Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1–4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.

Purpose This non‐randomized, patient‐access protocol, assessed both safety and efficacy outcomes following liposomal muramyl‐tripeptide‐phosphatidylethanolamine (L‐MTP‐PE; mifamurtide) in patients with high‐risk, recurrent and/or metastatic osteosarcoma. Methods Patients received mifamurtide 2 mg/m² intravenously twice‐weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration‐time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion‐related adverse events (IRAE); other AEs and overall survival (OS) were assessed. Results The study began therapy in January 2008; the last patient completed therapy in October 2012. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post‐infusion, then in a log‐linear manner 2–6 hours post‐dose; t_1/2 was 2 hours. There were no readily apparent relationships between age and BSA‐normalized clearance, half‐life, or pharmacodynamic effects, supporting the dose of 2 mg/m² mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One‐ and 2‐year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2‐year OS (39.9%) as the entire cohort (45.9%) Conclusions Mifamurtide had a manageable safety profile; PK/PD of mifamurtide in this patient access study was consistent with prior studies. Two‐year OS was 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes. Pediatr Blood Cancer 2014;61:238–244. © 2013 The Authors. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

Purpose: We sought to determine whether administration of a MGMT blocker, O⁶-benzyl guanine (O⁶BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth.