Lack of effective therapeutics for CNS malignancies led to our long term scientific interest in brain cancers and to our previous discoveries and preclinical development of two other small molecules of distinctly different classes (a topoisomerase II inhibitor-WP744 and an inhibitor of tumor cell metabolism-WP1122) specifically directed at the treatment of CNS malignancies. Currently, WP744 is in Phase II clinical trials following a very successful Phase I study. We have subsequently focused our interest on the unique molecular target Signal Transducer and Activator of Transcription 3 (STAT3) and obtained funding through a Phase I SBIR grant. Our very promising results, supported by our numerous publications, led to the selection of WP1066 for further preclinical and clinical development leading to submission of this Phase II SBIR grant proposal. STAT3 is a molecular hub controlling the transcription of a wide array of genes important to the survival and proliferation of tumor cells. P-STAT3 is among the most frequently activated oncogenic proteins in multiple solid tumor types and has been shown to be persistently activated in most human cancers. More specifically, a large body of data has demonstrated activation of the typically quiescent p-STAT3 pathway is crucial to tumorigenesis and a predictor of poor prognosis in many malignancies including gastric, renal, breast ovarian, squamous, hepatocellular carcinoma, anaplastic large cell lymphoma, melanoma and gliomas. In addition to regulating growth and proliferation, STATs are intimately involved in the regulation of immune function. We have identified a number of profound immunological suppressive factors including Tregs, immunosuppressive cytokines, and microglia that induce T cell anergy in the microenvironment of cancer cells. This finding suggests that even if a vigorous systemic immune response were generated to an antigen target, upon encountering the tumor microenvironment these responses would be rendered functionally inert. Currently available immune activators are insufficient to overcome this immune tolerance and immunosuppression. However, a novel small molecular inhibitor of the signal transducer and activator of transcription 3 (STAT3) has demonstrated marked immune activation properties in this setting in vivo, and could be employed to potently synergize with immunotherapies for patients with cancer. Our novel small molecule inhibitor of the STAT3 activation pathway, WP1066, possesses drug- like characteristics, is orally bioavailable, crosses the blood-brain barrier, and demonstrates in vivo activity, including immune activation, in a variety of preclinical tumor models. Given this high degree of efficacy we propose studies focused on IND-directed preclinical development of this novel, first in class drug to treat CNS malignancies.
The specific aims of this proposal are focused on completion of preclinical testing of WP1066 in order to rapidly start the first in man clinical trials and include: 1) scale-up synthesis and process development for the production of API, 2) further determination of the mechanism of action, selectivity, possible resistance mechanisms of WP1066, 3) determination of the oral safety profile and absorption of WP1066, 4) synthesize and screen putative metabolites of WP1066 for safety and efficacy, 5) development and validation of a quantitative analytical methodology, 6) defining the ADME, 7) determination of dose-scheduling and performing safety pharmacology, toxicology, and toxicokinetic studies, and 8) writing the IND application for WP1066 as a treatment for CNS malignancies.
Despite multimodality therapeutic strategies employed over the past three decades, the overall survival time for glioblastoma multiforme is still less than 14 months. Due to the invasiveness of these tumors and their association with critical brain structures, complete surgical ablation is not possible and adjuvant therapy, such as chemotherapy and radiation therapy, while required still has minimal impact on the disease. Results from our SBIR Phase I studies indicated the strong likelihood that an inhibitor of STAT3 activation (such as WP1066) would be an effective inducer of cancer cell death and positive modulator of immune activation in the local environment of CNS tumors.
|Jethwa, Krishan; Wei, Jun; McEnery, Kayla et al. (2011) miRNA-mediated immune regulation and immunotherapeutic potential in glioblastoma. Clin Investig (Lond) 1:1637-1650|
|Kong, Ling-Yuan; Gelbard, Alexander; Wei, Jun et al. (2010) Inhibition of p-STAT3 enhances IFN-alpha efficacy against metastatic melanoma in a murine model. Clin Cancer Res 16:2550-61|