A "Hot" Mystery: Herbal Therapy of Neurofibromatosisby Corn Lily (???), a source of "Cyclopamine"

A few days ago, just around the moment when we experienced the "hottest" day (over 46oC)
and the worst bush fire around Melbourne which took more than 170 lives and destroyed
so many homes, I received a "mysterious" e-mail from an Indian physician
who claims to live near Washington, DC. He wrote that his patient (or neighbor)
managed to get rid of his/her numerous NF1 neurofibromas by a herbal product
in months, although he did not reveal the specific name of this "miracle"
herb... I asked him to send me a pair of photos of this NF1 patient taken
before and after this herbal treatment, to convince me this miraculous recovery.
Also I added that if this herbal product is inexpensively available on
the market, we would be potentially interested in investigating further
its therapeutics effect on NF1 and NF2 tumor xenografts in mice. Since then
I have never heard from him, and started being puzzled what his real intention
was...

Perhaps it could have been a whisper/hint from God, although I wouldn't believe
in anything other than our own biomedical science. I used to work in California
and hillside of Rocky Mountains in US for a few years, before I moved to
Melbourne for more than two decades ago. If you walk through wet meadows
there, you will find a 1-2 meters tall plant which resembles corn, but its
flower looks like a small lily. It is commonly called "Corn Lily". Shepherds usually
avoid to pass through this area with his or her herd of cows, sheep or goats,
because this plant is teratogenic, causing a series of birth defects such
as cyclopia, if they ingest it while pregnant. It contains an alkaloid of
steroid structure called cyclopamine which blocks the oncogenic "hedgehog"/Gli
signaling pathways that are involved in both blood vessel formation (angiogenesis)
and forebrain development. Since just like thalidomide, teratogenic substances
in general have an anti-cancer potential, the development of cyclopamine
and its water-soluble derivative called IPI-609 as new anti-cancer drugs
are currently under way.

Historically, Corn Lily was used as a pain reliever and anti-convulsive (for
epilepsy). Native American Indians concocted an effective birth control
tea from the roots. Today it is used pharmaceutically to slow the heartbeat
and lower blood pressure.

So this "mysterious" e-mail suddenly reminded me of Corn Lily, and I started
finding a possible link of the "hedgehog"/Gli signaling to NF1 (a RAS GAP)
or PAK signaling. In short, loss of NF1 gene which causes abnormal activation
of RAS and PAK, eventually activates Gli gene, down stream of "hedgehog",
a growth hormone. In other words these two oncogenic pathways work synergestically.
In principle, like anti-PAK products such as Bio 30, cyclopamine or its
derivatives should suppress the growth of PAK-dependent tumors such as NF1/NF2
and pancreatic cancers. In fact, George Feldmann's team at Johns Hopkins
Medical School in Baltimore reported in late 2008 that IPI-609 (a product
of Infinity Pharmaceuticals, Boston) (20 mg/kg) suppresses the growth and
metastasis of pancreatic cancer xenograft in mice, in combination with Gemcitabine
(100 mg/kg) completely. Thus, it would be possible that the "mysterious"
herbal product might cure NF1 neurofibromas miraculously, if it is somehow
related to an ethanol extract of Corn Lily or Chinese (Sichuan) pepper called
"Hua Jiao" which we found a few years ago selectively blocks the oncogenic
PAK pathways...

Sherlock Holmes said: Perhaps this "mysterious" e-mail informer might live
somewhere between Baltimore and Washington, DC.
Dr. Watson asked: Why?


Mol Cancer Ther. 2008 Sep;7(9):2725-35.

An orally bioavailable small-molecule inhibitor of Hedgehog signaling (IPI-609)
inhibits tumor initiation and metastasis in pancreatic cancer.

Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H, Koorstra
JB, Habbe N, Karikari C, Mullendore M, Gabrielson KL, Sharma R, Matsui W,
Maitra A.

Department of Pathology, Johns Hopkins University School of Medicine, CRB2,
Room 316, 1550 Orleans Street, Baltimore, MD 21231, USA. gfeldma4@jhmi.edu


Pioneer work by Philip Beachy on Hedgehog and Cyclopamine

Philip A. Beachy, Ph.D., a Howard Hughes Medical Institute (HHMI) investigator,
moved from Johns Hopkins University Medical School to Stanford University
Cancer Center around 2006.

Beachy and colleagues during their Johns Hopkins days found that cyclopamine
blocks the Hedgehog pathway. Furthermore, in mouse studies, cyclopamine
caused permanent regression of grafted human and rodent tumors. This research
was published in Nature around 2003.

Even at 6 to 8 months after treatment ended, tumors did not regrow. "There
is good evidence in a number of tissues that cancers are propagated by a
minority of cells that seem to have properties of stem cells," he explained.
"These cancer stem cells probably derive from tissue stem cells." Their
results suggest that the cancer stem cells were wiped out, Beachy said. Hedgehog
and another signaling pathway called Wnt have roles in stimulating self-renewal
for stem cells.

Meanwhile, several drug companies such as Curis and Infinity Pharmaceuticals are
developing Hedgehog antagonists, and Beachy is pushing hard to get cyclopamine into
clinical trials, including working with farmers in Utah to harvest large
quantities of corn lily, the major source of this drug.

http://jnci.oxfordjournals.org/cgi/content/full/97/3/168


Clinical Trials (phase II) of Hedgehog Inhibitor "GDC-0449" in 2008:

HhAntag691 (GDC-0449), an inhibitor of the hedgehog (Hh) signaling pathway,
has been used to treat medulloblastoma in animal models and has recently
entered clinical trials for a variety of solid tumors.

GDC-0449 (IC50=40 nM) developed by Curis Inc. is a synthetic benzoimidazole derivative,
clearly unrelated to cyclopamine in the chemical structure,
and much more potent than cyclopamine (IC50=500 nM) in inhibiting Hedgehog (Hh)
signaling and the growth of cancer cells. It is the first Hh inhibitor in the clinical trials.

Curis Inc. reports that it is moving forward with its collaboration with
Genentech Inc. on development of Curis' Hedgehog antagonist drug for
treating cancer.

Genentech in Southern California plans to launch three Phase 2 clinical
trial plans for GDC-0449 in 2008. Upon the treatment of the first patient in
the trial, Curis in Cambridge/Boston could receive a $3 million cash milestone payment.

The planned Phase 2 clinical trials include a trial in metastatic
colorectal cancer during the first quarter 2008, and trials in advanced
basal cell carcinoma, as well as a trial in an undisclosed advanced solid
epithelial tumor during the second half of 2008. Once testing has begun
on that epithelial tumor, a second $3 million payment could be triggered.

http://www.bizjournals.com/eastbay/stories/2008/03/10/daily80.html