There are three main focuses of research surrounding the Hh pathway that could become relevant in a clinical application
1) Embryonic Stem cells for regenerative medicine (agonist/antagonist)
2) Agonist (turns pathway on)---which encompasses, degenerative diseases, stroke, hair growth in the adult body
3) Antagonist (turns pathway off)----Cancer

I will touch on the basics of each topic and in the science section of this forum you can dig into the details of each one.

1) Embryonic Stem cells for regenerative medicine.
The Hh pathway has three protein members: Indian Hedgehog (Ihh), Desert Hedgehog (Dhh), and the most famous Sonic Hedgehog (Shh). Ihh is critical in development of skeletal tissue[5], cartilage[6;7], and cardiac morphogenesis.[8] Dhh has been seen to help in testi formation[9], and Schwann cell-derived peripheral nerve sheaths.[10] Shh affects development of the cerebellum, eyes, gut, hair, heart, limbs, lung, muscle, neurons, pancreas, pituitary, prostate and teeth.[11]
The Hh proteins act as a mitogen and morphogen.[12;13] At varying concentrations of Hh proteins will cause a wide array of cellular responses. Recently Hh has exhibited long distance diffusion in stable multimeric form.[14] Being a key regulatory pathway in embryonic development, gross defects are seen from animal models to humans with mutations in the pathway. Animal studies are apparent from knock out gene or mutated gene studies. These animal studies have gross defects and often don�t survive. In animals and humans misregulation can lead to holorescphaly[15-22], syndactyly, polydactyl[23], and many other birth defects.
There is an enormous range of birth defects do to misregulation of the pathway, and it is not surprising that it is a hot topic in Embryonic Stem Cell (ESC) research. Studies have been conducted using ESC, and with the correct concentration of an agonist can create fully functioning motor neurons.[24-27] This could help people with muscular atrophy and other degenerative motor neuronal diseases. Studies have shown that dopamine neurons, which can hopefully treat Parkinson�s patients, can also be created with the aid of an Hh agonist and other factors, such as Fibroblast Growth Factor (FGF8).[28-31]

The Hh pathway is essential for proper cell choices and division, Curis's hope is that they can use an agonist to create tissues such that have neuronal or pancreas linage. Neuronal could potential help degenerative disease such as Parkinson�s. Pancreatic linage could help patients who have type 1 diabetes (see researchers Douglas Melton). Based on curis patents, it appears there main focus has been on pancreatic, motor and dopamine neuron differentiation. In theory they could then transplate these newly made cells into the patient.


2) Adult Stem cells which will encompasses, degenerative diseases, stroke, hair growth
While it is possible to convert adult stem cells into a linage this choice is more selective when compared to embryonic stem cells. Curis has partnered with Proctor and Gamble for hair growth with a Hh agonist. This will cause your hair to be put back into the growth phase if you have a hair follicle. While this does have some potential risk factors such as causing cancer like growth the potential revenue from this partnership is worth a shot. The Wyeth partnership deals with a systemic molecule (possibly for stroke) and is probably the most risky program in their pipeline. To take a molecule that turns on a pathway that is known to be essential for cancer is unsafe. Much more dicey than the hair growth program. They have already noted toxicity in animal models with the current Hh agonist. This already set the Wyeth program back and have to select a new compound.

3) Cancer
The adult Hh pathway is thought to be used during normal tissue maintenance and repair processes.[32-34] When tissue gets damaged, it has to repair itself. The Hh pathway is then activated and causes Adult Stem Cells (ASC) to divide, just like in ESC. Cancer is widely seen in tissues that are constantly being exposed to the environment, such as skin, smokers lungs, and intestinal lining. All of these tissues have a high risk of cancer and are the most damaged and repaired tissue.
A current theory states that cancer arises from an adult stem cell or progenitor cell. This progenitor cell gets fixed in growth and division phase by a mutation or a particular mechanism that is out of control which leads to cancer. Since Hh is an important factor in turning on an adult stem cell for growth, it is widely seen in cancers. ASC are not generally targeted for apoptosis, providing more evidence that cancer arises from a specific progenitor cell(s). It is meaningful, to point out that nestin and Bmi1 are regulated in a hedgehog dependent manner. These genes have been shown to be essential for self-renewal of somatic stem cells in hematopoietic and neural lineages.[35]
Curis has inhibitors of the pathway that can turn the pathway off. However, a new article came out that suggests that there could be a problem with cancers that have a mutation in the SUFU gene. This is not a commonly mutated pathway member but curis�s current Hh inhibitor will probably not work on these cancers.

Antagonist Therapeutic Regulation of the Hedgehog Pathway:
Smo seems to be the main player in the pathway do to its ability to transduce the activated form Ci/Gli. Pharmacological modulators of the pathway have been designed to inhibit activated Smo expression. These novel inhibitors don�t seem to have any effect on normal tissue. This can be explained because the Hh pathway is only turned on during maintenance and repair processes.

In a medulloblastoma animal study, the mice were subjected to HhAntag691, which is an antagonist of the pathway.[141] The scientists subjected the mice to 100mg/kg of HhAntag691 two times a day for two weeks. At this dose and frequency, the HhAntag691, completely eradicated the tumors. In the same study, they subjected the mice one time a day for 50 days at 10mg/kg per dose. For this prolonged period of time there were no side effects. An attractive therapeutic aspect of this model is that HhAntag691 was taken orally by the mice.

BCC studies have shown that Hh signaling is essential for BCC development. CUR61414, a hedgehog antagonist, has been found to be a specific inhibitor of Smo and did not affect proteins similar in structure.[142] CUR61414 inhibits the expression of Gli1 by acting on Smo. In another aspect of the experiment, they preformed a skin punch assay and showed that it prevented the formation of BCC like lesions and also caused apoptosis in UV-irradiated mice. There was noticeable apoptosis and no toxicity observed in the normal surrounding area.

Twenty-six pancreatic cancer cell lines have shown to have two or more Hh pathway components expressed .[143] However, when 12 samples expressed Smo, only half of them responded to cyclopamine, by inducing apoptosis. Either there is a downstream activating mutation, or there could be a mutation in Smo that cyclopamine can�t silence.

In a breast cancer experiment, researchers found 52/52, 50/52, and 52/52 of the specimens, which expressed Hh pathway activation.[144] They also showed that cyclopamine inhibited nuclear translocation. Interestingly 5E1 monoclonal antibody significantly inhibits the proliferation in breast cancer specimens.[145] Suggesting breast cancer is Hh ligand-dependent.

Prostate cancer has been shown to have loss of function in Su(fu).[146] However, this mutation in Su(fu) is not detected in all cancer specimens. Hedgehog interfering protein (Hip) and Ptc are shown to be expressed in 24 of 27 cancer samples. In another experiment, an animal with prostate cancer was subjected to 50mg/kg cyclopamine and showed a complete remission within 20-24 days. Furthermore the cancer did not grow back after 72days. 5E1 and cyclopamine provided similar same effects on specimens.[147]

These are only a few of the cancers that have been linked to the Hh pathway here is a complete list.
●Medulloblastoma (most common childhood cancer)
●Pancreatic Cancer
●Prostate Cancer
●Small Cell Lung Cancer
●Breast Cancer
●Esophageal Cancer
●Liver Cancer
●Stomach Cancer
●Ameloblastoma
●Oral Squamous Cell Carcinoma
●Rhabdomyosarcoma

Please note medulloblastoma shows about 25% Hedgehog expression not 100% in cancer samples.

Limitations to Hh antagonists?
The current model for inhibiting the Hh pathway is to target the Smo protein. This will hopefully prevent formation of the hedgehog signaling complex. The new way of inhibiting signaling pathways is to use ribonucleotide interference (RNAi). RNAi blocks mRNA from being translated. For the hedgehog pathway, the Gli proteins would be the target of RNAi technology. If inhibition of the Smo protein proves to be effective, then RNAi will probably not be needed in the clinic. Cells that don�t express Hh pathway activity will probably not respond to Hh pathway inhibition. Depending on how much the cancer relies on Hh pathway activity will determine how well these inhibitors work. For example, they might apoptos highly expressing Hh cancer cells but will not be able to eradicate the tumor if some of those cancer cells are not dependent on the Hh pathway activity.

Concluding remarks: While the animal models look great, there is a new challenge in getting these regulators approved by the FDA. Curis has to take the next step and bring them into the clinic. BCC interim phase 1 results were not what they anticipated, however they did see some tumors eradicated. BCC has to be close to 100% effective, and will be interesting to see how their drug is working on the tumor biology of BCC.

If you would like any of my references please ask or email me. thanks

hedgehog@pathway2curis.com