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Disease Domain	Count

Neoplasms	1

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Small molecule drug	1

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PLK4(Polo like kinase 4)	1

Author: Lam, Wing ; Bray, Mark Robert ; Zeng, Xiao-Yuan ; Kwok, Tsz-Ho ; Ng, Ka-Lam ; Man, Cheuk-Him ; Chan, Natalie Nok-Man ; Wong, Carmen Chak-Lui ; Dang, Chee-Chean ; Ng, Timothy Chi-Chun ; So, Chi Wai Eric ; Zheng, Li-Chuan ; Huen, Michael Shing-Yan ; Chan, Koon-Chuen ; Dou, Zhixun ; Goyama, Susumu ; Leung, Wing-Yan ; Mak, Tak Wah ; Leung, Anskar Yu-Hung

AbstractAcute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the “don’t-eat-me” signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

15 Nov 2022·Blood

Inhibition of Polo-like Kinase 4 Induced Both Cell Intrinsic and Non-Cell Intrinsic Anti-Leukemia Effects on TP53-Mutated Acute Myeloid Leukemia

Author: Leung, Wing Yan ; Lam, Wing ; Leung, Anskar Yu Hung ; Ng, Timothy Chi Chun ; Dou, Zhi Xun ; Chan, Koon Chuen ; Mak, Tak Wah ; Kwok, Tsz Ho ; Wong, Carmen Chak Lui ; Huen, Michael Shing Yan ; Zeng, Xiao Yuan ; Dang, Chee Chean ; Zheng, Li Chuan ; Man, Cheuk Him ; Ng, Ka Lam Nelson

09 Aug 2022·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma

Q1 · CROSS-FIELD

Article

Author: Chan, Cerise Yuen-Ki ; Mak, Tak Wah ; Khong, Pek-Lan ; Lee, Derek ; Bray, Mark Robert ; Cheu, Jacinth Wing-Sum ; Wong, Carmen Chak-Lui ; Law, Cheuk-Ting ; Tan, Kel Vin ; Ng, Irene Oi-Lin ; Chiu, David Kung-Chun ; Soria-Bretones, Isabel ; Cescon, David Ward ; Tse, Aki Pui-Wah ; Zhang, Misty Shuo ; Yau, Thomas Chung-Cheung ; Yuen, Vincent Wai-Hin ; Thu, Kelsie Lynn ; Wong, Bowie Po-Yee

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4 + T cells, and CD8 + T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

100 Deals associated with The Campbell Family Institute for Breast Cancer Research

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100 Translational Medicine associated with The Campbell Family Institute for Breast Cancer Research

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Pipeline

Pipeline Snapshot as of 19 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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