WP1066

The degree of cellular uptake for the self-assembled LNPs formed by the pegylated CGKRK-lipopeptide were found to be significantly higher than that for the self-assembled LNPs formed by the pegylated RGDK-lipopeptide in MCF-7, MDA-MB-231, HEK-293 and HFF cells.  Notably, about 60% TNBCs (MDA-MB-231 cells) were killed upon treatment with commercially available potent JAK2 inhibitor (WP 1066) loaded LNPs of the pegylated RGDK-lipopeptide. Contrastingly, the same treatment killed only about 20% non-cancerous HEK-293 cells. The self-assembled pegylated LNPs described herein open the door for undertaking preclinical studies in animal models for TNBCs.

In addition, METTL14-mediated m6A modification of SOCS3 inactivated the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, and in the METTL14-overexpressing TC cells, silencing SOCS3-induced upregulation of cell proliferation, EMT and suppression of apoptosis was reversed by JAK2/STAT3 inhibitor AG490 and WP1066. Together, we indicated that METTL14/m6A/SOCS3/ JAK2/STAT3 axis play an important role in the progression of TC.

We demonstrated WP1066 could inhibit colorectal cancer angiogenesis by blocking both the PDPN/CCL2/STAT3 feedback loop in CAFs and the STAT3 signaling pathway in endothelial cells. Altogether, our study suggests that STAT3 could be a potential therapeutic target for blocking angiogenesis in colorectal cancer. We provide theoretical basis and new therapeutic strategies for the clinical treatment of colorectal cancer.

P2, N=39, Recruiting, Northwestern University | Not yet recruiting --> Recruiting | Trial primary completion date: Dec 2025 --> Dec 2027

Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may layfoundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian cancer.

Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide or WP1066, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9, or signal transducer and activator of transcription 3 (STAT3). With our analysis pipeline, we gain single-cell level, three-dimensional information, as well as insights into the morphological appearance of the tumor cells.

P2, N=39, Not yet recruiting, Northwestern University | Trial completion date: Mar 2026 --> Dec 2028 | Initiation date: Jun 2023 --> Dec 2024 | Trial primary completion date: Mar 2025 --> Dec 2025

Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV-Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs.

Liposomally co-loaded STAT3siRNA and WP1066 (a commercially available inhibitor of the JAK2/STAT3 pathway) were used as cancer therapeutics...Importantly, the findings in tumor growth inhibition studies revealed that only in vivo DC-targeted genetic immunization or only tumor-selective chemotherapy using the presently described systems failed to eradicate the established mouse melanoma. The presently described combination approach is expected to find future applications in combating various malignancies (with well-defined surface antigens).

P2, N=39, Not yet recruiting, Moleculin Biotech, Inc.

Co-administration of a reduced effective dose of WP1066 is necessary with STING agonist 8803 to effectively enhance the anti-glioma immune reactivity in the tumor microenvironment.

P1, N=10, Completed, Emory University | Recruiting --> Completed | N=36 --> 10 | Trial completion date: Jul 2023 --> Feb 2023 | Trial primary completion date: Jul 2023 --> Feb 2023

It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies.

Immune analyses indicated that WP1066 inhibited systemic immune p-STAT3. WP1066 had an MFD identified at 8 mg/kg which is the target allometric dose based on prior preclinical modeling in combination with radiation therapy and a Phase II study is being planned for newly diagnosed MGMT promoter unmethylated glioblastoma patients.

STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

P1, N=8, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Jul 2022 --> Mar 2022 | Trial primary completion date: Jul 2022 --> Mar 2022

P1, N=8, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=33 --> 8 | Trial completion date: Jul 2021 --> Jul 2022 | Trial primary completion date: Jul 2021 --> Jul 2022

Orexin A could suppress the expression of exosomal PD-L1 in colon cancer cells and promote T cells activity by inhibiting JAK2/STAT3 signaling pathway.

As a specific micromolecule inhibitor of FAP, SP13786 indirectly inhibits the migration and invasion of A549 cells by affecting exosomes of CAFs. The possible mechanism is to inhibit the phosphorylation of Stat3 and thus affect the EMT of A549 cells.

Transfection of shRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) both led to sensitization of A549/GR cells towards IR...CXCR4 expression was further correlated with STAT3 activation, and suppression of STAT3 activity with siSTAT3 or a specific inhibitor (WP1066) significantly stymied the colony-forming ability and increased γ-H2AX foci formation in A549/GR cells, indicating that CXCR4-mediated STAT3 signaling plays an important role for IR resistance in NSCLC cells. Finally, CXCR4/STAT3 signaling was mediated with the upregulation of Slug and downregulation of the same with siRNA, which heightened IR sensitivity in NSCLC cells. Our data collectively suggests that CXCR4/STAT3/Slug axis is paramount for IR resistance of NSCLC cells, and can be regarded as a therapeutic target to enhance the IR sensitivity of this devastating cancer.

Subsequently, the STAT3 pathway in astrocytes was inhibited with WP1066 to determine the role of STAT3-mediated astrocyte reactivity, specifically, in brain metastasis...Inhibition of STAT3-mediated astrocyte reactivity in rats with brain metastases restored cerebrovascular function, as shown by in vivo imaging, and limited cerebrovascular changes associated with tumor growth. Together these findings suggest that inhibiting STAT3-mediated astrocyte reactivity may confer significant improvements in neurological outcome for patients with brain metastases and could potentially be tested in other brain tumors.

The overexpression of CSK1B could promote cell viability and invasion of PTC cells through activation of STAT3/PD-L1 signaling and Akt phosphorylation.

Conversely, inhibition of STAT3 activation using sub‑lethal doses of WP1066, completely abolished the cytoprotective effect of Epo. These observations indicated that Epo was able to hinder the cytotoxic effect of cisplatin in cervical cancer cells by activating anti‑apoptotic responses regulated by STAT3.

This study indicates that the combination of STAT3 inhibition and WBRT enhances the therapeutic effect against gliomas in the CNS by inducing dendritic cell and T cell interactions in the CNS tumor.

Nuclear phospho-STAT3 was increased dramatically following DEX treatment, and TMPRSS2 upregulation was significantly suppressed by the STAT3 inhibitor WP1066...Additionally, a reduction in ECM components fibronectin, collagen IV, matrix metallopeptidase 16, and Tenascin C was detected after DEX treatment, but was prohibited when TMPRSS2 or Rab11 were knocked down. This study provides evidence that DEX upregulates TMPRSS2 expression via the activation of α2-adrenergic receptor/STAT3 signaling and promotes TMPRSS2 secretion in exosomes through Rab11, thus resulting in degradation of the ECM, which is responsible for DEX-induced migration of breast cancer cells.

Importantly, we show that i.v. injection of WP1066 (a commercially sold small molecule inhibitor of JAK/STAT pathway) & STAT3siRNA co-solubilized within the liposomes of RGDK-lipopeptide leads to significant inhibition (>350% compared to the untreated mice group) of orthotopically growing mouse glioblastoma. The present strategy may find future use in combating GBM.

P1, N=36, Recruiting, Emory University | Not yet recruiting --> Recruiting