PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Thura, Min; Al-Aidaroos, Abdul Qader; Yong, Wei Peng; Kono, Koji; Gupta, Abhishek; Lin, You Bin; Mimura, Kousaku; Thiéry, Jean Paul; Goh, Boon Cher; Tan, Patrick; Soo, Ross A.; Hong, Cheng William; Wang, Lingzhi; Lin, Suling Joyce; Chen, Elya; Rha, Sun Young; Chung, Hyun Cheol; Li, Jie; Nandi, Sayantani; Yuen, Hiu Fung; Zhang, Shudong; Guan, Yeoh Khay; So, Jimmy Bok Yan; Zeng, Qi

doi:10.1172/jci.insight.87607

Cited by 49 publications

(67 citation statements)

References 53 publications

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“…Most recently, a novel PRL3 antibody that showed strong antitumor activity in vitro and in vivo has been developed, although the mechanism by which this antibody targets intracellular PRL3 is not completely understood (Fig. 1D; ref. 43).…”

Section: Proof Of Concept For Targeting the Prl Phosphatasesmentioning

confidence: 99%

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

et al. 2017

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Protein tyrosine phosphatases (PTP) are exciting and novel targets for cancer drug discovery that work in concert with protein tyrosine kinases (PTK) in controlling cellular homeostasis. Given the activating role that some PTKs play in initiating growth factor-mediated cellular processes, PTPs are usually perceived as the negative regulators of these events and therefore tumor suppressive in nature. However, mounting evidence indicate that PTPs do not always antagonize the activity of PTKs in regulating tyrosine phosphorylation, but can also play dominant roles in the initiation and progression of signaling cascades that regulate cell functions. It follows, therefore, that PTP malfunction can actively contribute to a host of human disorders, in particular, cancer, metabolic syndromes, and autoimmune diseases. The Src homology domain containing phosphatase 2 (SHP2) and the three-membered family of phosphatases of regenerating liver (PRL) are infamously oncogenic members of the PTP superfamily. Both are established regulators of major cancer pathways such as Ras/ ERK1/2, Src, JAK/STAT, JNK, NF-κB, and PTEN/PI3K/AKT. Furthermore, upregulation, mutation, or other dysregulation of these PTPs has been positively correlated with cancer initiation and progression. This review will provide topical coverage of target validation and drug discovery efforts made in targeting these oncogenic PTPs as compelling candidates for cancer therapy.

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Section: Proof Of Concept For Targeting the Prl Phosphatasesmentioning

confidence: 99%

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

et al. 2017

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“…While all of these small molecules target the entire PTP4A family, including PTP4A1, PTP4A2, and PTP4A3, the anti-cancer effects of these inhibitors have been demonstrated in cancer cells or xenotransplantation models. In addition, Qi Zeng's group has successfully developed humanized PTP4A3 antibody, which can specifically target PTP4A3 expressing tumors but not PTP4A1 expressing tumors [20,39]. These efforts support the concept that phosphatases are in fact druggable and suggest that PTP4A3 is a feasible therapeutic target in cancer.…”

Section: Introductionmentioning

confidence: 83%

Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

Min

Haney

Blackburn

2019

Preprint

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Highlights• A subset of T-cell Acute Lymphoblastic Leukemia (T-ALL) highly express the phosphatase PTP4A3• PTP4A3 expression promotes leukemia development in zebrafish T-ALL models• Loss of PTP4A3 prevents T-ALL engraftment in mouse xenograft models • Knock-down or small molecule inhibition of PTP4A3 prevents T-ALL migration in part via modulation of SRC signaling.Abstract T-cell Acute Lymphoblastic Leukemia (T-ALL) is an aggressive blood cancer, and currently, there are no immunotherapies or molecularly targeted therapeutics available for treatment of this malignancy. The identification and characterization of genes and pathways that drive T-ALL progression is critical for development of new therapies for T-ALL. Here, we determined that Protein Tyrosine Phosphatase 4A3 (PTP4A3) plays a critical role in disease initiation and progression by promoting cell migration in T-ALL. PTP4A3 expression was upregulated in patient T-ALL samples at both the mRNA and protein levels compared to normal lymphocytes. Inhibition of PTP4A3 function with a small molecule inhibitor and knock-down of PTP4A3 expression using short-hairpin RNA (shRNA) in human T-ALL cells significantly impeded T-ALL cell migration capacity in vitro and reduced their ability to engraft and proliferate in vivo in xenograft mouse models. Additionally, PTP4A3 overexpression in a Myc-induced zebrafish T-ALL model significantly accelerated disease onset and shortened the time needed for cells to enter blood circulation. Reverse phase protein array (RPPA) revealed that manipulation of PTP4A3 expression levels in T-ALL cells directly affected the SRC signaling pathway,which plays a well-characterized role in migratory behavior of several cell types. Taken together, our study revealed that PTP4A3 is a key regulator of T-ALL migration via SRC signaling, and suggests that PTP4A3 plays an important role as an oncogenic driver in T-ALL.

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“…Many studies have described a rise in PRL-3 expression during gastric cancer progression, which correlated with poor prognosis in these patients, suggesting that PRL-3 could serve as a potential prognostic biomarker in human gastric cancer [87][88][89][90]. Indeed, high levels of PRL-3 in primary tumors in the gastric mucosa correlated with advanced grades of cancer [91][92][93][94] and was highly expressed in metastases [95][96][97][98]. PRL-3 genomic amplification was proposed to be one of the predominant mechanisms inducing its overexpression, especially in more advanced stages [99].…”

Section: Prl Expression In Tumors and Metastases: Emerging Biomarker mentioning

confidence: 99%

Physiological and oncogenic roles of the PRL phosphatases

et al. 2018

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The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL-1, -2, -3; gene name PTP4A1, PTP4A2, PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport.

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PRL3-zumab, a first-in-class humanized antibody for cancer therapy

Cited by 49 publications

References 53 publications

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

Therapeutic Targeting of Oncogenic Tyrosine Phosphatases

Protein Tyrosine Phosphatase 4A3 (PTP4A3) modulates Src signaling in T-cell Acute Lymphoblastic Leukemia to promote leukemia migration and progression

Physiological and oncogenic roles of the PRL phosphatases

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