12/28/09

We have discussed the Curis/Roche drug candidate GDC-0449 at substantial length recently.  The upward movement in Curis (CRIS) shares is associated with the positive developments in this candidate as well as a recurring market speculation that the company may be an acquisition target of Roche.  We believe something much more fundamental is occurring. 

Our view is that the recent strength in the stock is also associated with a broadening realization that the hedgehog candidate is headed for several cancers outside of basal cell. 

The recent AACR Breast Cancer Symposium provides some positive reinforcement for the Curis pipeline in multiple ways.  We’ll discuss the hedgehog pathway first and then address the Curis candidate CUDC-101.

Cancer Stem Cells…Hedgehog and Notch

Recall in our previous discussion we identified a special ACTNOW funding project involving GDC-0449 and a notch pathway inhibitor from Roche. 

Another trial will explore the use of two experimental agents, an oral gamma-secretase inhibitor (which alters the function of certain protein machinery in cells) and GDC-0499 (an inhibitor of the hedgehog signaling pathway that has been implicated in numerous cancers), to treat women with invasive breast cancer.

(August 2009 Directors Update of the National Cancer Institute, bold our emphasis)

We have not seen any other disclosure that GDC-0449 is in a trial to specifically treat breast cancer.  Such disclosure will likely give shares a boost when revealed.

(Rick Currin, “Digging Deep into the Curis Hedgehog” ,12/10/09)

The latest spike in Curis, so close on the heels of the Breast Cancer Symposium, may not be a coincidence.

The ACTNOW funding program comes through the special emphasis the National Institutes of Health (NIH) and the National Cancer Institute have placed in the area of cancer stem cells research. 

The basic hypothesis of cancer stem cells is that there are fundamental cancer initiating cells that promote a tumor response in other cells.  These cancer stem cells lead to recurrence and metastasis even when all signs of the cancer have been removed by surgery or conventional chemotherapy. 

(source:Macrogenics)

The bottom path of the above illustration graphically illustrates this process.

The Cancer Stem Cell Dilemma

Cancer stem cells (sometimes called mother cells, or tumor initiating cells) are resistant to traditional chemotherapy and radiation.  This creates a difficult problem in that the percentage of tumor initiating cancer stem cells actually rises relative to healthy cells after chemotherapy and/or radiation.  Thus the table is actually set for continuation or acceleration of disease after certain treatments despite having knocked down or even eliminated existing tumor cells. 

The cancer stem cell dilemma thus places the elimination of cancer stem cells and/or their ability to generate through pathways as crucial if not mandatory for ever getting to the root issue of metastasis and relapse.  Both the Notch and Hedgehog pathways are thought to be key signaling pathways of cancer stem cells.  Substantial research now supports this as well.

The NIH declared Cancer Stem Cell (CSC) therapeutics a major initiative which is what has ultimately led to all the stimulus funding associated with the candidate GDC-0449. Recall the special funding we highlighted from the Cancer Therapy Evaluation Program (CTEP) originated from a drug development plan of the Cancer Stem Cell Task Force of the NIH.

The Cancer Stem Cell (CSC) Therapeutics Initiative will evaluate agents (GSIs, kinase inhibitors, DLL ligand inhibitors, antibodies, disruption of protein interactions) that target the cancer stem cells/progenitor cells and their altered embryonic signaling pathways, with a particular emphasis on Hedgehog (SHh), notch and wnt signaling.

(NIH.gov –Major Initiatives)

One exciting bit of news from the breast cancer symposium was research around a Merck gamma secretase inhibitor (i.e. notch inhibitor) presented in the Cancer Stem Cells session.  The hedgehog also made an appearance in that session though the study was an older one we had already seen.

Let’s take a cursory look at the older study first.

Hedgehog Signaling Pathway Is a New Target of Cancer Stem Cell Therapy for Breast Cancer Patients

 

Tanaka H, Nakamura M, Sohzaki M, Kai M, Kubo M, Ohnishi H, Tanaka M, Katano M. Kyushu University, Fukuoka, Fukuoka, Japan.

From the abstract:

“the Hh pathway may be a valuable therapeutic target for CSCs (cancer stem cells) therapy for breast cancer.

We’ll allow the title and snippet from the abstract to speak for itself.  

The second study involving the Notch pathway candidate from Merck was press worthy because it included a small clinical trial.

Targeting Intrinsically-Resistant Breast Cancer Stem Cells with Gamma-Secretase Inhibitors

 

Landis MD, Pavlick A, Dobrolecki L, Korkaya H, Zhang X, Froehlich A, Rodriguez A, Rimawi M, Wicha M, Lewis MT, Chang JC.  Baylor College of Medicine, Houston, TX; University of Michigan, Ann Arbor, MI.

In this study inhibiting the notch pathway was able to reduce cancer stem cells in both mouse models and a “small clinical trial”.  By inhibiting the notch pathway, the cancer stem cell (CSC) population was reduced.  This in turn prevented the ability of the CSCs from “initiating” new tumor cells and the tumors began shrinking. 

So what does that have to do with hedgehog signaling?  Inhibiting hedgehog signaling has already been shown to reduce the very same CSC’s in previous pre-clinical studies.  The CSC’s in the Merck study were primarily identified by expression of CD44/CD24 proteins (i.e. identified breast CSCs).  These same CD44/CD24 proteins are suppressed by inhibiting hedgehog signaling (and likely by GDC-0449).

For example:

The Hedgehog Signaling Pathway Plays an Essential Role in Maintaining the CD44+CD24-/low Subpopulation and the Side Population of Breast Cancer Cells

Tanaka et al

and

“Moreover, recent evidence suggests that Sonic Hedgehog ligand (SHH) might be specifically overepxressed in a subpopulation of CD24+/CD44+/ESA+ pancreatic cancer cells with increased tumorigenic potential and other stem cell–like properties. …these studies suggest an element of Hedgehog dependence in a subset of pancreatic cancer cells with tumor-initiating properties, also referred to as “cancer stem cells.”

(An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer)

- Feldman et al)

Inhibiting hedgehog combined with an mTOR inhibitor has been shown to eradicate cancer stem cells in pancreatic cancer.  (Reference: Mueller, M. T. et al. “Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer”. Gastroenterology, 2009).  We are especially excited about this research development in such a notoriously fatal cancer.

In short, we view the recent breast cancer symposium as further validating the Cancer Stem Cell hypothesis as well as the hedgehog and notch pathway roles in mitigating metastatic potential.  More to the point, the role of hedgehog, and the cancer stem cells that hedgehog could control, is being revealed clinically and pre-clinically in many cancers.  Basal cell is simply the gateway for this drug getting to much larger markets. 

The reason the NIH is supporting GDC-0449 is because of the broad implications of the hedgehog pathway mitigating general metastasis in multiple cancers through inhibition of cancer stem cells. 

This is bigger than the approval of GDC-0449 for basal cell by orders of magnitude. 

A small clinical confirmation of the cancer stem cells regulation by the notch pathway has now been revealed at a breast cancer symposium.  Hedgehog signaling is just as likely to confirm such activity as it has done so pre-clinically.  The NIH’s focus on hedgehog and notch by the cancer stem cell task force seems on target.

We believe the hedgehog signaling pathway is emerging as a fundamental and clinically validated pathway for limiting metastatic cancer.  That bodes well for tiny Curis.

CUDC-101 and “Whac-a-Mole”

Pathway targeting of cancer can result in a Whac-a-Mole effect.  Perhaps you know the arcade game where you repeatedly smack the little mole on the head with a mallet only to have another one pop up in another place?  In cancer, you can clobber one pathway target only to have enabling of the pathway rear its head downstream of the blockade as the cancer struggles to evade death. 

This Whac-a-Mole phenomena could occur with GDC-0449, as some patients certainly will develop a mutation resistance to blocking the hedgehog pathway activation in the method used by the drug. 

The Whac-a-Mole effect can also be described as having another pathway become a more active alternative route for cancer progression “because” you have blocked its typical pathway.  This is sort of like if “I can’t get in the front door to complete the circuit I’ll kick in the back door or maybe a window”.  

So while we like to call GDC-0449 “the hedgehog drug” we think of CUDC-101 as the “Whac-a-mole” drug trying to cover the front door, the back door and the window.

Playing Whac-a-Mole with More Mallets

We found validation for the platform of Curis candidate CUDC-101 in a combination study presented at the breast cancer symposium. 

CUDC-101 is a multi-targeting cancer drug targeting HDAC/EGFR/HER2.  In some respects CUDC-101 (the Whac-a Mole) is a self contained combination study of Tarceva plus Tykerb plus an HDAC inhibitor.  HDAC has been shown to improve the effectiveness of single agent targeting.  (i.e. Tarceva plus HDAC should work better than Tarceva alone if both are tolerated).

In a very interesting result of a clinical study it was found that Genentech’s Herceptin, when combined with Tykerb, allowed patients to live 20 weeks longer than patients given Tykerb alone.  Perhaps more interesting than the important, but seemingly still futile 20 weeks, is the fact that the patient population was made up of patients who had previously developed resistance to Herceptin.   So patients failing Herceptin actually began to benefit from Herceptin when Tykerb was added.  In other words, Tykerb defeated Herceptin resistance and Herceptin began to work in synergy with Tykerb. 

Tykerb targets one of the same targets as Herceptin.  It also targets the same pathway further downstream.  This study can be viewed in some respects as a Herceptin plus Herceptin downstream target/Tykerb study.  The results seem to indicate that the downstream target played “Whac-a-Mole” with Herceptin alone and got activated even with the pathway blockage that Herceptin imparts upstream.  Because Tykerb targets the downstream target as well, it brought two mallets to the Whac-a-Mole game in the HER pathway. 

Curis’s candidate CUDC-101 targets two of the same things Tykerb does.  CUDC-101 could be characterized in lay terms as an all in one Tarceva (EGFR) plus Tykerb (EGFR/HER) plus Zolinza (HDAC) combination drug.  To put things in even more lay terms, CUDC-101 is bringing at least 3 mallets to the cancer game of Whac-a Mole.  (Or to use the prior analogy, it covers the front door, the back door, and the window.) 

This approach has the potential to limit drug resistance, enhance combined effects seen through HDAC inhibition, take advantage of the now known effectiveness and proven synergy of EGFR and HER targets, and perhaps leave that mole no place to pop up his head.

While CUDC-101 is probably way too early in the clinical process to get too excited, Curis has certainly picked a combination that would seem to mimic if not substantially improve on the results of Herceptin plus Tykerb.  Only clinical results will tell us; but the implications of this Tykerb/Herceptin combination study are quite good for CUDC-101.

We are encouraged that Curis’s pipeline is aimed at diverse cancer markets with massive potential for expanding indications over time.  We remain very bullish on shares long term.