Pyrvinium pamoate therapies and methods of use

#The disclosure relates to the fields of molecular biology, oncology and human therapeutics for the treatment of cancer.

#Cancer is a proliferative disease in which the cells of a subject grow abnormally and in an uncontrolled way, in some cases leading to the death of the subject with cancer. There are many independent events and causes which can lead to cancer, and many different cell types and tissues that can give rise to cancers. As such, treatments developed for one type of cancer may not work on another type of cancer. Despite many years of research, and a plethora of treatments available to cancer sufferers, there is still a long felt need in the art for additional cancer therapies. This need is particularly acute in rare cancers, which in many cases may be under-resourced because of their rarity. The disclosure provides additional methods for the treatment of cancer.

#The disclosure provides methods of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising 3-carboxy-1-[(3-carboxy-2-oxidonaphthalen-1-yl)methyl]naphthalen-2-olate; 2-[(E)-2-(2,5-dimethyl-1-phenylpyrrol-3-yl)ethenyl]-N,N,1-trimethylquinolin-1-ium-6-amine (pyrvinium pamoate).

#FIG. 1 is a plot showing the effect of pyrvinium pamoate on the ovarian carcinoma cell line SKOV-3 cell viability. Cells were treated with nine serial dilutions of pyrvinium pamoate (0 to 2 μM) for 72 hours.

#FIG. 2A, FIG. 2B and FIG. 2C are each a plot showing the effect of pyrvinium pamoate treatment on cell viability at 72 hours in an Ewing's sarcoma cell line. FIG. 2A shows the TC-71 cell line. FIG. 2B shows the TC-32 cell line. FIG. 2C shows the CHLA-9 cell line. Cells were treated with nine serial dilutions of pyrvinium pamoate (0-2 μM).

#FIG. 3A and FIG. 3B are each a plot showing the effect of pyrvinium pamoate treatment on cell viability at 72 hours in a neuroblastoma cell line. FIG. 3A show the IMR-32 cell line. FIG. 3B shows the CHP-212 cell line. Cells were treated with nine serial dilutions of pyrvinium pamoate (0-2 μM).

#The present invention is related to the finding that the anti-helminthic drug pyrvinium pamoate (PP) can affect several relevant molecular pathways in tumor growth and metastasis. Pyrvinium pamoate is an antihelmintic drug that was first offered for sale in 1977 or earlier. Unlike some other anthelmintics, pyrvinium pamoate works exclusively against pinworms, where it is thought to impede exogenous carbohydrate metabolism. Pyrvinium pamoate has been well studied in humans, and has low toxicity.

#Pyrvinium pamoate's potential anti-cancer activities are thought to have multiple potential mechanisms of action, which makes pyrvinium pamoate an attractive candidate for treating any number of cancers. Without wishing to be bound by any particular theory or limited to any one mode of action, a few of the pathways thought to be affected by pyrvinium pamoate are laid out below.

#For example, pyrvinium pamoate is thought to inhibit the Wingless/Integrated (Wnt) signaling pathway. Wnt signal transduction occurs through several pathways, and the best characterized are the canonical Wnt pathway, the non-canonical pathway, and Wnt signaling involvement in planar cell polarity. All three pathways are activated by binding of the Wnt ligand to the Frizzled transmembrane receptor, which acts through Dishevelled to transduce the signal inside the cell. In the canonical pathway, binding of Wnt to its receptor complex (Frizzled and the LDL receptor related protein 5 and LDL receptor related protein 6) leads to the disruption of the adenomatous polyposis coli (APC)/Axin/Glycogen synthase kinase 3 (GSK3) complex. The APC/Axin/GSK3 complex is required for the targeted destruction of β-catenin in the cytoplasm, and upon its disruption, β-catenin translocates to the nucleus where it can regulate gene expression. The activity of Dishevelled can be regulated through phosphorylation by a number of kinases, including Casein Kinase 1, Casein Kinase 2, Metastasis Associated Kinase, Protein Kinase C and Parl. The non-canonical Wnt pathways proceed downstream of Dishevelled largely independent of beta-catenin, and are thought to signal through additional cellular pathways such as through Rho-associated protein kinase (ROCK), the c-JUN N-terminal kinase (JNK), or through Protein Kinase C (to name a few). There are thus a number of mechanisms by which pyrvinium pamoate could affect Wnt signaling. Without wishing to be bound by any particular theory, for example, pyrvinium pamoate could bind to all casein kinase 1 (CK1) family members in and selectively potentiate casein kinase 1α (CK1α) kinase activity to inhibit Wnt signaling activity.