Summary of Invention
The present invention relates to the treatment of pancreatic cancer with a group of small molecules that target Sonic Hedgehog (Shh). Shh is a signaling protein which plays a critical role in promoting pancreatic cancer. These compounds work by inhibiting the enzyme Hedgehog Acyltransferase (Hhat), which attaches a palmitate to Shh and is needed for signaling. A proprietary in vitro assay enabled the inventors to take a directed approach to identifying small molecule inhibitors of Hhat.
All current Shh-pathway inhibitors target a downstream molecule called Smoothened (Smo). However, Smo inhibitors have failed in the clinic for pancreatic cancer, most likely because pancreatic tumor cells signal via non-canonical Smo-independent pathways. The Hhat inhibitors provide a more effective treatment because they act upstream in the Shh pathway and block all downstream signaling. These compounds might be able to treat other Shh-driven cancers such as estrogen-receptor positive breast cancer and gastric cancer as well.
Pancreatic cancer is the 4th leading cause of cancer-related deaths in the U.S. The National Cancer Institute projects 45,220 new cases and 38,460 deaths from pancreatic cancer in the U.S. in 2013, at a cost of ~$1 billion/year. For patients with pancreatic cancer, the current standard of care, gemcitabine, is largely ineffective with a five-year survival rate of roughly 5%.
For estrogen-receptor positive breast cancer, the NCI estimates that there will be 176,000 new cases and 30,000 deaths in the U.S. in 2013, at a cost of ~$6.5 billion/year. Current treatments block estrogen production, but over time, cancer cells can become resistant to estrogen deprivation. Gastric cancer has become less prevalent over the last decade, yet it is still the 5th most common cancer worldwide and the 3rd most common cause of cancer-related deaths worldwide. With 21,600 new cases per year in the U.S, its cost is ~ $1 billion/year.
Areas of Application
- Pancreatic cancer
- Other Shh-driven cancers such as estrogen-receptor positive breast cancer and gastric cancer
Stage of Development
Marilyn D. Resh, PhD
PCT application number PCT/US2013/031311 filed March, 14, 2013
Yashodhara Dash, MBBS, PhD, MBA
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