Sonic Hedgehog (SHH) Pathway Inhibitors

One reason that cancer is so deadly is the small therapeutic window of current therapeutic regiments. For example, the negative effects on local healthy tissue of radiation therapy often limits the ability to apply therapeutically useful doses to many tumors. In particular, the risk of permanent damage to brain tissue along with a lack of response to chemotherapy in glioblastoma patients limits therapeutic options after surgery. Therefore, strategies specific to signaling pathways involved in the development and expansion of malignant tissue will be required to successfully treat many tumor types.

A number of cancers have been found to utilize the sonic hedgehog (SHH) signaling pathway, including some of the most prevalent in the world. Small-cell lung carcinoma, basal cell carcinoma, medulloblastoma, glioblastoma, as well as breast, liver, colon, pancreatic, and prostate cancer have all been shown to use the SHH pathway (1). According to International Agency for Research on Cancer and the World Health Organization, these cancers together make up approximately 35 to 40 percent of all cancer deaths in the United States.

Treatment of tumors through inhibition of Shh signaling has been an attractive strategy for treating cancer as cell proliferation has been linked to this pathway (2, 3).  In fact, inhibiting the SHH pathway targets tumor stem cells that are resistant to standard chemotherapy therapy. Cyclopamine is a naturally found smoothened antagonist with the ability to inhibit SHH signaling. It has been shown to be efficacious in preventing expansion and metastasis while increasing cell death in cancer cells (4, 5). Despite promising preclinical data, translation of cyclopamine into a useful clinical therapy has been complicated by a number of factors including the prohibitive costs of its manufacture and cyclopamine’s low water solubility and acid lability. Current clinical trials testing cyclopamine analogues for treatment of many of the SHH-associated cancers have shown promising results, but are also plagued by problems, including relying on the expensive starting material cyclopamine, as well as possible acquired resistance to inhibition. Clearly, new analogs are needed in order to exploit the potential for treating cancer by inhibition of SHH signaling. 

We have generated novel steroid derived cyclopamine analogue that address the shortcomings of cyclopamine and are derived from readily and cheaply available steroidal precursors. The novel and simple synthesis procedure removes the need for the expensive natural cyclopamine product. Importantly, these analogues demonstrate better solubility and biological stability than cyclopamine (6-9).

Testing of a series of steroid derived analogues for SHH signaling inhibition was done using a SHH-Light2 cell-based luciferase reporter, inhibition of SHH-induced proliferation of mouse granule neuron precursor and DAOY medulloblastoma cell viability assays. After testing a series of compounds one molecule was found to be significantly superior to cyclopamine. This molecule was three times as efficacious as cyclopamine in the GNP proliferation assay, provided a significant reduction in Shh activity in the luciferase assay compared to cyclopamine, and proved as efficacious in decreasing medullablastoma cell viability as cyclopamine.

The promising activity profile of the analogues in vitro supports the necessity to move to in vivo models.

A robust issued patent portfolio has been assembled to protect the novel compositions and methods of use. US8575141; US8669243; US8759367.

We are actively seeking a collaborator to facilitate the final stages of lead optimization, preclinical research and initiation of clinical trials. 

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