Delving into the Latest Updates on NP-G2-044 with Synapse

Aim:Fascin is an actin-binding protein that promotes tumor metastasis. The inhibition of fascin on the progress of non-small cell lung cancer (NSCLC) is not very clear. Hence, this study explored the potential effect of NP-G2-044, a novel fascin inhibitor, in human NSCLC lines and the Lewis lung cancer (LCC) mice model.Methods:The growth of cells was analyzed via CCK-8 assays, and the flow cytometry was adopted for cell cycle and apoptosis analysis, as well as the migration and invasion of NSCLC cells with or without NP-G2-044. The therapy of NP-G2-044, which synergizes with cisplatin and PD-1, was evaluated in the established xenograft Lewis’s lung cancer of mice.Results:Fascin was overexpressed in human NSCLC cells, and inhibition of fascin by NP-G2-044 attenuated NSCLC cell growth and remarkably undermined the ability of migration and invasion in vitro, which was related to the reduced epithelialmesenchymal transition (EMT) including downregulation of N-cadherin and vimentin, and upregulation of E-cadherin. Further results implied that the above changes may be partially mediated by the Wnt/β-catenin pathway. In vivo, NP-G2-044 slowed down tumor development and enhanced overall survival alone, leading to synergistic anticancer effects with cisplatin or PD-1 inhibitor.Conclusion:Fascin inhibition could inhibit the metastasis of NSCLC and has the potential to enhance the efficacy of cisplatin and PD-1 inhibitors by blocking the Wnt/β- catenin pathway.

01 May 2024·The Journal of Pathology

KAT8/SIRT7‐mediated Fascin‐K41 acetylation/deacetylation regulates tumor metastasis in esophageal squamous cell carcinoma

Article

Author: Li, Da-Jia ; Zhang, Zhi-Da ; Zhao, Hui ; Pan, Jin-Mei ; Wang, Shao-Hong ; Liao, Lian-Di ; Li, En-Min ; Dong, Geng ; Xu, Xiu-E ; Huang, Qing-Feng ; Guo, Zhen-Chang ; Cheng, Yin-Wei ; Wu, Zhi-Yong ; Nie, Ping-Juan ; Zhang, Kai ; Wu, Jian-Yi ; Wen, Bing ; Zhong, Jin-Ling ; Shi, Wen-Qi ; Xu, Li-Yan

AbstractFascin actin‐bundling protein 1 (Fascin) is highly expressed in a variety of cancers, including esophageal squamous cell carcinoma (ESCC), working as an important oncogenic protein and promoting the migration and invasion of cancer cells by bundling F‐actin to facilitate the formation of filopodia and invadopodia. However, it is not clear how exactly the function of Fascin is regulated by acetylation in cancer cells. Here, in ESCC cells, the histone acetyltransferase KAT8 catalyzed Fascin lysine 41 (K41) acetylation, to inhibit Fascin‐mediated F‐actin bundling and the formation of filopodia and invadopodia. Furthermore, NAD‐dependent protein deacetylase sirtuin (SIRT) 7‐mediated deacetylation of Fascin‐K41 enhances the formation of filopodia and invadopodia, which promotes the migration and invasion of ESCC cells. Clinically, the analysis of cancer and adjacent tissue samples from patients with ESCC showed that Fascin‐K41 acetylation was lower in the cancer tissue of patients with lymph node metastasis than in that of patients without lymph node metastasis, and low levels of Fascin‐K41 acetylation were associated with a poorer prognosis in patients with ESCC. Importantly, K41 acetylation significantly blocked NP‐G2‐044, one of the Fascin inhibitors currently being clinically evaluated, suggesting that NP‐G2‐044 may be more suitable for patients with low levels of Fascin‐K41 acetylation, but not suitable for patients with high levels of Fascin‐K41 acetylation. © 2024 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

01 Jan 2023·Technology in Cancer Research & Treatment

The Role of Fascin-1 in Human Urologic Cancers: A Promising Biomarker or Therapeutic Target?

Review

Author: Bian, Qiang ; Zhang, Naibin ; Wang, Qianqian ; Chen, Huiyuan ; Gao, Yankun ; Ma, Xiaolei ; Shi, Ying ; Li, Xiangling ; Yu, Honglian ; Zhao, Zhankui

Human cancer statistics show that an increased incidence of urologic cancers such as bladder cancer, prostate cancer, and renal cell carcinoma. Due to the lack of early markers and effective therapeutic targets, their prognosis is poor. Fascin-1 is an actin-binding protein, which functions in the formation of cell protrusions by cross-linking with actin filaments. Studies have found that fascin-1 expression is elevated in most human cancers and is related to outcomes such as neoplasm metastasis, reduced survival, and increased aggressiveness. Fascin-1 has been considered as a potential therapeutic target for urologic cancers, but there is no comprehensive review to evaluate these studies. This review aimed to provide an enhanced literature review, outline, and summarize the mechanism of fascin-1 in urologic cancers and discuss the therapeutic potential of fascin-1 and the possibility of its use as a potential marker. We also focused on the correlation between the overexpression of fascin-1 and clinicopathological parameters. Mechanistically, fascin-1 is regulated by several regulators and signaling pathways (such as long noncoding RNA, microRNA, c-Jun N-terminal kinase, and extracellular regulated protein kinases). The overexpression of fascin-1 is related to clinicopathologic parameters such as pathological stage, bone or lymph node metastasis, and reduced disease-free survival. Several fascin-1 inhibitors (G2, NP-G2-044) have been evaluated in vitro and in preclinical models. The study proved the promising potential of fascin-1 as a newly developing biomarker and a potential therapeutic target that needs further investigation. The data also highlight the inadequacy of fascin-1 to serve as a novel biomarker for prostate cancer.

100 Deals associated with NP-G2-044

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	US	Novita Pharmaceuticals, Inc.	07 Dec 2021
Colonic Cancer	Discovery	US	TGen Drug Development Services	03 Nov 2017
Krukenberg Tumor	Discovery	US	Novita Pharmaceuticals, Inc.	03 Nov 2017
Krukenberg Tumor	Discovery	US	TGen Drug Development Services	03 Nov 2017
Lymphoma	Discovery	US	Novita Pharmaceuticals, Inc.	03 Nov 2017
Lymphoma	Discovery	US	TGen Drug Development Services	03 Nov 2017
metastatic non-small cell lung cancer	Discovery	US	Novita Pharmaceuticals, Inc.	03 Nov 2017
metastatic non-small cell lung cancer	Discovery	US	TGen Drug Development Services	03 Nov 2017
Metastatic Prostate Carcinoma	Discovery	US	TGen Drug Development Services	03 Nov 2017
Pancreatic Carcinoma	Discovery	US	TGen Drug Development Services	03 Nov 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03199586 (ASCO2021) Manual	Phase 1	Metastatic Solid Tumor \| Neoplasms	23	NP G2 044	(vpktgphwpu) = dwkrmnpzwv vgxhkqjjyl (ogvumltyhh ) View more	Positive	20 May 2021
				NP G2 044 (Ovary + Last Prior Therapy:CSF1R Inhibitor)	wuebvucaut(qtxysmpfbl) = ixttzqrgzl hgielmcohq (ngeqagchuh )