Notch inhibition in desmoids: “Sure it works in practice, but does it work in theory?”

In a phase 1 trial of PF-03084014, an oral Notch inhibitor, 5 of 7 patients (approximately 70%) with desmoid tumors (DTs) had a partial response. This was an unprecedented response in DTs. When the first DT patient enrolled in the study, there was no published evidence to support Notch inhibition in DTs. Nevertheless, this serendipitous discovery led to further studies. Biomarker studies in peripheral mononuclear cells showed a predictable decrease in HES4 levels, a downstream target; however, preand posttreatment tumor biopsies were unrevealing. Why did DT patients respond to the Notch inhibitor? Our usual approach to drug development is bench to bedside, but on occasion, bedside observations can in themselves lead to new insights into biology. In this issue of Cancer, Shang et al attempt to provide preclinical insights into Notch inhibition in DTs. To get a better perspective on their important findings, it is helpful to review the biology of DTs and notch signaling. DTs are rare with an annual incidence of 2 to 4 per million, and they affect adults in the third decade of life. They commonly arise in the extremities, abdominal wall, mesenteric root, and chest wall. They do not metastasize, but their natural history is variable and ranges from an asymptomatic, indolent course (with rare spontaneous regressions) to aggressive infiltration of neurovascular structures and vital organs resulting in pain, loss of function, organ dysfunction, and death. After surgical resection, they are firm, bland, and interspersed with blood vessels and infiltrate muscles and/or nerves (Fig. 1A). Microscopically, they are indistinguishable from a healing wound. They are composed of fibroblasts and blood vessels in a dense collagenous matrix (Fig. 1B). The malignant cell of origin is unknown, although evidence points to mesenchymal stem cells (MSCs). The hallmark of DTs is constitutive activation of the Wnt signaling pathway. Although gains and losses in chromosomes 8, 5, 6, and 20 have been infrequently reported, the DT genome is bland except for activating mutations in CTNNB1(>95%) or inactivating mutationsin adenomatous polyposis coli (APC; approximately 3%), which are suspected to be the initiating events or oncogenic drivers. Therefore, in the context of a single mutation, it is difficult to explain the variable behavior of DTs. DTs respond to different classes of inhibitors that target inflammation (sulindac), estrogen (tamoxifen), cytokines (interferon-a), cell cycle (doxorubicin), multitargeted kinases (sorafenib and gleevec), Wnt (OMP-54F28), and Notch (PF-03084014). Recently, growth inhibition was seen with a hyaluronan (HA) inhibitor. Attempts to identify biomarkers of response have been entirely unrevealing. In this context, how do we interpret the current data on Notch inhibition in DTs? Briefly, Notch, Wnt, transforming growth factor B, and Hedgehog are critical pathways that have pleiotropic functions ranging from embryonic development to adult homeostasis. Notch is activated when one of several ligands (Deltalike 1 [DLL 1–3, Jagged 1 [JAG1], and JAG2) binds to 1 of 4 receptors (NOTCH 1–4). A 2-step proteolytic cleavage is first mediated by ADAMS10/17 and then by c-secretase (GS) releasing Notch intracellular domain (NICD); a transcription factor, that activatesHES1 and others. PF-03084014 is a GS inhibitor that inhibits this step (Fig. 2). In this article, Shang et al evaluate the expression of NICD, JAG1, and Hairy and enhancer of split, induced by Notch (HES1) in a large collection of patient tissue microarrays. According to immunohistochemistry, there was significantly greater HES1 staining in comparison with a normal scar, but surprisingly, this was not seen with NICD or JAG1. The status of the NOTCH1 receptor is not known, and the authors note that this is due to limitations of available NOTCH1 antibodies; however, an evaluation of the messenger RNA expression of Notch, Hes1, and Jag1 would have