At the annual American Association of Cancer Research (AACR) annual meeting earlier this year, Prof Bert Vogelstein presented a fascinating lecture on the critical cancer pathways and how targeting the aberrant signalling may potentially lead to new breakthroughs in treatment. I've been meaning to write a series on those particular pathways, but things have been very busy since the conference in DC!
It was therefore with great interest that a new paper came out yesterday in the Cancer Research journal entitled, "Gamma-Secretase Inhibitors Enhance Temozolomide Treatment of Human Gliomas by Inhibiting Neurosphere Repopulation and Xenograft Recurrence."
This is also hot on the heels of negative news from Lilly the other week regarding their gamma secretase inhibitor, semagacestat, in Alzheimer's disease. Now, if I were on their oncology team, I'd snap it up and investigate the possibilities in cancer indications, because one's man's poison is another man's nectar: there aren't too many NOTCH inhibitors in oncology development that I know of, and those that are, are still in relatively early phase I development. More about the pipeline compounds later.
So what's all the fuss about and how does γ-Secretase connect with NOTCH signalling? Let's take a look at the basic pathway:
Source: Cell Signal
NOTCH signalling is an evolutionary pathway that has been shown to regulate cell-fate determination (renewal) during development and also in stem cells. Without going into too much biochemistry, it essentially enables cell-cell communication and continually enables renewal of adult tissues such as blood, skin, and gut epithelium not only to maintain stem cells in a proliferative, pluripotent, and undifferentiated state.
You can gather from this, therefore, that aberrant NOTCH signalling might also drive or be involved with the dreaded word in cancer: proliferation. Why? Because Notch signaling appears to play a role in regulating the cellular actions of VEGF, ie angiogenesis. For those interested in this area, there is a link to a review article on angiogenesis and NOTCH below.
You can also see from the picture above that gamma secretase is a protease that cleaves the NOTCH ligand across the cell membrane. How then does this relate to gliomas? According to the study authors:
"Notch activity is upregulated in many gliomas and can be suppressed using gamma-secretase inhibitors (GSI)."
What they found was very interesting:
Basically, in a mouse xenograft model adding a gamma-secretase inhibitor to a standard glioma drug, temozolomide, reduced tumour growth and recurrence and increased survival more effectively than either drug alone. When you consider that NOTCH may play a role in angiogenesis, these findings make a lot of sense.
What about NOTCH inhibitors in the pipeline?
This is good news for Merck in particular, since they market temozolomide, a standard treatment for gliomas and have a gamma-secretase inhibitor, MK-0752, in phase I development for breast and pancreatic cancers. There is also a single agent phase I dose finding trial ongoing with recurrent or refractory CNS tumours, but the new data from Cancer Research may excite their scientists to consider combining MK-0752 with temozolomide in gliomas. It's certainly worth a shot.
We mentioned Lilly's agent, semagacestat, but as far as I know that is only being tested in Alzheimer's disease although they appear to be testing a NOTCH inhibitor in oncology, as this advanced solid tumour trial suggests. It may a different compound, however, as the agent is not named.
The only other NOTCH inhibitor I'm aware of is from Roche/Genentech (RO4929097), which is being tested in a much broader range of cancers than Merck's, including a trial about to start in newly diagnosed gliomas, with temozolomide and a phase II study as a single agent in relapsed/refractory glioblastomas. Nice work, Roche/Genentech!
If you know of any other NOTCH or gamma secretase inhibitors in development for cancer indications, do drop a note in the comments. I'm sure Vogelstein would agree that this is a very promising area of research indeed so far.
Gilbert, C., Daou, M., Moser, R., & Ross, A. (2010). -Secretase Inhibitors Enhance Temozolomide Treatment of Human Gliomas by Inhibiting Neurosphere Repopulation and Xenograft Recurrence Cancer Research DOI: 10.1158/0008-5472.CAN-10-1378
Cook, K., & Figg, W. (2010). Angiogenesis Inhibitors: Current Strategies and Future Prospects CA: A Cancer Journal for Clinicians, 60 (4), 222-243 DOI: 10.3322/caac.20075