Notch targeting 2.0

In this issue of Blood, Cullion and colleagues add an encouraging chapter to the saga of Notch1 as a therapeutic target in T-ALL.

Notch1 is a member of a family of highly conserved receptors that normally signal by way of a series of ligand-induced proteolytic cleavage events. These permit the intracellular portion of Notch1 (ICN1) to gain access to the nucleus, where it forms a short-lived transcriptional activation complex. The final cleavage that liberates ICN1 is carried out by γ-secretase, a multiprotein complex that also implicated the generation of amyloidogenic peptides from β-amyloid precursor protein in the brains of patients with Alzheimer disease. Interest in Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) has been sparked by the recognition that acquired Notch1 mutations leading to elevated levels of ICN1 are found in the majority of human T-ALLs as well as many murine T-ALL models.¹  Subsequent studies have shown that ICN1 drives the growth of T-ALL cells, in large part due to its ability to up-regulate c-Myc expression and enhance signaling through the PI3-kinase/AKT/mTOR pathway.

The increases in ICN1 levels caused by Notch1 mutations are counteracted by drugs that inhibit γ-secretase, a large number of which are in preclinical development due to the link between γ-secretase and Alzheimer disease. This fortuitous circumstance made Notch1 a very attractive rational therapeutic target, but the first attempt to treat patients with refractory/relapsed T-ALL with an oral γ-secretase inhibitor (GSI) was plagued by both treatment failures and “on-target” gut toxicity.²  The latter probably resulted from goblet cell metaplasia, as in the absence of Notch signaling the differentiation of epithelial cells lining the small bowel and colon is skewed toward goblet cell fate and away from enterocyte fate. Although these were the early days, the disappointing results of this trial raised serious questions about the future of Notch-directed therapeutics.

The tide may have turned, however, based on 2 recent reports. Earlier this year, Ferrando's group reported that GSI and dexamethasone, long known to be highly active against ALL, have strongly synergistic anti–T-ALL effects in vitro and in murine xenografts.³  This, in and of itself, is not completely surprising, as Notch1 signaling had been shown through retroviral mutagenesis screens conducted more than a decade ago to protect against dexamethasone-mediated killing of murine T-cell lines.⁴  What was entirely unexpected was that dexamethasone also protected mice against GSI-induced gut toxicity by blocking goblet cell development and shifting differentiation back toward enterocyte fate. One critical uncertainty hangs over this remarkable observation, however. The dose of dexamethasone used in these studies was very high (15 mg/kg), well above that which can be tolerated by patients, and it remains to be determined whether clinically achievable doses of dexamethasone will have the same salutary effect on GSI-limiting gut toxicity.

Now, Cullion et al provide an alternative way forward, again using mouse models.⁵  Cullion et al take advantage of the fact that it takes about 5 to 7 days for a stem cell in a gut crypt to give rise to enterocytes and goblet cells and show that an intermittent, 3-day on/4-day off GSI dosing schedule largely avoids gut toxicity while maintaining significant anti–T-ALL effects. They also demonstrate that the efficacy of GSI is enhanced by the addition of rapamycin, an inhibitor of mTOR. This is in line with prior work showing that mTOR is activated by Notch signaling,⁶  at least in part through its ability to suppress PTEN,⁷  an important brake on the PI3-kinase/AKT/mTOR pathway. Of note, Armstrong's group has shown that rapamycin also synergizes with glucocorticoids to kill ALL cells,⁸  raising the possibility that some combination of Notch and mTOR inhibitors and glucocorticoids might ultimately prove to have the most activity against malignant T lymphoblasts. Substantial further improvements in therapeutic index are needed if Notch inhibitors are to move into clinical practice, but with a number of promising paths to pursue, there is new reason for optimism.