Posted by Jeff Berk; BOLT International
Here in Arizona the scorpions are out. While that can mean a lot of things to a lot of people, to us it means that it’s not too soon to be thinking about ASCO 2011. One of the emerging stories we expect to see is the development of Hedgehog / Smoothened inhibitors for pancreatic ductal adenocarcinoma. The Ph-II trials for Infiniti’s IPI-926 in combination with gemcitabine (Gemzar®) in patients with metastatic pancreatic cancer and as a single agent in patients with metastatic or locally advanced, inoperable chondrosarcoma should be presented. We may also see data on Genentech’s (Curis) GDC-0449 (Follow this link to a list of relevant ongoing studies).
- A couple of months back we asked BOLT’s THOUGHT LEADER panel to rank new approaches for the treatment of PDA. Use of hedgehog pathway inhibitors to target the signaling between pancreatic stromal and tumor cells, as well as the stromal cells directly, is the approach that generated the most excitement amongst this thought leader panel. These drugs seem to convert what were very stromal tumors into ones that are more epithelial, and thus sensitizes them to both chemotherapy and targeted therapy. Hedgehog pathway inhibitors may also be killing stem cell populations, and at least in the laboratory they improve the activity of Abraxane.
“The other one we are expecting are the hedgehog and smoothened inhibitors, which I think is a little bit earlier, but we will see that at ASCO 2011. But certainly there is a lot of interest based on the idea of targeting cancer stem cell and targeting the stroma these molecules may be effective. A couple of panelists have mentioned that. Why is hedgehog pathway inhibition relevant to the fibrosis, to the desmoplasia? Well there is a paper by David Tuveson and his group in mouse models published about a year ago that shows that the hedgehog inhibitors are very effective in eradicating the stroma. So all of a sudden pancreatic cancer stops being a very fibrotic tumor and became a more epithelial type of tumor and the delivery of chemotherapy improves. So you get better activity because you deliver the drug. I mean it is an idea. And then we are still willing to deal with the cancer stem cell which may be different and sensitive to only certain agents. So still it will be a three prong approach, likely to be more sequential rather than combinatory because I don’t think we are going to put all that many drugs together without causing a lot of toxicity”.
“I am not sure that increasing the expression of the SPARC by 20 percent is going to make things any better. I think what is really is of interest, I would go another route, I would rather combine a SPARC with hedgehog inhibitors which we are doing in the laboratory and combine the SPARC with other anti-stromal agents”.
“If I am convinced that when I use these agents I am able to get an indicator that I am hitting what I am supposed hit then if I could get an indication from the tumors themselves whether they have the profile they are sensitive to it. Then I think that I would be enthusiastic in moving these agents higher up on the list so I need to can get some real understanding. Otherwise, we are going to go back to the old fashioned approach of trying a new thing on and seeing how well it works. So that is kind of a very hedging response, but I think it is a realistic response. So hedgehog inhibitor, we are very enthusiastic for a number of reasons. We are going with that for study and we will find out hopefully in a few years whether it is going to make an impact”.
“What is the involvement of hedgehog in these stromal cells? So that is a leading question to what will be the opportunity for a hedgehog inhibitor in the treatment of pancreatic cancer? With the studies we are launching now it is interesting because I would say we had a naïve perspective because the hedgehog pathway is elevated and tumor cells that same concepts that if you go in after that you will hit it. I think it is becoming more complicated because there seems to be an interplay between the stromal cells and the tumor cells with regards to hedgehog pathways. So it is not just the tumor cell that is actually sensitive to hedgehog signaling. So again preclinical data is going to have to be generated and I think they are coming out in pretty good succession showing that hedgehog inhibitors may actually have some effect on the stroma itself as well. And so I think this tumor is quite intriguing, there seems to be this symmetrical relationship; at the minimum two compartments. At the end we going to see the clinical read out, but I think that we still need some mechanistic insight to really know what combinations makes sense. For example, if you were to use hedgehog with Abraxane and gemcitabine is that overlap with some components of FOLFIRINOX? We really need to understand the mechanism at that level”.
“I think we are all desperate for new drugs and people because of this preclinical model are kind of excited about hedgehog inhibition, but only time will tell. Again my kind of naïve thoughts are that a single targeted medication is going to be insufficient in what we know is a highly complex disease”.
- The theory that’s most en-vogue right now is that the Hedgehog pathway inhibitor is leading to greater penetration through the stroma and into the primary tumor. There is a mechanistic basis for this “improved delivery”, however some panelists believe that it is more a matter of resistance than necessarily a delivery mechanism.
“You know hedgehog inhibitors, for instance, the people who work with that have said there is a greater likelihood of circumventing that difficulty. There is a greater penetration and there are mechanistic reasons why those would work. But I think we heard that story with Avastin as well; that you decrease interstitial pressure and improve delivery. I think it is fibrotic stroma is important; however, when the drug works you see shrinkage and I think Abraxane/gemcitabine as well, you see quite significant responses in the primary. So the drug has to get there some way or the other. My own bias is that it is more a matter of resistance of the cancer cells to therapy rather than necessarily a delivery mechanism”.
GDC-0449 (Curis / Genentech)
- GDC-0449, an orally available hedgehog inhibitor, is in a Ph-I trial in patients with localized neoadjuvant pancreatic ductal adenocarcinoma (NCT01096732); called HIPPoS. The trial is aimed at delineating whether GDC-0449 directly affects the tumor or stromal cells. The estimated enrollment is 20. The start date was July 2010, and completion is set for January 2012. NCT01088815 is an open-label, single arm, multi-center, 80 patient Phase II trial to evaluate the progression free survival in patients with metastatic adenocarcinoma of the pancreas treated with a hedgehog inhibitor (GDC-0449) in combination with chemotherapy (gemcitabine and nab-Paclitaxel). The start date was May 2010, and estimated completion is December 2012.
“Please remind me if you had seen any response data for any of the hedgehogs with pancreatic cancer? No, I don’t think any of that is out yet. In the clinical setting I think the Genentech compound is ongoing in the Chicago consortium”.
IPI-926 (Infinity / Purdue / Mundipharma)
- IPI-926 is an orally available hedgehog inhibitor being jointly developed by Infinity, Purdue and Mundipharma. NCT01130142 is a Ph-I/II study of gemcitabine +/- IPI-926 in previously untreated PDA.
“The Infinity compound, that study we were approached to join it and we are not joining it. I know from that that study is going to open or has already just opened. There is no response data out yet. It just looks very promising in the lab, certainly the Hopkins group have promoted this very strongly. It remains to be seen what kind of effectiveness. So they are doing those sort of studies that you mentioned with gemcitabine/Abraxane and hedgehog inhibitors. So we will see. It is a leap of faith, but yeah”.
“Given that you mentioned those, I think conceptually the hedgehog data also look interesting and the preclinical model that Ken Olive and David Tuveson and that group have put together provides a framework that makes sense in pancreas cancer demonstrating reversal of gemcitabine resistance combining gemcitabine with Infinity hedgehog inhibitor preclinically. So there are early stage studies underway that are designed to explore that but I think we are all kind of humbled all the time that the challenges of pancreas cancer and much in all we would love to believe it is as straightforward as that I doubt that is going to prove true in practice, but it might add an incremental step with relatively low toxicity which could be built on further for pancreas cancer development”.
“The marked desmoplasia, the fibrosis, may hint to a molecular pathway or pathways and that is why the hedgehog inhibitors have become a little fashionable thing nowadays because they can target that area”.