The other day I came across an interesting journal article on Hedgehog signalling, how it might be implicated in some cancers, and the potential issues associated with targeting the pathway:
“… several issues surrounding the basic biology of the Hh pathway in human cancers remain unclear. These include the influence of specific oncogenic events on Hh signal transduction, the precise mode of Hh signaling (i.e., autocrine or paracrine) that occurs within human tumors, and the best means to inhibit aberrant pathway activity in the clinical setting.
The cancer stem cell (CSC) hypothesis may explain a number of clinical phenomena, such as unchecked self-renewal and the development of metastatic disease, and to some extent, the Hh signaling pathway has been implicated in all of these processes.
Therefore, Hh pathway inhibitors may also represent some of the first agents to formally examine the CSC hypothesis in the clinical setting.”
We’ve covered a little about the basics on Hedgehog and Smoothened in the past on this blog (see here and here for examples), but the latest journal article covers some new topics of discussion. In particular, I loved Fig 4 but cannot reproduce it here for copyright reasons, but you can check it out through the Research Blogging for peer reviewed science articles link below.
In the past, it was thought that Hedgehog signalling was associated with basal cell carcinoma and medulloblastoma, both fairly rare cancers.
The new review provides some useful references for involvement in other cancers including:
- Multiple myeloma
- Ewings sarcoma
- Breast cancer
- Ovarian cancer
- Prostate cancer
And a few others as well. Of course, it is still unclear whether Hedgehog is a critical driving aberration in these tumours, but as early clinical trials expand into new indications with pipeline drugs, so we will learn more. It is possible that multiple combinations with a cocktail of therapies each aimed at different targets may be the way to go, but most likely an incremental and conservative approach will be reflective of the initial offerings.
In terms of agents targeting Hedgehog, a number of companies are active in this space:
- Roche Genentech/Curis have GDC-0449, a small molecule inhibitor.
- Curis have Debio-0932, a heat shock protein inhibitor, which they are developing with Debiopharm.
- Another Hsp90 inhibitor that is in very early development for solid tumours and pancreatic cancer is IPI-926 from Infinity.
- Novartis have LDE225, which targets Hedgehog and Smoothened.
- Exelixis/BMS are testing XL139, which also targets Smoothened, in gastric and small cell lung cancers and multiple myeloma.
There are probably a few others, both those are the ones that jumped to mind just now. If you know of any I’ve missed, please do add them in the comments section below.
The Pharma pipeline in this field is obviously burgeoning, but most are in fairly early trials having not long moved out of preclinical, so it will be a while before we know whether this is a useful target for therapeutic intervention or not.
Photo Credit: Dave-F
Merchant, A., & Matsui, W. (2010). Targeting Hedgehog — a Cancer Stem Cell Pathway Clinical Cancer Research, 16 (12), 3130-3140 DOI: 10.1158/1078-0432.CCR-09-2846