Prostate Cancer --- Hedgehog Antagonist

Posted: Wed Jan 25, 2006 2:24 pm

All of this articles are related to the Hedgehog pathway and Prostate cancer. Some of the them may be general and others are scientific studies.

This is a very good review the Hh pathway, but pays close attention to prostate cancer. I scanned and uploaded it to the forum.

Cell Mol Life Sci. 2006 Jan 2;
Sonic Hedgehog signaling in advanced prostate cancer.

Datta S, Datta MW.

Department of Biochemistry and Biophysics, Department of Biology, MS 2128, Texas A&M University, College Station, Texas, 77843-2128, USA, sumad@tamu.edu.

The Hedgehog family of growth factors activate a highly conserved signaling system for cell-cell communication that regulates cell proliferation and differentiation during development. Abnormal activation of the Hedgehog pathway has been demonstrated in a variety of human tumors, including those of the skin, brain, lung and digestive tract. Hedgehog pathway activity in these tumors is required for cancer cell proliferation and tumor growth. Recent studies have uncovered the role for Hedgehog signaling in advanced prostate cancer and demonstrated that autocrine signaling by tumor cells is required for proliferation, viability, and invasive behavior. The level of Hedgehog activity correlates with the severity of the tumor and is both necessary and sufficient for metastatic behavior. Blockade of Hedgehog signaling leads to tumor shrinkage and remission in preclinical tumor xenograft models. Thus, Hedgehog signaling represents a novel pathway in prostate cancer that offers opportunities for prognostic biomarker development, drug targeting and therapeutic response monitoring.

Link to paper download
article

Posted: Fri Jan 27, 2006 4:05 pm

Johns Hopkins Medicine
Office of Corporate Communications
Media Contact: Joanna Downer
410-614-5105; jdowner1@jhmi.edu
September 12, 2004

"HEDGEHOG" SIGNAL DISTINGUISHES LETHAL
FROM LOCALIZED PROSTATE CANCERS

Johns Hopkins researchers have discovered a possible way to distinguish lethal metastatic prostate cancers from those restricted to the walnut-size organ.

If future studies show their test -- measuring the level of activity of a signaling pathway called Hedgehog -- can predict which prostate cancers will spread, the results could revolutionize decision making processes for prostate cancer patients, the researchers say.

Most prostate cancers grow slowly, making "watchful waiting" a common alternative to immediate surgical removal of the prostate. However, there's no sure-fire way to tell whose cancer will stay put in the gland, and whose will be aggressive and spread -- a development that despite aggressive treatment is usually fatal.

In the September 12 advance online edition of Nature (Oct. 7 print issue), the Hopkins researchers report that only three of 12 localized prostate tumors obtained at surgery had detectable activity of the Hedgehog signaling pathway. In contrast, all 15 samples of metastatic prostate cancers, donated at patients' deaths, had Hedgehog activity, which was 10 to 100 times higher than the highest levels seen in localized tumors. It remains to be seen whether Hedgehog activity in localized cancers will predict the ability to be metastatic.

The Hedgehog pathway produces a well-known growth and development signal during embryonic and fetal stages. It is also active in some cancers, including prostate, pancreatic and stomach cancers and the brain tumor medulloblastoma, but the researchers' study is believed to provide the first evidence of its role in cancer's spread.

"If we can use Hedgehog activity to predict whether a tumor will metastasize, we will have a great diagnostic tool, but manipulating the Hedgehog signaling pathway may also offer a completely new way to treat metastatic prostate cancer," says David Berman, M.D., Ph.D., assistant professor of pathology, urology and oncology at Johns Hopkins. "Right now nothing works very well -- you can help temporarily by cutting off testosterone, but the cancer always comes back."

In experiments with mice, fellow Sunil Kahadkar, M.D., showed that blocking the Hedgehog signal with daily injections of either a natural plant compound called cyclopamine or an antibody slowed and even reversed growth of highly aggressive rat prostate tumors implanted into the animals. Without treatment, the aggressive cancers, from a collection established by Hopkins' John Isaacs, Ph.D., killed the animals within 18 days. A low dose of cyclopamine gave the animals an extra week to 10 days, but at a higher dose, these aggressive cancers not only didn't metastasize, they actually disappeared and didn't return.

In a similar set of experiments using human prostate cancers implanted into mice, treatment with cyclopamine also caused those tumors to regress and not return -- even months after treatment was stopped, the researchers report.

"Cyclopamine may not itself become an anti-cancer drug, in part because it's already in the public domain -- it's been known since the mid 1960s as the cause of one-eyed sheep in the western U.S.," says Philip Beachy, Ph.D., professor of molecular biology and genetics in Hopkins' Institute for Basic Biomedical Sciences and a Howard Hughes Medical Institute investigator. "But our finding that cyclopamine inhibits Hedgehog signaling has provided the basis for drug companies' very active efforts to develop new mimics of cyclopamine."

Right now, prostate cancer is evaluated largely by levels of prostate specific antigen (PSA) circulating in the blood. However, the ranges associated with various potential diagnoses -- non-cancerous growth, cancer, and aggressive cancer -- are fairly rough guides. And even under a microscope, aggressive prostate cancer doesn't always look appreciably different from its wallflower counterpart.

In sharp contrast, levels of Hedgehog activity weren't even close between still-localized tumors removed during prostatectomies and those from lethal metastatic prostate cancers, which were collected as part of a research program run by G. Steven Bova, M.D., assistant professor of pathology, to try to figure out what makes them so deadly.

To investigate Hedgehog's role in metastasis, Karhadkar genetically engineered normal prostate cells to activate their Hedgehog signal. These cells then grew unchecked and formed aggressive tumors when implanted into mice, he found. He also discovered that triggering Hedgehog activity in a low-metastasizing rat prostate cancer line made it metastasize aggressively.

"Hedgehog isn't just making these cells grow and divide more, the signal is really converting them from being indolent to being highly invasive and dangerous," says Beachy.

Exactly how the Hedgehog signal is involved in other cancers, including pancreatic and stomach cancers and medulloblastoma, a childhood brain cancer, is still being worked out. Critical in normal embryonic development, the signal is supposed to be turned off when cells take on the "grown-up" identity of a differentiated cell type.

Karhadkar, Beachy and Berman -- and a growing number of other scientists -- point to the involvement in cancer of embryonic proteins and pathways like Hedgehog as evidence that aggressive cancer in particular might form not by accumulation of genetic errors in regular cells, but because a smaller number of errors occurs in a more primitive cell, what might be called a "stem cell," in the tissues. And it would be these "cancer stem cells" -- transformed versions of the tissue's normal stem cells -- that metastasize and travel through the body to form new tumors in distant places.

"Perhaps aggressive prostate cancers get started from a more primitive prostate cell or from a different initiating lesion than do prostate cancers that don't metastasize," says Beachy. "It's an idea we're exploring."

The research was funded by the National Institutes of Health, the Prostate Cancer Foundation, and the Howard Hughes Medical Institute. Authors on the paper are Karhadkar, Bova, Nadia Abdallah, Surajit Dhara, Anirban Maitra, Isaacs, Berman and Beachy, all of Johns Hopkins; and Dale Gardner of the U.S. Department of Agriculture's Poisonous Plant Research Laboratory.

---

Under a licensing agreement between Curis Inc. and the Johns Hopkins University, Beachy and Berman are entitled to a share of royalty received by the University on sales of products described in this article. Beachy and the University own Curis Inc. stock, which is subject to certain restrictions under University policy. Beachy and Berman are paid consultants to Curis Inc. and Berman is a paid consultant to Genentech Inc. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

--JHMI--

On the Web:

http://www.nature.com/cgi-taf/DynaPage.taf?file=/nature/journal/v431/n7009/full/nature02962_fs.html

Related releases:
http://www.hopkinsmedicine.org/press/2002/August/020829.htm
http://www.hopkinsmedicine.org/Press_releases/2003/10_22_03b.html
http://www.hopkinsmedicine.org/press/2003/March/030328.htm
http://www.hopkinsmedicine.org/press/2002/August/020823.htm

Posted: Sun Jan 29, 2006 7:41 pm

Hedgehog, Cyclops and Dandelion: The "root" of prostate cancer

BY JACQUELINE STRAX

December 3. 2005. Think of prostate cancer as a dandelion in a lawn -- pull the leaves off the weed and the root still remains dug in there, and the plant regenerates and pops up again.

This is one way Norman Maitland, Professor of Molecular Biology at University of York, UK, explains a breakthrough that he and his colleague Dr. Anne Collins have made. They extracted stem cells from prostate cancer tumors. They pulled the root of future metastatic growth.

Existing therapies for treating prostate cancer, Maitland says, attack the 'leaves' rather than the 'root,' making it likely for many men that the disease will recur after primary treatment such as radical surgery. Maitland's team at the Yorkshire Cancer Research (YCR) Unit have discovered how to isolate the tumor stem cells, which make up one in 1,000 of cancer cells. These stem cells Maitland likens to the root of prostate cancer.

The next step is to find therapies for treating stem cells to stop them regenerating.

Extraction of prostate cancer tumor stem cells may bring a pay off from earlier work that's shown how 'Sonic hedgehog' signaling promotes prostate and other cancers. Drugs modeled on a North American Indian remedy, may be able to target the cancer stem cells and inhibit tumor spread.

If drugs can be developed to kill tumor stem cells in prostate and other cancers without harming the patient, it will be because Collins and Maitland's achievement builds on two strands of worldwide work involving genes:
work with Sonic hedgehog, Shh for short, a protein named after the video game hero, Sonic the Hedgehog. Sonic hedgehog signaling helps make sure a newborn has midline structure with two sides to its body, a back and front and symmetrical arrangement of arms, legs, hands, feet and eyes.
work with a chemical found in a poisonous lily family plant (Veratrum californicum) Western false hellebore, also called corn lily, that causes a characteristic birth defect spoiling this symmetry. This birth defect, a one-eyed cyclops face caused by lack of a facial midline structure, is seen in lambs born to ewes that have browsed on the plant. Cyclops face gave rise to the name Cyclopamine for a small molecule steroidal alkaloid extracted from this plant, now of interest as a possible agent to kill tumor stem cells.
Sonic Hedgehog

In the 1990s, biologists working on fruit fly genes discovered a segment polarity signaling protein which, if mutated, made the larvae spiny-backed. Needing a memorable descriptive name they called it Hedgehog. It has a number of equally cute downstream genetic sidekicks including Smoothened (Smo for short), Scribbler, Patched and Wingless. Hedgehog has some 3 variants in its family so far. Sonic hedgehog, Shh for short, is a signalling gene named after a video game hero, Sonic the Hedgehog.

Hedgehog was added to a rapidly growing roster of places in embryonic fruit fly (Drosophila) where something can go either beautifully right, to make the insect perfectly formed (and usually symmetrical) or go wrong and botch the "segmental pattern" of the larva. As even more proteins and lethal mutants in embryonic fruit fly were identified, scientists found themselves rediscovering at the genetic level what the poet William Blake in his poem The Tyger calls "fearful symmetry."

Hedgehog is a growth factor necessary for "polarity during segmentation of the fly, and during the development of appendages." Hedgehog helps makes sure the fly emerges from the larva with paired wings, paired eyes, paired legs back and forth, and well-formed organs.

Why bother with fruit fly, though, when what matters to people, we may suppose, is human biology and to some extent that of other backboned animals (vertebrates) on which drugs for humans can be tested? The focus on fruit fly arose along with genetic mapping of the web of life. Scientists bother a good deal over fruit fly because processes that shape up a Drosophila larva for metamorphosis into a no see 'em hovering about an overripe banana for a sip of juice play no less critical roles in the development of mammals.

Sonic hedgehog protein regulates patterning of the human spinal cord, limbs, eyes, brain, pancreas, lungs and other organs - even, in males, the ductal structure of the prostate. David Schaffer, a chemical engineer at Lawrence Livermore Laboratory, Berkeley, CA calls Shh gene a critical "cell fate switch." In the brain, Schaffer discovered, Sonic hedgehog can cause the normally small number of adult neural stem cells in the hippocampus to proliferate. This holds promise for future treatments of brain damage suffered as a result of Alzheimer's, Parkinson's, and Huntington's diseases, strokes, or head traumas.

But the stem cells in tumors are not the same type of stem cells being explored as potential therapies to treat degenerative diseases. As Nancy Touchette points out in a sidebar to her article The Real Problem in Breast Tumors: Cancer Stem Cells, "Both normal embryonic and adult stem cells are being actively studied for their ability to proliferate and replace damaged cells in diseases such as diabetes, Parkinson's disease, and heart disease. But stem cells in tumors develop because of mutations that accumulate over years and often decades. The mutations are thought to promote the tumor stem cells' ability to proliferate, eventually leading to cancer."

And tumor stem cells, Max Wicha, an Ann Arbor researcher, told Touchette, are difficult to kill. "Because they are so important throughout a person's lifetime, they have developed mechanisms that protect themselves."

What about drugs with negative effects on genetic signaling, like compunds that cause birth defects? Some evidence suggests that Sonic hedgehog signaling pathways, after they've finished sculpting the embryo and fetus into shape, may at some point switch back on and do the same for embryonic cells in tumors, Could drugs that normally interfere with the original embryonic process attack tumor stem cells via the signaling pathways that target them?

A "pathological role" for Hedgehog and related genetic pathways was noted by Jussi Taipale and Philip A. Beachy in an article in Nature (2001). They pointed to studies showing "a high frequency of specific human cancers associated with mutations that constitutively activate the transcriptional response of these pathways." These tumors, they suggested, "may result from mis-specification of cells towards stem-cell or stem cell-like fates."

As Cynthia Wetmore at Mayo pointed out in 2002, malignant change in a cell or group of cells may exploit warps in signaling pathways used originally by genes that lick the young animal's body parts into proper shape. Signaling via the Sonic hedgehog pathway, Wetmore says, while critical to vertebrate development, also "appears to play an integral role in the initiation and propagation of some tumors of the muscle, skin and nervous system." How does this happen? Mutations can occur in components of the signaling pathway itself, resulting in messages that help stimulate tumor cells to grow like embryonic stem-cells.

Insight into this process began to pay off for solid tumor research when urologist Wade Bushman, a professor at University of Wisconsin Medical School, looked to see whether hedgehog signaling may be involved in prostate cancer.

"Once human development is complete, hedgehog genes are normally turned off," Bushman says. "But in the prostate, hedgehog signaling continues into adulthood."

"Inappropriate activation of the hedgehog signaling pathway," Bushman says, "has recently emerged as a key factor in oncogenesis and hyperproliferative disease, particularly in those organs in which Shh plays an important embryologic role."

Bushman and his team confirmed that the pathway that is active during fetal development to form ducts in tissue is reactivated later in life, when benign prostate growth frequently begins. "Shh signaling is down-regulated at the conclusion of prostate ductal development, " he says, but "a survey of adult human prostate tissues reveals substantial levels of Shh signaling" in normal, benignly enlarged and malignant prostate tissue.
Cyclops poison as cure?

Bushman's laboratory was the first in the USA to study hedgehog signaling in the prostate gland. They were the first to show that Shh plays a role in normal prostate development and to describe how activation of hedgehog signaling in a mouse model of prostate cancer increases tumor growth. Bushman did not pinpoint prostate tumor stem cells. Even so, he has collaborated with Curis Inc., a biotechnology company that is developing agents to inhibit hedgehog signaling and suppress tumor growth. Bushman suggests that using an inhibitor to shut down the hedgehog pathway could potentially slow tumor growth, offering a significant advantage to patients who develop prostate cancer at or after middle age.

"The great advantage is that you can use an inhibitor for a pathway that is not active in most adult tissues," Bushman explains. "The result would be effective treatment without the toxic side effects of standard chemotherapy or radiation."

A natural model for patent compounds that are already undergoing tests as Hedgehog signaling inhibitors is corn lily or Western Hellebore, a poisonous plant known to cause one-eyed, cyclops birth defects in sheep. Although it is highly toxic, a number of native North American Indian tribes found this plant to be useful both as a wound salve and as a contraceptive.

In the 1990s Sonic the Hedgehog, a popular video game hero, gave his name to a protein found in fruit flies, now known to control symmetrical patterning of all animal bodies including human brain structures, eyes, the backbone, limbs and the prostate gland.

David Schaffer (above) identified the Sonic hedgehog protein as a critical "cell fate switch" that can cause adult neural stem cells to proliferate.

Leela the female cyclops in Futurama

The plant chemical cyclopamine in false hellebore, also called corn lily (Veratrum californicum), named after the one-eyed monster Cyclops, interferes with Sonic hedgehog signaling, causing birth defects. What if this could be put to positive effect?

Veratrum Californicum

In 2005, Professor Norman Maitland and Dr Anne Collins, biologists in Yorkshire, UK, extracted stem cells from prostate cancers and grew them in the lab. These tumor stem cells occur not only in prostate cancer but also in cancers of the breast and colon and in brain tumors. By using cyclopamine to block Sonic hedgehog signaling, Maitland says, these tumor stem cells could be killed off.

Professor Norman Maitland

Curis Inc. is developing Hedgehog systemic small molecule antagonist and antibody antagonist drugs in collaboration with Genentech. They have begun clinical testing of a topical drug for basal cell skin cancer. Curis states that "levels of Hedgehog pathway activity are abnormally high in advanced stages of prostate cancer."
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Posted: Thu Apr 06, 2006 1:58 pm