The data are being presented by a Genentech, Inc. researcher as part of the "New Horizons in the Development of Targeted Therapies for the Treatment of Cancer" Symposium. These data were generated as part of Curis' ongoing collaboration with Genentech to develop systemically administered Hedgehog small molecule antagonists for the potential treatment of solid tumors.

The presentation at the AACR described the use of a Hedgehog antagonist in small cell lung and pancreatic cancers, diseases that both have very low survival rates. For these studies, researchers used a primary tumor xenograft model, whereby a human tumor is grown and expanded directly in recipient mice. Treatment with a small molecule Hedgehog antagonist inhibited the rate of tumor growth in mouse xenograft models initiated from both a human small cell lung cancer.

According to the American Cancer Society, in 2006 there will be about 174,470 new cases of lung cancer (both small cell and non-small cell) in the United States. About 162,460 people will die of this disease. About 6 out of 10 people with lung cancer die within 1 year of finding out they have lung cancer. Between 7 and 8 will die within 2 years.

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See more info ilung cancer in the science section
http://www.pathway2curis.com/lung-cancer-therapy-hedgehog-antagonist-vt38.html

Target for New Lung Cancer Therapy in Embryonic Cell Pathway


New work by researchers in the Kimmel Cancer Center at Johns Hopkins may allow them to halt the smoking-induced cellular events that lead to 99 percent of all small cell lung cancers (SCLC). The research is reported in the March 20, 2003, issue of Nature.

The researchers found that a primitive cellular pathway, called Sonic Hedgehog (named for the cartoon character and spiky hairs it develops on fruit flies) stays turned on long after it should be turned off in some lung cancers.

"We believe chronic injury to the lungs by cigarette smoking re-activates genes in the Hedgehog pathway to repair cell damage in the lining of the lungs. The ongoing and regular assault to the lungs by cigarettes causes the usually dormant pathway to be stuck in activation mode making too many new cells, ultimately resulting in cancer," says Neil Watkins, Ph.D., research associate at the Kimmel Cancer Center and lead author of the study.

The Sonic Hedgehog pathway has been well studied for its role in the development of mammalian embryonic cells, and more recently, for its relationship to cancer. Now, Kimmel Cancer Center investigators are testing drugs on mice, including one called cyclopamine, that block the Hedgehog pathway. Human clinical trials are not planned at this time and may be three to four years away.

The scientists analyzed tissue samples and tumor cell lines from SCLC and non-small cell lung cancer (NSCLC) patients. Of ten SCLC tissue samples studied, half showed activation of the Hedgehog pathway and increased expression of one of its targets called the Gli1 gene. They confirmed these findings by looking at SCLC cell lines in which five of seven lines examined showed similar activation of the Hedgehog pathway and Gli1 gene. Limited activation of the pathway was found in NSCLC.

"This study represents one of the first attempts to therapeutically manipulate this cell pathway, and it's a perfect example of how basic developmental science can have clinical implications in a relatively short period of time," says Stephen B. Baylin, M.D., Ludwig professor of oncology and director of research at the Kimmel Cancer Center.

Lung cancer is the leading cancer killer. Close to 172,000 cases are diagnosed each year. Unresponsive to standard therapy, SCLC is the most lethal form of lung cancer. It typically cannot be treated with surgery and though it initially responds to chemotherapy, most patients relapse. "As cigarette smoking persists among young people, we expect to be dealing with this disease for years to come. As a result, the search for potential new therapies are key to controlling this disease," says Watkins.

In addition to Watkins and Baylin, other Johns Hopkins participants in this research include David Berman, Scott G. Burkholder, Baolin Wang, and Philip Beachy. The research was funded by the Flight Attendant Medical Research Institute and a National Cancer Institute lung cancer SPORE (Specialized Projects of Research Excellence).

Related Web Sites:
www.hopkinskimmelcancercenter.org

Under a licensing agreement between the Johns Hopkins University and Curis, Inc., Dr. Beachy is entitled to a share of royalty received by the University from sales of products related to the research described in this press release. The University and Dr. Beachy own Curis, Inc. stock, the sale of which is subject to certain restrictions. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.
http://www.hopkinsmedicine.org/press/2003/MARCH/030305.HTM

* 19:00 05 March 2003
* NewScientist.com news service
* Shaoni Bhattacharya

Lung cancer may be caused by a faulty repair mechanism triggered by smoking, according to a new study.

US researchers have found that a primitive cell pathway, which is crucial for the development of lungs in the embryo, could be the major culprit in small cell lung cancer (SCLC).

The pathway is found in all creatures, from worms to humans. It is called Sonic Hedgehog, after a mutant form in fruit fly embryos that leads to the sprouting of hairs all over their bodies.

"The hypothesis was that smokers chronically injure their airways and pathways such as hedgehog get turned on to repair damage - but chronic injury results in persistent pathway activation, which leads to cancer," says Neil Watkins, team leader at the Sidney Kimmel Comprehensive Cancer Center, part of Johns Hopkins University in Maryland.

The group's experiments showed that the Sonic Hedgehog pathway was indeed activated in half of 10 SCLC human tissue samples. Furthermore, they successfully stopped tumour growth in mice by blocking this pathway and believe this may lead to potential therapies in humans.
Tiny survival rate

About a quarter of all lung cancer cases are SCLC, and 99.9 per cent of SCLC cases are associated with smoking. There are 38,000 new cases of lung cancer in the UK every year and the five-year survival rate is just five per cent.

Richard Sullivan, head of clinical programmes for charity Cancer Research UK, says the team's work is interesting but warns that the small number of samples used requires cautious interpretation.

The team showed that Sonic Hedgehog was active in the human SCLC tissue samples by looking at the expression of a key gene - Gli1 - in the pathway. Non-small cell lung cancer samples showed only limited activation of this gene.

Watkins, a respiratory specialist and oncologist, told New Scientist that Sonic Hedgehog, which regulates the surface cells of the lung, is rarely switched on outside the embryo. "This pathway is falsely telling the tumour cell that it's an embryonic cell," he says.
Possible therapy

The research team then tested a drug called cyclopamine - known to block the Hedgehog pathway - in tumour cells from mice. They found it not only stopped the growth of the cancer but also caused the cells to start differentiating into more adult lung cells, said Watkins.

"That's very encouraging," says Sullivan, adding that the lack of new treatments means that SCLC survival rates have not improved since the 1960s.

But he warns that it has been particularly difficult to successfully transfer animal research on lung cancer to humans. This may be because lung cancer takes 20 years to develop in humans, leading to selection for the most aggressive cells.

Journal reference: Nature (doi:10.1038/nature01493)
http://www.newscientist.com/article/dn3469.html