Notch Holds Promise, but Presents Obstacles as Cancer Target

Benjamin W. Purow, MD

Associate Professor, Clinical Neurology, University of Virginia School of Medicine,

Charlottesville, VA

1

How does the research in your laboratory relate to Notch signaling and cancer?

2

Why does Notch make a promising target for cancer therapy?

Working in a laboratory at the National Institutes of Health, Benjamin W. Purow, MD, became the first researcher to demonstrate that the Notch pathway plays a role in gliomas. Today, he is pursuing the pathway at the University of Virginia School of Medicine in Charlottesville. He spends the majority of his time in the lab, where his research focuses on glioblastomas, the most common and most lethal primary brain tumors, with the ultimate goal of developing new therapies for this deadly disease. The remainder of his time is spent in the clinic and with patients in whom these treatments may one day be applied. Our primary focus is on glioblastoma brain tumors, and we are interested in a number of novel therapeutic approaches to these and other kinds of cancer. One of the foci of the lab is targeting the Notch pathway in these tumors. But we are also interested in other novel targets such as microRNAs, which we transitioned into through some of our Notch studies several years ago. We are interested in microRNAs both upstream and downstream of Notch (in other words, those that could regulate Notch or that are themselves being regulated by Notch). We have found some microRNAs that suppress the Notch pathway and offer a potential therapeutic angle in these tumors, though we face the significant challenge of efficient delivery to brain tumors. Notch has been attracting increasing interest in oncology in recent years, although the first evidence came from some much older studies that showed that if you engineered a constitutively active form of the Notch protein into mice it could lead to T-cell leukemia. That was a beautiful indication that Notch activity could be causal or at least tumor−promoting in certain cancers. Since then, Notch has actually been found to play opposing roles in different kinds of cancer. In certain cancers, such as gliomas/glioblastomas, Notch seems to play a pro-tumor role. Interestingly, though in some cancers (such as T-cell leukemia) it plays a “classic” oncogenic role, in others it displays tumor-promoting activity without common mutations or amplifications in the gene. Then there are other cancers where it plays more of a tumor−suppressive role, such as skin and lung cancers and possibly B-cell malignancies, in which the Notch pathway is suppressed to foster tumorigenic activity.

Another reason that interest in the Notch pathway has been enhanced is that we had small-molecule inhibitors ready and waiting in the wings that had originally been developed for use in Alzheimer patients: the gamma secretase inhibitors (or GSIs), which block the enzymatic processing of a number of different proteins, including Notch. A lot of clinical research thus far has focused on testing these inhibitors in various cancers.

3

What is the most significant recent development relating to Notch signaling in cancer?

4

In your opinion, which of the Notch-targeted agents holds the most promise?

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What are the major hurdles to the development of Notch-targeted anticancer agents?

Finally, we tend to think of cancers as very primitive kinds of cells, stem cells gone awry, or mature cells that have reverted to a more primitive state, and, since Notch has a key role in maintaining the stem-cell state, it makes sense that it may have a role in fostering the development of cancers. Furthermore, in recent years we have realized that not all cancer cells are the same and in a lot of cancers there seems to be a subset called cancer stem cells, which may be the original cells that got the tumor going and replenish the tumor after treatment with traditional therapies. By targeting Notch, we may be able to get leverage against these cells and sensitize cancers to chemotherapy or radiation treatment. There have been a lot of really fascinating developments in recent years. With respect to the end goal of getting agents approved for use in patients, the trials in T-cell leukemia were actually somewhat disappointing. There were some serious toxicity issues with the GSIs. Researchers are now finding ways to get around this⎯ with weekly dosing, for example⎯and there are ongoing clinical trials in a number of different cancers. Some of the pharmaceutical companies have been somewhat discouraged by the results of trials with a Notch inhibitor as a single agent, but it seems there may be increasing enthusiasm for combining Notch with other agents to sensitize cancer cells to chemotherapy or other anticancer agents. Also, Notch (specifically the delta-like ligand 4 [DLL4]) has been found to play an important role in angiogenesis (new blood vessel development). Monoclonal antibodies directed against DLL4 have been shown to significantly disrupt the tumor vasculature. One caveat of this is that it may lead to a certain kind of blood vessel tumor, so further work is clearly needed. The gamma-secretase inhibitors are very nonspecific. They block processing of a number of proteins and affect a whole range of cellular processes, as well as being very nonspecific within the pathway itself, inhibiting all of the different Notch receptors. There have been hints that we might gain benefits from more selective and targeted inhibition of a single Notch receptor or ligand, and a number of pharmaceutical companies are working on developing antibodies to block these proteins. Interestingly, antibodies that activate certain Notch family members are also being looked at, and these may have interesting applications in tumors where Notch has a tumor-suppressive role. I think these more specific agents probably hold the most promise at the moment. Notch is not an enzyme, so developing drugs to block it has been a challenge. Enzymes, like kinases, are much more easily druggable. It was a bit of luck really that there is a druggable protein that processes Notch, namely gamma-secretase. Another issue has been the diversity and sheer level of complexity within the pathway; there are four Notch receptors and several different ligands as well, and it’s starting to become clear that they can have different functions within the cell. A third issue is the toxicity I mentioned. It is not harmless to block Notch, with side effects like severe diarrhea. All of these present significant challenges in the pursuit of Notch-targeting agents.