A few months ago Dr. Sauvage from Genentech hinted at new Hh inhibitors that targeted the pathway downstream of SUFU and SMO. I have included a pathway diagram to help in the explanation. However, this is a very old diagram and a lot of new components and regulation properties have been discovered it will work for explanation purposes.




As seen above current Hh inhibitors target SMO or smoothened. A few cancer cell lines have Hh pathway activation but are insensitive to current SMO antagonist. Thus rendering the current antagonists useless (in cell line experiments). A paper just came out that talked about small molecules that actually inhibit Gli1(the most potent Hh target gene activator) from binding to the DNA or somehow disrupt the process of translating Hh target genes.


There have also been a few experiments that have also said that cancer cell lines and vivo animal models (with the same cancer cell line) act very differently when subjected to current SMO antagonists. They have noted that even tho SMO antagonist don't work on some cancer cell lines they seem to work very well in the animal models. The reason for this could be because of the surrounding stromal tissue of the tumor. Because the SMO antagonist can stop the stromal tissue from Hh pathway activation researchers see a decrease size in tumor volume. It remains to be seen if it (current SMO antagonist) will have any effect on the REAL the cancer stem cells that are subjected to current antagonist in the animals or patients. My guess is that we might see a decrease in tumor volume and hopefully a halt of metastasis but if patients have a relapse it is probably because of what I have just talked about. However, if there are no mutations in the cancer stem cells Hh pathway downstream of SMO and the pathway is activated it will probably yield a potentially much better outcome.

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Article published about New Hh inhibitors

http://www.pnas.org/cgi/content/full/104/20/8455
Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Matthias Lauth, Åsa Bergström, Takashi Shimokawa, and Rune Toftgård*

Department of Biosciences and Nutrition, Karolinska Institutet, Novum Research Park, Hälsovägen 7, SE-141 57 Huddinge, Sweden

Edited by Craig B. Thompson, University of Pennsylvania, Philadelphia, PA, and approved April 2, 2007 (received for review November 1, 2006)

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.


Fig. 5. Human prostate cancer xenograft. (A) Change of tumor volume during treatment period. Time points of injections are given as arrows above the curve. (B) Macroscopic appearance of xenografts at the beginning of treatment (day 0) and at the end of treatment (day 1. No tumor could be seen in GANT61-treated animals (the bulge in the picture is part of the rib cage). (C) Quantification of PTCH mRNA by quantitative PCR in treated 22Rv1 tumors. Values were normalized against GAPDH. Shown is the mean of the analysis of two tumors for each treatment.



Fig. 1. Inhibition of GLI-induced transcription in transfected HEK293 cells. (A) Schematic illustration of the compound screen to identify small-molecule GLI antagonists. GliBS, Gli binding site; Luc, firefly luciferase. The structures of two hits, GANT61 and GANT58, are given in the upper right. (B) GLI1 inhibition. (C) GLI2 ({Delta}N-GLI2) inhibition. SUFU (SF) was cotransfected as a positive control. To achieve equal transfection efficiencies in all wells, transfections were done on large plates and then split on smaller wells and treated. All values were normalized to total protein amount. Treatment time was 24 h, and control cells were treated with DMSO only. Shown is the mean of three independent experiments. Error bars indicate SD.

With respect to the numerous potential mutational targets within the Hh pathway downstream of Smo already discovered, the group of tumors for which direct GLI inhibition is beneficial is substantial and likely to increase. Hence, the small-molecule inhibitors of GLI-mediated transcription described here will be valuable research tools in elucidating the involvement of GLI in normal embryonic development and tumor growth. In addition, data presented in this work might encourage further medicinal chemistry efforts to explore the full potential of these compound classes. Having the latter in mind, it is interesting to note that both GANT molecules meet the criteria concerning effective absorption and distribution of potential drug molecules (37).