptor and mitochondrial membrane potential in renal cell carcinoma
Authors: Rupert Christopher , Pili Roberto , DeNigris Filomena 
Published: April 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common lethal subtype of kidney cancer. Large-scale metabolomics data have associated metabolic alterations with the pathogenesis and progression of renal cell carcinoma and have correlated mitochondrial activity with poor patient survival. Our group has recently reported that the lysosome purinergic receptor P2 × 4 (P2 × 4R) regulates neoangiogenesis. As ccRCC is characterized by increased angiogenesis we hypothesized that P2 × 4R may play a role in this disease. Interestingly, TCGA data suggest that P2 × 4R over-expression correlates with poor overall ccRCC patient survival. Our preliminary results also suggest that oxophosphorylation is the main source of tumor-derived ATP, which exerts a critical impact on tumor energy metabolism and mitochondrial activity in ccRCC. P2 × 4 receptor expression appears to contribute to the homeostasis of intracellular calcium and integrity of mitochondrial membrane potential in different ccRCC models. Seahorse experiments showed that P2 × 4R inhibition by 5BDBD, a potent and selective antagonist, caused a rapid dose-dependent reduction of mitochondrial activity. Moreover, prolonged mitochondrial failure induced by 5BDBD was associated with increased radical oxygen species, changes in mitochondrial permeability (i.e. opening of the transition pore complex, dissipation of membrane potential and calcium overload), and cell death via both necrosis and apoptosis. P2 × 4R inhibition by 5BDBD was associated with a significant anti-tumor effect both in vitro and in vivo by utilizing several ccRCC cell lines and patient-derived organoids. Interestingly, higher mitochondrial activity was associated with greater sensitivity to 5BDBD. Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2 × 4R inhibition may be a therapeutic strategy for a subset of renal carcinoma patients
Citation Format: Christopher Rupert, Roberto Pili, Filomena DeNigris. Therapeutic targeting of P2 × 4 receptor and mitochondrial membrane potential in renal cell carcinoma. [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 4828.
Abstract 483: Hederacolchiside A1 inhibits autophagy via CTSC inhibition and inhibits growth in colon cancer
Authors: Kim Solbi , Kim Eunji , Han Minju , Oh Youn Seo , Kang Sora , Jeon Heung Jin , Lee Hyo Jin 
Published: April 2023

Abstract
Background: Autophagy is a normal regulatory process that degrades non-functional or unnecessary cellular components. The degradation of components provides materials for the synthesis of cellular components and, during tumor development, may provide energy. Therefore, autophagy regulation may have potential therapeutic uses in oncology. The triterpenoid saponin hederacolchiside A1 (HA1) has potent antitumor effects; however, its role in autophagy is still unknown.
Methods: In the present study, we used human colon cancer cells (SW480 and HT29) and mouse colon cancer cells (CT26) for the main experiments, and several additional cancer cell lines for other experiments. To assess the autophagy dysregulation caused by HA1, we evaluated the protein expressions of two autophagy markers (LC3 and SQSTM1) using Western blotting and the changes in organelles using LC3 puncta assay and transmission electron microscopy. We compared the effects of HA1 and other autophagy inhibitors. Additionally, we compared the HA1-induced decrease in cathepsin C (CTSC) expression in tumors and non-tumors using publicly available data. The effect of HA1 on tumor growth was evaluated in vitro using a three-dimensional spheroid model and patient-derived colon organoids, and in vivo based on tumor growth in a subcutaneous injection mouse model.
Results: HA1 treatment resulted in marked vacuolization of colon and other cancer cells. Additionally, autophagy was induced by the accumulation of LC3-II and SQSTM1. These findings were supported by increased LC3 puncta and abnormal organelle morphology. Compared to treatment with other autophagy inhibitors, HA1 treatment resulted in the formation of distinct vacuoles and increased LC3 and SQSTM1, similar to chloroquine treatment. The publicly available data showed that the lysosomal protease CTSC was increased in several cancers, including colon cancer, compared to the normal tissues. Furthermore, HA1 decreased the CTSC expression and enzymatic activity independently of the proteasome degradation, resulting in autophagy dysregulation and, subsequently, autophagy flux inhibition. HA1 inhibited cell growth and induced cell cycle arrest in the two-dimensional culture, three-dimensional spheroids, patient-derived colon cancer organoids, and the in vivo experiments.
Conclusion: HA1 inhibits cell growth and induces autophagy dysregulation. Therefore, HA1 may be a potential therapeutic agent in colon cancer.
Citation Format: Solbi Kim, Eunji Kim, Minju Han, Youn Seo Oh, Sora Kang, Heung Jin Jeon, Hyo Jin Lee. Hederacolchiside A1 inhibits autophagy via CTSC inhibition and inhibits growth in colon 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 483.
Abstract 4936: Activity of carfilzomib in head and neck cancer cell lines in vitro
Authors: Eldaly Abdullah S. , Stairs Douglas B. , Machtay Mitchell 
Published: April 2023

Abstract
Background: Carfilzomib (CF) is a 2nd generation proteasome inhibitor with activity in hematologic cancer, but its study in solid tumors like squamous cell carcinoma of the head and neck (SCCHN) is limited. We investigated its antitumor activity in three SCCHN cell lines.
Methods: Cells: We studied two human tongue cell lines (CAL27; SCC-25) and one pharynx line (FaDu); all HPV-negative and p53-mutant. MTT assays: We utilized MTT assays to evaluate cytotoxicity of CF, cisplatin, and their combination. The IC50 of CF and Combination Index (CI) of varying concentrations of combined CF and cisplatin were calculated. Clonogenic assays: Cells were seeded at low density and after 24 hours, cells were treated with varying concentrations of CF. Plates were incubated for 10 days. The cells were fixed and stained with crystal violet dye and colonies counted. Wound Healing assays: After cells reached 100% confluence, a scratch was created using a 200 µL micropipette. Cells were treated with CF and images were acquired at 0, 24, 48, and 72 hours post-scratch.
Results: MTT assays: IC50 values as a function of exposure lengths are shown in Table 1. CAL27 was the most sensitive while SCC-25 was the most resistant. In all cell lines, the results of combined CF and cisplatin were complex: at lower doses there was evidence of antagonism, while at higher doses there was synergy. Clonogenic assays: CF significantly inhibited clonogenicity compared to DMSO control (P≤ 0.05). The surviving fraction for CF 2.5, 5, and 10 nM were 0.411. 0.151, 0.051, and 0.5, 0.339, 0.102 in CAL27 and SCC-25 cell lines, respectively. Wound Healing assays: Wound closure % after treatment with CF5 was significantly different from DMSO control (P≤0.05). Wound closure % for CF5 were 30.97, 56.75, and 28.03% compared to 94.65, 75.88, and 42.05% for control in CAL27, FaDu, and SCC-25 cell lines, respectively.
Conclusion: CF exhibits antitumor effects in SCCHN in vitro. Our findings support further investigation of CF in combination with conventional agents in vitro and in vivo.
IC50 values for carfilzomib in head and neck cancer cell lines Cell line 24 hours 48 hours 72 hours CAL27 18.02 (11.76- 28.22) 9.364 (7.189- 12.45) 6.401 (5.579- 7.373) FaDu 57.34 (41.98-84.90) 16.22 (13.438- 19.446) 8.237 (7.260- 9.365) SCC25 77.78 (67.18- 91.30) 12.87 (11.36- 14.64) 11.49 (10.51- 12.58)
Citation Format: Abdullah S. Eldaly, Douglas B. Stairs, Mitchell Machtay. Activity of carfilzomib in head and neck cancer cell lines in vitro. [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 4936.
Abstract 495: Discovery of BPI-221351, a potent, selective, orally available, and brain penetrating dual inhibitor of mutant IDH1/2
Authors: Shen Hongling , Xu Xiaofeng , Li Yabin , Song Xizhen , Chen Jie , Bi Yunting , Guo Jing , Xu Tong , Zhang Huijuan , Liu Lijia , Zou Zhengyao , Ren Jialin , Tong Jun , Liu Xiaoyun , Rong Hongfei , Ma Teng , Wang Chao , Liu Xiangyong , Chen Hong , Zhao Jiayu , Ju Xuepeng , Chen Haibo , Shen Haidi , Lan Hong , Ding Lieming , Wang Jiabing 
Published: April 2023

Abstract
Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are critical enzymes of the tricarboxylic acid cycle, which convert isocitrate into α-ketoglutarate (α-KG). IDH1 or IDH2 mutations are observed in more than 80% of low- to mid-grade gliomas and in ~20% of acute myeloid leukemia (AML). Tumor-related IDH1/2 mutants acquire a novel function of using α-KG as a substrate to produce R-2-hydroxyglutarate (2-HG). 2-HG is an oncogenic metabolite, and reducing it by inhibiting mutant IDH1 or IDH2 has been shown to be an effective treatment approach. Although agents targeting IDH1 or IDH2 have been approved to treat IDH-mutant cancers, existing IDH1 inhibitors do not cross the blood-brain barrier, a feature needed for treating glioma. Furthermore, resistant mutations do occur, including cross-isoform mutations, which call for the development of dual IDH1/2 inhibitors with good brain penetration. However, IDH1/2 dual inhibitors are rarely discovered. Here we report the discovery of BPI-221351, a potent inhibitor of mutant IDH1 and mutant IDH2. BPI-221351 shows excellent inhibitory activities against both IDH1 and IDH2 enzymes, and potently suppresses 2-HG levels in tumor cells harboring IDH1 or IDH2 mutants. In an IDH-mutant xenograft model, BPI-221351 reduced 2-HG to baseline level up to 24 h after a single oral dose administration. In addition, BPI-221351 possesses excellent blood-brain-barrier penetration with a higher drug concentration in the brain than that in plasma. In conclusion, BPI-221351 exhibits strong activity towards both IDH1 and IDH2 mutants in vitro and in vivo with favorable pharmacological properties, presenting a new therapeutic opportunity for treating glioma and other relevant cancers.
Citation Format: Hongling Shen, Xiaofeng Xu, Yabin Li, Xizhen Song, Jie Chen, Yunting Bi, Jing Guo, Tong Xu, Huijuan Zhang, Lijia Liu, Zhengyao Zou, Jialin Ren, Jun Tong, Xiaoyun Liu, Hongfei Rong, Teng Ma, Chao Wang, Xiangyong Liu, Hong Chen, Jiayu Zhao, Xuepeng Ju, Haibo Chen, Haidi Shen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-221351, a potent, selective, orally available, and brain penetrating dual inhibitor of mutant IDH1/2 [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 495.
Abstract 4957: The targeting drug conjugate Tye1001 displayed its potent anti-tumor efficacy in lymphoma
Authors: Sun Lichun , Yang Mengli , Xiao Haihua , Tian Yuan , Vasilevich Natalya , Fuselier Joseph , Coy David 
Published: April 2023

Abstract
Multiple drug-targeting strategies have been applied to drug development in order to reduce the toxic side effects of the traditional chemotherapy while enhancing its anti-tumor efficacy. Various peptides, proteins and antibodies are usually used to conjugate cytotoxic agents via acting as drug delivery vehicles. In our previous studies, we identified that peptides displayed their efficacious functions to deliver small molecules or oligo DNA to the target sites through ligand-receptor interactions and quick internalization. In our present study, we attempt to synthesize serial drug conjugates via coupling these compounds to peptide or protein vehicles. Tye1001, one of these conjugates, displayed similar potent anti-proliferation activities in lymphoma cells and many other cancer cells compared to the small molecule itself. In particular, this conjugate significantly enhanced its potent anti-tumor efficacy in xenografts. Meanwhile, this conjugate has much less toxic side effects. In our in vivo assays, the similar results were also observed in multiple other tumors such as gastric cancer and leukemia. Our findings provide a more potential druggable opportunity in the clinical applications of cancer patients and the treatment of different types of cancers.
Citation Format: Lichun Sun, Mengli Yang, Haihua Xiao, Yuan Tian, Natalya Vasilevich, Joseph Fuselier, David Coy. The targeting drug conjugate Tye1001 displayed its potent anti-tumor efficacy in lymphoma. [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 4957.
Abstract 4959: TIC10/ONC201 activates ClpP to degrade ALAS1 while PG3 does not degrade ALAS1 in pathway to HRI, ATF4 and CHOP activation leading to tumor cell death
Authors: Tian Xiaobing , El-Deiry Wafik S. 
Published: April 2023

Abstract
TRAIL-inducing compound TIC10/ONC201 binds and activates mitochondrial protease ClpP leading to integrated stress response (ISR) and ATF4 transcription factor activation. Our lab previously reported that ONC201 activates HRI (heme-regulated inhibitor) kinase but does not signal eIF2-alpha phosphorylation through PERK or GCN2. However, the connection between ClpP activation of HRI remains unknown. PG3, a prodigiosin analog that bypasses a defective p53 pathway potently induces ATF4 and pro-apoptotic PUMA. Our data indicate that PG3 activates ATF4 through ISR via HRI as knockdown of HRI but not PKR blocked upregulation of ATF4 and CHOP in several tumor cell lines. We have been exploring how ClpP activation leads to HRI and ISR activation, and the mechanism by which PG3 leads to HRI activation. We find that activation of HRI by PG3 or ONC201 is not through the OMA1/DELE1◊HRI activation pathway. Moreover, ROS and NO are not responsible for ONC201- or PG3-induced HRI activation. ALAS1 (5'-aminolevulinate synthase 1) catalyzes the first rate-limiting step in heme (Iron-protoporphyrin) biosynthesis. ONC201 treatment leads to potent downregulation and inhibition of ALAS1, indicating that ONC201 inhibits heme biosynthesis. It is well known that reduced heme results in activation of the HRI kinase. We show that an inhibitor of heme biosynthesis or knockdown of ALAS1 results in HRI activation, while knockdown of HRI blocks upregulation of ATF4 by ONC201. Knockdown of ClpP rescues ONC201-induced downregulation of ALAS1 which blocks ONC201-induced upregulation of CHOP. Our studies identify a novel link between ClpP activation induced by ONC201 treatment and ATF4 upregulation, via the ClpP/ALAS1◊HRI◊ATF4/CHOP pathway. However, PG3 does not inhibit ALAS1, reduce its expression or therefore signal through ClpP. PG3 treatment did not lead to degradation of ALAS1, indicating that PG3 does not activate ClpP as ALAS1 is a known ClpP direct substrate. We are further investigating the signaling pathway that leads to PG3-induced activation of HRI. Our results suggest that different small molecule inducers of the ISR such as ONC201 and PG3 can achieve an anti-tumor effect through different pathways involving kinase HRI ultimately leading to ATF4/CHOP activation and tumor cell death.
Citation Format: Xiaobing Tian, Wafik S. El-Deiry. TIC10/ONC201 activates ClpP to degrade ALAS1 while PG3 does not degrade ALAS1 in pathway to HRI, ATF4 and CHOP activation leading to tumor cell death. [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 4959.
Abstract 4968: Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut cancers
Authors: Simoneau Antoine , Wu Hsin-Jung , Bandi Madhavi , Lazarides Katherine , Sun Sining , Liu Shangtao , Meier Samuel , Choi Ashley , Zhang Hongxiang , Shen Binzhang , Whittington Douglas , Sudsakorn Sirimas , Zhang Wenhai , Yu Yi , Liu Yong , Liang Colin , Palmieri Michael , Chen Yingnan , Haines Brian , Tsai Alice , Zhang Minjie , Huang Alan , Andersen Jannik , Feng Tianshu , Throner Scott , Maxwell John 
Published: April 2023

Abstract
TNG348 is a selective and potent inhibitor of the deubiquitinating enzyme USP1 specifically designed to target BRCA1/2mut vulnerabilities in breast and ovarian tumors. Here we present the biochemical, mechanistic, and in vitro and in vivo characterization of TNG348, an oral, allosteric and highly potent inhibitor of USP1. Upon treatment, TNG348 causes loss of viability in a panel of breast and ovarian BRCA1/2mut cancer cell lines and displays dose-dependent tumor growth inhibition in BRCA1/2mut xenograft models. Furthermore, TNG348 activity extends beyond BRCA1/2mut models with PARP inhibitor (PARPi) sensitivity and oncogene-induced replication stress being additional features correlating with USP1 inhibitor sensitivity based on cell line panel and CRISPR screening results. We show that TNG348 induces cell death through a pathway that is distinct from PARPi and TNG348 demonstrates robust synergy when combined with first- or second-generation PARPi. The clinical development plan intends to evaluate TNG348 in patients with BRCA1/2 mutations as single agent and in combination with PARP1i in patients naïve to PARPi and with prior PARPi treatment history.
Citation Format: Antoine Simoneau, Hsin-Jung Wu, Madhavi Bandi, Katherine Lazarides, Sining Sun, Shangtao Liu, Samuel Meier, Ashley Choi, Hongxiang Zhang, Binzhang Shen, Douglas Whittington, Sirimas Sudsakorn, Wenhai Zhang, Yi Yu, Yong Liu, Colin Liang, Michael Palmieri, Yingnan Chen, Brian Haines, Alice Tsai, Minjie Zhang, Alan Huang, Jannik Andersen, Tianshu Feng, Scott Throner, John Maxwell. Characterization of the clinical development candidate TNG348 as a potent and selective inhibitor of USP1 for the treatment of BRCA1/2mut 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 4968.
Abstract 5055: Targeting BRAFV600E/NRASQ61K-melanoma brain metastases by pharmacological intervention modulating ER/redox stress and EMT
Authors: Jandova Jana , Park Sophia L. , Snell Jeremy A. , Wondrak Georg T. 
Published: April 2023

Abstract
Intracranial melanoma metastases originating from peripheral malignancy remain a frequent clinical condition with unsatisfactory pharmacological options. After screening a focused library of clinical artemisinin-combination therapeutic (ACT) antimalarials with established brain availability, we report here that an oral antimalarial regimen {(R,S)/(S,R)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol; BQPM} blocks (i) melanoma cell invasiveness and EMT-related gene expression and (ii) tumor growth in a bioluminescent murine model of BRAFi-resistant intracranial melanoma. First, we examined apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi-resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 versus BRAFi-resistant A375-BRAFV600E/NRASQ61K). Among ACT antimalarials tested, BQPM was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression-array analysis (A375-BRAFV600E/NRASQ61 versus A375-BRAFV600E/NRASQ61K) revealed that BQPM is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede BQPM-induced loss of viability. Moreover, we observed that BQPM treatment blocked EMT-related gene expression and phenotypic invasiveness in both BRAFi-sensitive and -resistant human cell lines, observable also in murine CNS-tropic Ret-melanoma cells. These data (combined with clinical evidence that documents brain availability of BQPM) suggest that blockade of brain metastasis and inhibition of intracranial tumor growth, even if BRAFi-resistant, can be achieved using BQPM as a repurposed ACT-antimalarial.
Citation Format: Jana Jandova, Sophia L. Park, Jeremy A. Snell, Georg T. Wondrak. Targeting BRAFV600E/NRASQ61K-melanoma brain metastases by pharmacological intervention modulating ER/redox stress and EMT. [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 5055.
Abstract 5111: VentX-modulated tumor associated macrophages revert immune suppression in tumor microenvironment and promote efficacy of gemcitabine against pancreatic cancer
Authors: Le Joanna , Gao Hong , Le Yi , Richards William , Radig Scott , Bleday Ronald , Clancy Thomas , Zhu Zhenglun 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with median survival of less than one year and overall 5-year survival less than 5%. Gemcitabine has been the cornerstone in PDA treatment, yet its efficacy remains limited. Over the past decades, extensive investigations suggested a role of tumor microenvironment (TME) in rendering PDA resistance to gemcitabine, however, its underlying mechanism remained largely unknown. Cellular profiling has revealed the macrophages as a major immune cell component of PDA-TME. Our recent study showed that the expression of the homeobox protein VentX, a master regulator of macrophage plasticity, is significantly down-regulated in tumor associated macrophages (TAMs) of PDA. We demonstrated that restoration of VentX expression in PDA-TAMs polarizes the TAMs from a pro-tumor M2-like phenotype to an anti-tumor M1-like phenotype. We showed further that VentX-regulated-TAMs (VentX-TAMs) revert immune suppression of PDA-TME by inhibiting CD4 Treg differentiation and by promoting CD8 proliferation and activation. Using a newly developed tumor immune microenvironment-enabling model system (TIME-EMS), we showed that VentX-TAMs drastically promote efficacy of gemcitabine against PDA for about 4-fold but not cytotoxicity on normal pancreatic tissue. As such, our data suggested a function of VentX-TAMs to promote chemosensitivity of gemcitabine and to improve PDA prognosis.
Citation Format: Joanna Le, Hong Gao, Yi Le, William Richards, Scott Radig, Ronald Bleday, Thomas Clancy, Zhenglun Zhu. VentX-modulated tumor associated macrophages revert immune suppression in tumor microenvironment and promote efficacy of gemcitabine against pancreatic 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 5111.