bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4909: Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201
Authors: Uruchurtu Ashley Sanchez Sevilla , Liguori Nicholas , Zhang Leiqing , Huntington Kelsey , Zhou Lanlan , Lee Young , Abbas Abbas E. , Azzoli Christopher G. , El-Deiry Wafik S. 
Published: April 2023

Abstract
We previously explored the combination of novel imipridone TIC10/ONC201 and small molecule RNA polymerase inhibitor lurbinectedin as a potentially effective treatment regimen for small cell lung cancer (SCLC). Data from cell viability experiments demonstrated synergistic killing of SCLC cells with minimal death of healthy control cells. Analysis of intracellular proteins via Western blot indicated that combinatorial treatment induces the integrated stress response, DNA damage/cell cycle checkpoint responses, and increased apoptosis of tumor cells. We have utilized the Luminex 200 platform to perform analyses of cytokine levels in SCLC cell lines with various genetic alterations before and after ONC201 and lurbinectedin treatment. Our results revealed significant changes in cytokine levels following treatment indicating potential immunomodulatory and angioregulatory effects of ONC201 and lurbinectedin. CCL3, known to recruit and activate granulocytes, was found to be elevated by treatment with lurbinectedin, ONC201 and combination versus control. Angiopoietin 1, which contributes to blood vessel maturation, and angiopoietin 2, which promotes neovascularisation, were elevated by all drug treatments in H1882 SCLC cells. Our ongoing studies are further analysing the importance of specific cytokines in tumor vascularity and in recruitment and killing of SCLC cells by immune cells. Results from these experiments are helping to elucidate the molecular mechanisms underlying SCLC, its immune landscape, and treatment response.
Citation Format: Ashley Sanchez Sevilla Uruchurtu, Nicholas Liguori, Leiqing Zhang, Kelsey Huntington, Lanlan Zhou, Young Lee, Abbas E. Abbas, Christopher G. Azzoli, Wafik S. El-Deiry. Molecular analysis of small cell lung cancer provides insights into mechanism of action underlying the novel drug combination of lurbinectedin and TIC10/ONC201. [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 4909.
Abstract 4929: ICX-101, a novel MYC inhibitor, shows antitumor activity in patient-derived cells of advanced lung cancer with high MYC expression
Authors: Choi Wonyoung , Jeong Kyung-Chae , Park Seog-Yun , Kim Sunshin , Kang Eun Hye , Hwang Mihwa , Han Ji-Youn 
Published: April 2023

Abstract
Background: MYC is an attractive therapeutic target in lung cancer. ICX-101 is a novel potent, selective small molecule that directly inhibits the binding of MYC/MAX dimers to the DNA binding sequence E-box. Here, we show that ICX-101 shows antitumor activity in patient-derived cells (PDC) of advanced lung cancer and that the drug responses are correlated with the MYC expression levels.
Methods: PDCs of lung cancer were treated with ICX-101, and the area under the dose-response curve (AUC) was measured as the readout for antitumor efficacy. MYC expression level of each PDC was measured with the fold expression of mRNA compared to the normal lung tissue. The patient’s clinical data and survival outcomes were analyzed to correlate with the drug responses of PDCs.
Results: We collected 100 PDCs from 82 lung cancer patients. The histologic types included adenocarcinoma (N = 82), squamous cell carcinoma (N = 10), non-small cell lung cancer (NSCLC) not otherwise specified (NOS) (N = 4), and small cell lung cancer (SCLC, N = 4). PDCs derived from SCLC showed higher MYC expression levels than NSCLC (P = 0.004). MYC was a prognostic factor, as the patient groups with the top and bottom 25 percentiles of MYC mRNA expression had an overall survival of 932.5 and 256 days, respectively (P = 0.029). However, MYC expression was predictive for the response to ICX-101, as the PDCs with the top 25 percentiles of MYC levels showed markedly lower AUC values than those with the bottom 25 percentile (P &lt; 0.001). Additionally, the MYC mRNA levels and AUC values were inversely correlated with statistical significance (R = -0.46, P &lt; 0.001).
Conclusion: ICX-101 is a potent MYC inhibitor that shows antitumor activity in lung cancer PDCs. Our results suggest the potential of ICX-101 as a possible therapeutic option in advanced lung cancer with high MYC expressions.
Citation Format: Wonyoung Choi, Kyung-Chae Jeong, Seog-Yun Park, Sunshin Kim, Eun Hye Kang, Mihwa Hwang, Ji-Youn Han. ICX-101, a novel MYC inhibitor, shows antitumor activity in patient-derived cells of advanced lung cancer with high MYC expression. [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 4929.
Abstract 494: BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid tumors
Authors: Wang Pingping , Yang Rongwen , Sun Yun , Ju Xuepeng , Zhao Jiayu , Liu Yanju , Liu Xiaoyun , Zou Zhengyao , Ren Jialin , Wang Min , Chen Haibo , Yi Xuegang , Zhang Jian , Ma Teng , Cheng Gaoliang , Liu Lijia , Guo Jing , Liu Xiangyong , Lan Hong , Ding Lieming , Wang Jiabing 
Published: April 2023

Abstract
The most observed alteration in clear cell renal cell carcinoma (ccRCC) is the inactivation of the tumor suppressor von Hippel-Lindau (VHL) E3 ligase due to genetic predisposition, somatic mutations, or methylation. Loss of VHL can lead to hypoxia-inducible factor 2α (HIF-2α) accumulation and elevated expression of HIF target genes, such as VEGFA, many of which facilitate angiogenesis, proliferation, and metastasis of ccRCC. Therefore, inhibiting HIF-2α has become a new strategy for the treatment of ccRCC. Here, we present the discovery of BPI-452080, a selective small molecule HIF-2α inhibitor. In VHL defective ccRCC cell lines, BPI-452080 potently and selectively blocked the heterodimerization of HIF-2α with HIF-1β, but not that of HIF-1α with HIF-1β. It inhibited the downstream hypoxia-responsive gene transcription and VEGFA protein secretion. In multiple xenograft mouse models, oral administration of BPI-452080 significantly inhibited tumor growth in a dose-dependent manner. BPI-452080 demonstrated good PK/PD correlation in the 786-O xenograft model after a single dosing, as shown by a concentration-dependent inhibition of VEGFA secretion in plasma and a reduction of the mRNA levels of VEGFA, CXCR4, CCND1, and GLUT1 genes in tumor tissue. Moreover, BPI-452080 exhibited good bioavailability in multiple pre-clinical species, favorable ADME properties, and good tolerance in toxicology studies. In conclusion, BPI-452080 is a potent, selective, and orally bioavailable HIF-2α inhibitor which presents a novel therapeutic option for ccRCC, von Hippel-Lindau disease, and other solid tumors. BPI-452080 is planned to enter Phase I clinical trial in China in early 2023.
Citation Format: Pingping Wang, Rongwen Yang, Yun Sun, Xuepeng Ju, Jiayu Zhao, Yanju Liu, Xiaoyun Liu, Zhengyao Zou, Jialin Ren, Min Wang, Haibo Chen, Xuegang Yi, Jian Zhang, Teng Ma, Gaoliang Cheng, Lijia Liu, Jing Guo, Xiangyong Liu, Hong Lan, Lieming Ding, Jiabing Wang. BPI-452080: A potent and selective HIF-2α inhibitor for the treatment of clear cell renal cell carcinoma, von Hippel-Lindau disease, and other solid 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 494.
Abstract 4946: TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models
Authors: MacDougall John R. , Bradley John , Mak Raymond , Dhawan Neil , Chen Wei 
Published: April 2023

Abstract
PI3Kα is frequently mutated in a variety of cancer types, and the PI3K-AKT signaling axis also plays a role in insulin signaling and glucose homeostasis. TOS-358 is a highly selective first-in-class covalent inhibitor of PI3Kα and is currently in clinical development in multiple solid malignancies. Interestingly, TOS-358 potently and specifically inhibits PI3Kα deeply and durably, but does not induce significant hyperglycemia in a variety of animal models. TOS-358 has consistently demonstrated superior efficacy comparing to reversible PI3Kα inhibitors (ATP-competitive and Allosteric) across 30+ different PDX and CDX mutant PI3Kα dependent cancer models. Detailed metabolic studies also revealed TOS-358 does not induce significant hyperglycemia effects in mice, rats and dogs at efficacious doses, which mirrors previous finding that show that PI3Kα knockout does not induce significant hyperglycemia. Furthermore, we elucidate that previous reversible PI3Kα inhibitors lead to dramatic hyperglycemia due to their potent inhibition of multiple PI3K isoforms at effective concentrations of the molecules in a cellular setting. This data reveals that highly specific and potent covalent inhibition of PI3Kα leads to dramatically superior efficacy and an improved safety profile.
Citation Format: John R. MacDougall, John Bradley, Raymond Mak, Neil Dhawan, Wei Chen. TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal 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 4946.
Abstract 4979: Evaluation of heme inhibitory therapy in combination with radiation of lung cancer
Authors: Salamat Narges , Wang Tianyuan , Berisha Eranda , Castro Maria Del Carmen Chacon , Ashrafi Adnin , Saha Debabrata , Mason Ralph P. , Liu Li , Zhang Li 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer-related death in the United States, with a 5-year survival rate of less than 25%. While most lung cancer patients receive radiation therapy, radioresistance severely impacts treatment outcomes. Thus, development of therapeutics to potentiate durable response to radiation therapy may be key to improving treatment outcomes. Research in our lab has previously implicated heme, a central biosynthetic molecule with important functions in diverse molecular and cellular processes, in lung cancer development and progression. To target heme, we designed heme-sequestering protein 2 (HeSP2) which displays potent anti-tumor activity in mouse tumor models. By decreasing tumor metabolic demand through heme sequestration, HeSP2 can significantly alleviate tumor hypoxia, a dominant radioresistance mechanism. Tumor hypoxia correlates with poor clinical outcomes by acting via multiple mechanisms such as inhibiting radiation-induced DNA damage and inducing the HIF-1 pathway that leads to antioxidant generation. Here, our preliminary data show that HeSP2 potentiates the antitumor efficacy of ionizing radiation. To see the effect of HeSP2 in combination with radiotherapy, in summary we subcutaneously implanted A549-luc, NSCLC cell lines with mutation in Kras and KLB1 in SCID mice. After 1-2 weeks mice were treated with saline (Control), HeSP2(25 mg/kg, i.v, twice a week), radiation (5 Gray, once per week at week 2 and 3), and HeSP2 combined with radiation (25 mg/kg, i.v, twice a week plus 5 Gray, once per week at week 2 and 3. Tumor tissues were harvested, processed and paraffin embedded for immunohistochemistry (IHC). Preliminary results indicate HeSP2 in combination with radiation reduce the levels of multiple angiogenic markers and vascular markers as well as microvessel density. These results indicate that heme sequestration in combination with radiation can be an effective strategy for suppressing lung tumors.
Citation Format: Narges Salamat, Tianyuan Wang, Eranda Berisha, Maria Del Carmen Chacon Castro, Adnin Ashrafi, Debabrata Saha, Ralph P. Mason, Li Liu, Li Zhang. Evaluation of heme inhibitory therapy in combination with radiation of lung 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 4979.
Abstract 4984: Integrated platform enables KRAS-targeted drugs discovery
Authors: Liu Beibei , Li an , Zuo Xiangyang , Yang Jie , Wang Ruifeng , Fan Feifei , Shi Wenting , Gu Qingyang 
Published: April 2023

Abstract
The Kirsten rat sarcoma viral oncogene homolog (KRAS) is mutated in approximately 25% of all human cancers and is known to be a major player promoting and maintaining tumorigenesis through the RAS-MAPK pathway. Activating mutations in KRAS increase the ability for GTP-loading, making it difficult to displace, thus constitutively activate downstream MAPK pathway and promote cancer formation. Fortunately, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for KRAS inhibitor development efforts. These inhibitors, such as AMG510 and MRTX849, show promising results in patients with tumors harboring KRAS G12C mutation. While the approval of AMG510 was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors is unavoidable. Therefore, develop new drugs direct various KRAS mutants and combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.
To enable the discovery of novel KRAS inhibitors, we established a one-stop service platform, covering affinity detection of compounds to KRAS mutants, KRAS upstream and downstream protein-protein interaction detection, pathway activation detection, cell proliferation assay (2D/3D culture system), and in vivo efficacy evaluation in KRAS mutant xenograft models. Our platform provides assays on nearly all the current mainstream mutants of KRAS, such as G12C/G12D/G12R/G12S/G13D, and engineered Ba/F3 cell lines that harboring single or double KRAS mutation. In addition, we developed a panel of resistant models to KRAS G12C inhibitor that bringing a better understanding of the biological basis of drug resistance, and will serve as a new tool to optimize KRAS-G12C inhibitor regimens and combinatorial strategies. The comprehensive KRAS-targeted drug discovery platform is empowering new drug research and development.
Citation Format: Beibei Liu, an Li, Xiangyang Zuo, Jie Yang, Ruifeng Wang, Feifei Fan, Wenting Shi, Qingyang Gu. Integrated platform enables KRAS-targeted drugs discovery. [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 4984.
Abstract 4993: Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers
Authors: Stafford Jessy , Chapagai Danda , Merhej George , Pressley Justin , Nageswara-Rao Chintada , Wyatt Michael , Mcinnes Campbell 
Published: April 2023

Abstract
Polo-like kinase 1 (PLK1) has a plethora of roles within the cell of which mitotic regulation is the best characterized. This kinase is overexpressed and upregulated in cancer cells, making it an attractive target for therapeutics. Drug discovery efforts have mainly focused on the ATP binding site however have met with little clinical success to date. Targeting substrate recognition and subcellular localization through the Polo-Box domain represents an attractive alternative to generating PLK1 specific compounds and to avoid the tumor suppressor functions of PLK3. REplacement with Partial Ligand Alternatives through Computational Enrichment, REPLACE, is validated strategy used to convert peptide inhibitors of protein-protein interactions into more drug like compounds. Through the use of this methodology, we have discovered promising non-ATP competitive inhibitors based on a 2-(4-AlkylBenzamido) Benzoic Acid (ABBA) pharmacophore which bind to the polo-box domain of PLK1. These compounds, designated as abbapolins, engage PLK1 as evidenced by their ability to block phosphorylation of TCTP, a key substrate of PLK1, induce PLK1 degradation and are potently anti-proliferative in prostate cancer cell lines. Based on these observations, lead compounds were investigated further for their pharmacokinetic properties and in vivo efficacy and key compounds showed development potential based upon preliminary results. To further investigate their potential in other tumors, selected abbapolins were tested against the NCI-60 tumor cell panel and other cancers with poor prognosis. Results indicate that neuroblastoma, lung, colorectal and certain leukemias are the most sensitive cell lines and thus provide impetus to investigate the abbapolins for difficult to treat and resistant tumors. We present the further optimization of the abbapolins to determine their structure-activity relationship and identify compounds with novel structures and improved drug-like properties. This includes their ability to engage PLK1 and anti-proliferative activities against selected cell lines that represent therapeutically challenging cancers. Furthermore, these compounds serve as chemical biology probes to elucidate roles of the PBD in conformationally regulating PLK1 activity, through in vitro experiments and specifically in the abbapolin sensitive cell lines.
Citation Format: Jessy Stafford, Danda Chapagai, George Merhej, Justin Pressley, Chintada Nageswara-Rao, Michael Wyatt, Campbell Mcinnes. Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging 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 4993.
Abstract 5004: DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma
Authors: Do Trong Phat , Khan Sajid , Zhou Daohong , Hart Matthew , McHardy Stanton , Rao Manjeet 
Published: April 2023

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is the second most significant cause of cancer-related mortality, with a 5-year survival rate of just 11%. PDACs are one of the most difficult to treat cancers, mainly because of the desmoplastic tumor microenvironment enriched with tumor-supportive extracellular matrix (ECM) and stromal cells. Unfortunately, the efficacies of current pancreatic cancer therapies are limited partly by stroma-mediated drug resistance. We reason that Discoidin Domain Receptors, which belong to the receptor tyrosine kinase family and bind to fibrillar collagens present in the ECM, may be a critical promoter of PDAC growth and progression. Though several drugs targeting DDR proteins have been developed, no inhibitors specific to DDR proteins have been developed. Moreover, those drugs have not been approved for treating PDACs.
Methods. A high throughput screen using small molecule inhibitors was performed to identify bonafide inhibitors of DDR proteins. Structural and reported-based essays were done to determine the specificity. Functional assays were performed to test the potency of the candidate inhibitors. Mechanistic studies were done using RNA-seq, real-time PCR, and western blot.
Results: Using an unbiased screening approach, we identified inhibitors that specifically target DDR proteins. Our studies revealed that small molecule inhibitors blocked the short and long-term viability as well as migration/invasion of PDAC cells. In addition, they induced apoptosis and halted the cell cycle at the G1-S checkpoint. Mechanistic studies revealed that the pro-growth signaling cascade was significantly inhibited.
Conclusions: Our results showing specific DDR inhibitors blocking the growth and progression of PDAC cells without affecting the viability of normal cells suggest that these inhibitors may serve as a safe and potent regimen for treating pancreatic cancers.
Citation Format: Trong Phat Do, Sajid Khan, Daohong Zhou, Matthew Hart, Stanton McHardy, Manjeet Rao. DDR-targeting small molecule inhibitor as a novel therapeutic for treating pancreatic ductal adenocarcinoma. [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 5004.
Abstract 501: Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations
Authors: Shen Hongling , Xu Xiaofeng , Rong Hongfei , Song Xizhen , Gao Jinheng , Chen Jie , Zhu Di , Zhao Xiangdong , Tong Jun , Zou Zhengyao , Liu Xiaoyun , Guo Jin , Xu Yan , Li Yabin , Liu Xiangyong , Chen Hong , Zhao Jiayu , Liu Yanju , Ju Xuepeng , Chen Haibo , Lan Hong , Ding Lieming , Wang Jiabing 
Published: April 2023

Abstract
The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations, such as NF2-deficiency or LATS1/2 mutations leading to hyperactivation of YAP/TAZ and subsequent activation of TEAD, have been reported in many cancers, including mesothelioma, meningioma, soft tissue sarcoma and non-small cell lung cancer. Inhibiting TEAD auto-palmitoylation by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Here we present BPI-460372, a novel small molecule that directly blocks the TEAD auto-palmitoylation. BPI-460372 covalently and irreversibly binds to the cysteine residue in the TEAD palmitoylation pocket, preventing TEAD palmitoylation and inhibiting its biological function. BPI-460372 significantly inhibits the expression of a TEAD-responsive element reporter, as well as the mRNA of downstream target genes such as CTGF and CYR61 in NF2-deficient cells. At the cellular level, BPI-460372 strongly inhibited the proliferation of tumor cells harboring Hippo pathway aberrations. BPI-460372 also significantly suppressed tumor growth in NF2-deficient or LATS1/2 mutation xenograft models. In addition, BPI-460372 exhibited excellent oral bioavailability, high exposure across multiple species, and adequate ADME properties. In conclusion, BPI-460372 is a potent and selective TEAD palmitoylation inhibitor for the treatment of solid tumors harboring Hippo pathway aberrations. It is planned to enter Phase I clinical trial in China in early 2023.
Citation Format: Hongling Shen, Xiaofeng Xu, Hongfei Rong, Xizhen Song, Jinheng Gao, Jie Chen, Di Zhu, Xiangdong Zhao, Jun Tong, Zhengyao Zou, Xiaoyun Liu, Jin Guo, Yan Xu, Yabin Li, Xiangyong Liu, Hong Chen, Jiayu Zhao, Yanju Liu, Xuepeng Ju, Haibo Chen, Hong Lan, Lieming Ding, Jiabing Wang. Discovery of BPI-460372, a potent and selective inhibitor of TEAD for the treatment of solid tumors harboring Hippo pathway aberrations [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 501.