Drug Discovery & Development - July 06, 2010
Pre-clinical trials show a compound discovered and developed by ENDECE, LLC, (Mequon, Wis.) stops the growth of many types of human cancers at the gene level for genes essential to cancer cell replication. The ENDECE compound not only stops chromosome (DNA) replication, which kills cancer cells, but also stops Hedgehog cancer pathway, present in many aggressive tumors. Preclinical toxicology and dosing studies for the compound, called NDC-1308, are expected to be completed this year, followed with Human Phase 1 clinical studies.
"ENDECE has a completely different approach to treating cancer," said Dr. James Yarger, co-founder, CEO and lead researcher for ENDECE. Yarger explained that currently most cancer drugs target single mutations (targeted to single proteins) to control cancer growth. While the current hot approach of "targeted" therapeutics is leading to novel drugs that prove effective for awhile, said Yarger, they generally extend life by only a few months. In order to survive, cancer cells are great at finding a way around this single target approach. Therefore, cancer cells quickly become resistant to many of the newest cancer drugs—and often within months. "ENDECE’s novel approach to fighting cancer involves targeting and controlling multiple pathways that are essential to cancer replication and ultimately shutting down a tumor’s ability to survive by switching tumor cells’ own pathways from proliferation to death," said Yarger. "Because ENDECE impacts multiple pathways and multiple targets, we believe it will be much more difficult for cancers to become resistant to NDC-1308."
Yarger, who has degrees in molecular biology and metabolic engineering and was a Post doctoral fellow at Harvard, established ENDECE, LLC in 2006 to design compounds with an approach he calls the "BioSwitch Concept". The approach identifies and regulates naturally occurring biomolecular switches thought to be used by normal, non-cancerous tissues to control cell proliferation. Endece’s compound substantially turns these switches down resulting in cancer cell death.
"What is one of the few characteristics all cancer cells have in common?" asks Yarger. "It’s rapid replication of cells. Our lead compound, NDC-1308, binds to an estrogen receptor known as ER-beta, not only shutting down a tumor’s ability to grow but also switching tumor cells from proliferation to death. NDC-1308 does this by controlling at least 21 genes at the "switch level" whose encoded proteins are absolutely required for cell proliferation. To date NDC-1308 has proven effective against a broad panel of human tumors in vitro and against selected human tumors in animal cancer studies.
Unexpectedly, data suggest that when NDC-1308 binds to receptor ER-beta, it also controls at least 4 genes that are essential for aggressive and lethal human cancers driven by the Hedgehog pathway. The Hedgehog signaling pathway is one of the key regulators of human development. Uncontrolled activation of the Hedgehog pathway has been implicated in the development of cancers in various organs, including brain, lung, breast, prostate and skin. As an example, over 80% of pancreatic cancers appear to be driven by mutations in the Hedgehog pathway. Hedgehog represents a new frontier in cancer treatment, and drug companies around the world are racing to generate and test new compounds to control it. With NDC-1308, ENDECE is now at the forefront of research in this area.
NDC-1308 is scheduled to begin Phase 1 human clinical studies in early 2011, but ENDECE’s results with Hedgehog could expedite drug development. "Our oncology board is particularly excited about NDC-1308 not only because it has a unique mechanism of action towards cancers and thus may stop cancers where other drugs have failed (giving oncologists an additional tool to keep their patients alive) but also because it effects Hedgehog," says Yarger. "We believe we have discovered a compound that could provide years of quality life for those patients who today who are dying from so many forms of cancer."
"ENDECE has a completely different approach to treating cancer," said Dr. James Yarger, co-founder, CEO and lead researcher for ENDECE. Yarger explained that currently most cancer drugs target single mutations (targeted to single proteins) to control cancer growth. While the current hot approach of "targeted" therapeutics is leading to novel drugs that prove effective for awhile, said Yarger, they generally extend life by only a few months. In order to survive, cancer cells are great at finding a way around this single target approach. Therefore, cancer cells quickly become resistant to many of the newest cancer drugs—and often within months. "ENDECE’s novel approach to fighting cancer involves targeting and controlling multiple pathways that are essential to cancer replication and ultimately shutting down a tumor’s ability to survive by switching tumor cells’ own pathways from proliferation to death," said Yarger. "Because ENDECE impacts multiple pathways and multiple targets, we believe it will be much more difficult for cancers to become resistant to NDC-1308."
Yarger, who has degrees in molecular biology and metabolic engineering and was a Post doctoral fellow at Harvard, established ENDECE, LLC in 2006 to design compounds with an approach he calls the "BioSwitch Concept". The approach identifies and regulates naturally occurring biomolecular switches thought to be used by normal, non-cancerous tissues to control cell proliferation. Endece’s compound substantially turns these switches down resulting in cancer cell death.
"What is one of the few characteristics all cancer cells have in common?" asks Yarger. "It’s rapid replication of cells. Our lead compound, NDC-1308, binds to an estrogen receptor known as ER-beta, not only shutting down a tumor’s ability to grow but also switching tumor cells from proliferation to death. NDC-1308 does this by controlling at least 21 genes at the "switch level" whose encoded proteins are absolutely required for cell proliferation. To date NDC-1308 has proven effective against a broad panel of human tumors in vitro and against selected human tumors in animal cancer studies.
Unexpectedly, data suggest that when NDC-1308 binds to receptor ER-beta, it also controls at least 4 genes that are essential for aggressive and lethal human cancers driven by the Hedgehog pathway. The Hedgehog signaling pathway is one of the key regulators of human development. Uncontrolled activation of the Hedgehog pathway has been implicated in the development of cancers in various organs, including brain, lung, breast, prostate and skin. As an example, over 80% of pancreatic cancers appear to be driven by mutations in the Hedgehog pathway. Hedgehog represents a new frontier in cancer treatment, and drug companies around the world are racing to generate and test new compounds to control it. With NDC-1308, ENDECE is now at the forefront of research in this area.
NDC-1308 is scheduled to begin Phase 1 human clinical studies in early 2011, but ENDECE’s results with Hedgehog could expedite drug development. "Our oncology board is particularly excited about NDC-1308 not only because it has a unique mechanism of action towards cancers and thus may stop cancers where other drugs have failed (giving oncologists an additional tool to keep their patients alive) but also because it effects Hedgehog," says Yarger. "We believe we have discovered a compound that could provide years of quality life for those patients who today who are dying from so many forms of cancer."
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