AL101, a gamma-secretase inhibitor, has potent antitumor activity against adenoid cystic carcinoma with activated NOTCH signaling

Abstract

Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy with limited treatment options for recurrent or metastatic disease. Due to chemotherapy resistance and lack of targeted therapeutic approaches, current treatment options for the localized disease are limited to surgery and radiation, which fails to prevent locoregional recurrences and distant metastases in over 50% of patients. Approximately 20% of patients with ACC carry NOTCH-activating mutations that are associated with a distinct phenotype, aggressive disease, and poor prognosis. Given the role of NOTCH signaling in regulating tumor cell behavior, NOTCH inhibitors represent an attractive potential therapeutic strategy for this subset of ACC. AL101 (osugacestat) is a potent γ-secretase inhibitor that prevents activation of all four NOTCH receptors. While this investigational new drug has demonstrated antineoplastic activity in several preclinical cancer models and in patients with advanced solid malignancies, we are the first to study the therapeutic benefit of AL101 in ACC. Here, we describe the antitumor activity of AL101 using ACC cell lines, organoids, and patient-derived xenograft models. Specifically, we find that AL101 has potent antitumor effects in in vitro and in vivo models of ACC with activating NOTCH1 mutations and constitutively upregulated NOTCH signaling pathway, providing a strong rationale for evaluation of AL101 in clinical trials for patients with NOTCH-driven relapsed/refractory ACC.

Targeted therapy for head and neck cancer: signaling pathways and clinical studies

“…In an adenoid cystic carcinoma xenograft model with Notch1 mutations, the tumor volumes and body weight were reduced by AL101, which provided fairly broad therapeutic prospects in adenoid cystic carcinoma. 351 …”

“…In an adenoid cystic carcinoma xenograft model with Notch1 mutations, the tumor volumes and body weight were reduced by AL101, which provided fairly broad therapeutic prospects in adenoid cystic carcinoma. 351 JAK/STAT inhibitors AZD1480 is an inhibitor targeting JAK1/JAK2 that has been investigated in several tumor models. In PDX models from two independent HNSCC patients, treatment with AZD1480 significantly decreased tumor volumes and weight by decreasing pSTAT3 Tyr705 phosphorylation.…”

Notch Partners in the Long Journey of T-ALL Pathogenesis

“…However, the observation of severe adverse effects, particularly intestinal toxicities, in the first patients orally receiving GSIs [ 65 , 66 ] hampered the implementation of this therapy. Although these adverse effects could be minimized by coadministration of glucocorticoids [ 67 ], and novel GSI compounds have recently entered into clinical trials (i.e., AL101, AL102, PF-03084014, and RO4929097 [ 64 , 68 , 69 , 70 ]; Figure 1 , Table 1 ), GSI treatment is still not widely established in the clinic. Indeed, PF-03084014 (Nirogacestat) was evaluated in a Phase I trial, including relapsed/refractory T-ALL patients, and although well tolerated, no conclusive anti-leukemic effects were obtained [ 70 ].…”

“…Indeed, PF-03084014 (Nirogacestat) was evaluated in a Phase I trial, including relapsed/refractory T-ALL patients, and although well tolerated, no conclusive anti-leukemic effects were obtained [ 70 ]. AL101, a potent GSI showing very promising anti-tumor efficacy in preclinical models [ 69 ]), is currently being evaluated against triple-negative breast cancer (NCT04461600) and adenoid cystic cancer (NCT04973683, NCT03691207), but no T-ALL trials have been opened. On the other hand, RO4929097 was well tolerated in several trials against different types of cancer, but their therapeutic efficacy in T-ALL patients has not been established.…”

Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment

“…However, multiple cycles of treatment were required to yield benefits from this treatment [ 165 ]. In a recent pre-clinical study of GSI inhibition of adenoid cystic carcinoma xenograft models treatment with AL101 was associated with inhibition of tumor growth, in models with Notch gain of function mutations [ 166 ]. The role of GSIs has been investigated in early clinical trials in patients with leukemia [ 167 ], and solid cancers [ 168 ] including breast, colorectal, and brain cancers, and have shown no significant effect from single agent use of GSI MK-0752 alone.…”