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MIAMI, FL, United States

Li B.,University of Miami | Fei D.L.,University of Miami | Flaveny C.A.,University of Miami | Dahmane N.,University of Pennsylvania | And 12 more authors.
Cancer Research | Year: 2014

The Hedgehog (HH) signaling pathway represents an important class of emerging developmental signaling pathways that play critical roles in the genesis of a large number of human cancers. The pharmaceutical industry is currently focused on developing small molecules targeting Smoothened (Smo), a key signaling effector of the HH pathway that regulates the levels and activity of the Gli family of transcription factors. Although one of these compounds, vismodegib, is now FDA-approved for patients with advanced basal cell carcinoma, acquired mutations in Smo can result in rapid relapse. Furthermore, many cancers also exhibit a Smo-independent activation of Gli proteins, an observation that may underlie the limited efficacy of Smo inhibitors in clinical trials against other types of cancer. Thus, there remains a critical need for HH inhibitors with different mechanisms of action, particularly those that act downstream of Smo. Recently, we identified the FDA-approved anti-pinworm compound pyrvinium as a novel, potent (IC50, 10 nmol/L) casein kinase-1α (CK1α) agonist. We show here that pyrvinium is a potent inhibitor of HH signaling, which acts by reducing the stability of the Gli family of transcription factors. Consistent with CK1α agonists acting on these most distal components of the HH signaling pathway, pyrvinium is able to inhibit the activity of a clinically relevant, vismodegib -resistant Smo mutant, as well as the Gli activity resulting from loss of the negative regulator suppressor of fused. We go on to demonstrate the utility of this small molecule in vivo, against the HH-dependent cancer medulloblastoma, attenuating its growth and reducing the expression of HH biomarkers. © 2014 American Association for Cancer Research.


Barham W.,Vanderbilt University | Frump A.L.,Vanderbilt University | Sherrill T.P.,Vanderbilt University | Garcia C.B.,Baylor College of Medicine | And 10 more authors.
Cancer Discovery | Year: 2013

Synovial sarcoma is an aggressive soft-tissue malignancy of children and young adults, with no effective systemic therapies. Its specific oncogene, SYT-SSX (SS18-SSX), drives sarcoma initiation and development. The exact mechanism of SYT-SSX oncogenic function remains unknown. In an SYT-SSX2 transgenic model, we show that a constitutive Wnt/β-catenin signal is aberrantly activated by SYT-SSX2, and inhibition of Wnt signaling through the genetic loss of β-catenin blocks synovial sarcoma tumor formation. In a combination of cell-based and synovial sarcoma tumor xenograft models, we show that inhibition of the Wnt cascade through coreceptor blockade and the use of small-molecule CK1α activators arrests synovial sarcoma tumor growth. We find that upregulation of the Wnt/β-catenin cascade by SYT-SSX2 correlates with its nuclear reprogramming function. These studies reveal the central role of Wnt/β-catenin signaling in SYT-SSX2-induced sarcoma genesis, and open new venues for the development of effective synovial sarcoma curative agents. SIGNIFICANCE: Synovial sarcoma is an aggressive soft-tissue cancer that afflicts children and young adults, and for which there is no effective treatment. The current studies provide critical insight into our understanding of the pathogenesis of SYT-SSX-dependent synovial sarcoma and pave the way for the development of effective therapeutic agents for the treatment of the disease in humans. © 2013 American Association for Cancer Research.


Li B.,University of Miami | Flaveny C.A.,University of Miami | Giambelli C.,University of Miami | Liang Fei D.,University of Miami | And 10 more authors.
PLoS ONE | Year: 2014

Mutations in the WNT-pathway regulator ADENOMATOUS POLYPOSIS COLI (APC) promote aberrant activation of the WNT pathway that is responsible for APC-associated diseases such as Familial Adenomatous Polyposis (FAP) and 85% of spontaneous colorectal cancers (CRC). FAP is characterized by multiple intestinal adenomas, which inexorably result in CRC. Surprisingly, given their common occurrence, there are few effective chemotherapeutic drugs for FAP. Here we show that the FDA-approved, anti-helminthic drug Pyrvinium attenuates the growth of WNT-dependent CRC cells and does so via activation of CK1α. Furthermore, we show that Pyrvinium can function as an in vivo inhibitor of WNT-signaling and polyposis in a mouse model of FAP: APCmin mice. Oral administration of Pyrvinium, a CK1α agonist, attenuated the levels of WNT-driven biomarkers and inhibited adenoma formation in APCmin mice. Considering its well-documented safe use for treating enterobiasis in humans, our findings suggest that Pyrvinium could be repurposed for the clinical treatment of APC-associated polyposes. © 2014 Li et al.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 259.45K | Year: 2012

DESCRIPTION (provided by applicant): Despite significant advancements in modern medicine with regards to surgery, radiation therapy and imaging of tumors, the survival rate for patients with non-small-cell lung carcinoma (NSCLC) remain almost identical to20 years ago. Current therapies targeting the proliferative mechanisms of NSCLC cancers such as K-RAS and EGFR have been the focus of a large effort in the pharmaceutical industry and academic laboratories. Such therapies have benefits over classical chemotherapy agents in prolonging median progression-free survival but have almost no effect on overall survival. In recent years, it has become clear that cancers are highly heterogeneous and the initial sensitivity to chemotherapy is the effect on the more differentiated (highly proliferative) cell types. The cancer stem cell population distributed within the initial tumor mass is resistant to chemotherapy and displays a highly invasive/metastatic phenotype. StemSynergy Therapeutics Inc. (SSTI) is a biopharmaceutical company focused on the discovery, development, and commercialization of drugs that target pathways fundamental to stem cells and cancer stem cells. Recent high profile literature studies have shown that cancer stem cell populations in NSCLC demonstrate aberrant Wnt pathway activity are sensitive to secreted Wnt inhibitors. There is an urgent need for inhibitors of the Wnt pathway because currently, there are no FDA-approved drugs or drugs in late-stage clinical trials that target this pathway. This application describes the discovery and development of a new class of Wnt pathway inhibitors that activate Casein Kinase 1a (CK1a). Additional to the highly potent Wnt inhibitory activity, these small molecules activate p53. StemSynergy aims to develop atreatment for NSCLC that synergizes with current FDA approved drugs for NSCLC by targeting the drug resistant cells/cancer stem cells to eliminate ALL cancer cells and therefore increase survival for lung cancer patients. PUBLIC HEALTH RELEVANCE:Lung cancer is the largest cause of mortality and morbidity with 1.4 million deaths per year worldwide. StemStynergy is developing Wnt inhibitors to target the drug resistant cancer stem cell population to decrease metastasis and increase overall survival.


Provided herein are novel compounds, pharmaceutical compositions for use, inter alia, in methods of reducing Wnt-mediated effects and treating cancer.

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