Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘hedgehog’

Back in 2009 at the American Association for Cancer Research (AACR) Molecular Targets meeting, a researcher (Anirban Maitra) from Boston had a most interesting poster about the use of nanotechnology to deliver nab-paclitaxel (Abraxane) to pancreatic adenocarcinomas in a more targeted fashion.  You can read about it in more detail from the meeting coverage at that time.

Essentially, one of the things that stops chemotherapy being more effective in advanced pancreatic cancer is that the stromal layer forms a physical, almost impenetrable layer, that slows drugs from getting through to the tumour.

Using nanotechnology, the MIT researchers were able to direct nab-paclitaxel to the stromal layer more effectively, wiping it out and allowing subsequent gemcitabine to be more effective in their animal models.

Fast forward two years and there has been a new paper in Cancer Discovery by a different group (see Frese et al., (2012) from the University of Cambridge in the references) looking at the mechanistic role of nab-paclitaxel in pancreatic adenocarcinomas.

Their findings were as follows:

  • Combination of nab-Paclitaxel and gemcitabine causes tumour regression and reduces metastasis
  • Treatment with nab-Paclitaxel targets tumour epithelial cells
  • nab-Paclitaxel promotes elevated intratumoural gemcitabine levels
  • nab-Paclitaxel decreases cytidine deaminase protein levels

Taken together, the authors concluded that, mechanistically:

“Paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine.

Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA (pancreatic ductal adenocarcinoma) and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.”

In an AACR press release, the leader author, David Tuveson, was quoted as saying:

“We predict from this mechanistic study that nab-paclitaxel may be most effective if we administer it first, and delay administration of the gemcitabine. The next step is to test this prediction, since it could help a great deal with patient treatment.”

Based on the earlier Boston research in 2009, I think that this sequencing approach makes logical sense, because the nab-paclitaxel will wipe out the stromal layer and create an opportunity for the subsequent gemcitabine infusion (or other therapy) to be more effective.

What are significance of these findings?

Firstly, there are a number of trials ongoing in pancreatic cancer, including a phase III trial of gemcitabine plus nab-paclitaxel, which is expected to mature next year. Based on the promising interim data, I’m hopeful that this combination may move the needle in terms of improved survival (as measured by OS) for patients with this devastating cancer.

More recently, Infinity reported that their phase II trial with their Hedgehog inhibitor (saridegib) plus gemcitabine was stopped for futlity. I wasn’t surprised to hear this based on the 2009 data mentioned above, because without blasting out the stromal layer, neither the TKI nor gemcitabine can impact the tumour cells effectively. Another Hedgehog inhibitor, vismodegib (Genentech/Roche) is being evaluated in a triple combination trial with gemcitabine and nab-paclitaxel. I like this trial design a lot better, but we will have to see whether sequencing is also important, as shown in this latest research, ie nab-paclitaxel first, followed by gemcitabine (plus the Hedgehog inhibitor).

All in all, Frese et al., (2012) provide novel insights into the antitumour activity of nab-paclitaxel. They also offer a potential mechanism for improving gemcitabine delivery to pancreatic tumours that deserves research in the clinical setting. This more targeted smart approach to trial design may well yield improved results in the clinic, rather than the old method of throwing random doublets and triplets at the (tumour) wall hoping something will stick.

References:

ResearchBlogging.orgFrese, K., Neesse, A., Cook, N., Bapiro, T., Lolkema, M., Jodrell, D., & Tuveson, D. (2012). nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0242

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Yesterday was a travel day for many of us at AACR and the weather doesn’t always cooperate in ensuring timely arrivals.  Never fear, there are ways to catch up on what was missed…. wondering what was hot on Day 1?  Check out the short video clip below:

http://www.youtube.com/watch?v=JS8ycFmI9x0

AACR have posted their webcast and podcasts links for those following remotely that are worth checking out – many are free as well, making them great value.

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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.”

3657524851_b1936f3830_mWe’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
  • Pancreatic
  • Ewings sarcoma
  • Melanoma
  • 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

ResearchBlogging.orgMerchant, 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

 

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