Background: As a bioactive composite extracted from American cockroach, Xinmailong injection (XML) is used for the

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Giant cell tumor of bone (GCT) is the most commonly reported non-malignant bone tumor in Hong Kong. This kind of tumor usually affects people aged 20–40 years. Also, it is well known for recurrence locally, especially when the tumor cannot be removed completely. Filamins are actin-binding proteins which contain three family members, filamin A, B and C. They are the products of three different genes, FLNA, FLNB and FLNC, which can generate various transcript variants in different cell types. In this study, we focused on the effects of FLNBv2 and FLNBv4 toward GCT cells. The only difference between FLNBv2 and FLNBv4 is that FLNBv4 does not contain hinge 1 region. We found that the relative abundance of FLNBv4 varies among different GCT cell lines while the expression level of FLNBv4 in normal osteoblasts was only marginally detectable. In the functional aspect, overexpression of FLNBv4 led to upregulation of RANKL, OCN, OPG and RUNX2, which are closely related to GCT cell survival and differentiation. Moreover, FLNBv4 can have a negative effect on cell viability of GCT cells when compare with FLNBv2. In conclusion, splicing variants of FLNB are differentially expressed in GCT cells and may play a role in the proliferation and differentiation of tumor cells.

PTP4A3 is a highly attractive molecular target for ovarian cancer (OvCa). Elevated levels of PTP4A3 mRNA and protein in human ovarian tumors correlate with disease progression, poor prognosis and poor survival. Genetic depletion of PTP4A3 in OvCa cell lines diminishes their ability to migrate and reduces their in vivo tumorigenicity while PTP4A3 overexpression increases tumor cell migration, invasion, and dissemination. Together, these data suggest PTP4A3 is a novel molecular target for OvCa; however, the lack of potent and selective PTP4A3 small molecule inhibitors has hindered PTP4A3’s definitive validation in OvCa and in other cancers. To drive the pharmacological validation of PTP4A3, we developed JMS-631-053 (7-imino-2-phenylthieno[3,2-c]pyridine-4,6(5H,7H)-dione), a potent (Ki=3 nM in vitro), specific, noncompetitive, PTP4A3 inhibitor. JMS-631-053 inhibited cellular migration, invasion, and colony formation in soft agar. Potent OvCa cell-based effects were observed by profiling JMS-631-053 against a panel of 8 OvCa cell lines using a 2D drug susceptibility assay, with EC50 values as low as 600 nM. Likewise, JMS-631-053 killed OvCa 3D spheroids, including those derived from high grade serous OvCa cell lines, with EC50 values as low as 300 nM. The OvCa drug resistant cell lines (i.e., A2780CP20 and HeyA8MDR) retained responsiveness to JMS-631-053 (using 2D and 3D culturing conditions) suggesting that inhibition of PTP4A3 may be a viable therapeutic strategy for chemoresistant OvCa. Preliminary data also suggests that JMS-631-053 synergizes with cisplatin when used in combination studies. Hence, JMS-631-053 will be a valuable chemical tool for further validation of PTP4A3 as an OvCa target as well as provide potential leads for future drug discovery. Citation Format: John S. Lazo, Paula Pekic, Alex Cheung, Kelley McQueeney, Joseph Salamoun, Peter Wipf, Charles N. Landen, Elizabeth R. Sharlow. Targeting PTP4A3 phosphatase in ovarian cancer with the potent noncompetitive inhibitor JMS-631-053 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3210. doi:10.1158/1538-7445.AM2017-3210