The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma: a target for PI-3 kinase inhibitor intervention

Abstract

PurposeStudies of SF1126, an RGDS targeted, water-soluble prodrug of LY294002, are currently nearing completion in two adult Phase I trials. Herein, we performed a preclinical evaluation of SF1126 as a PI-3K inhibitor for Phase I trials in the treatment of recurrent neuroblastoma (NB).MethodsThe effects of SF1126 on pAkt-MDM2 cell signaling, proliferation, apoptosis, and migration were determined using a panel of NB cell lines, and anti-tumor activity was determined using a xenograft model of NB.ResultsSF1126 blocks MDM2 activation, IGF-1 induced activation of Akt, and the upregulation of survivin induced by IGF-1. It also increases sensitivity to doxorubicin in vitro and was found to exhibit marked synergistic activity in combination with doxorubicin. Treatment disrupts the integrin αvβ3/αvβ5-mediated organization of the actin cytoskeleton as well as the α4β1/α5β1-mediated processes essential to metastasis. In vivo, SF1126 markedly inhibits tumor growth in NB xenografted mice (P < 0.05).ConclusionsA pan PI-3 kinase inhibitor has potent antitumor activity and induces apoptosis in multiple neuroblastoma cell lines. The observed effects of SF1126 on the p-Akt-MDM2-survivin axis suggest a patient selection paradigm in which NB tumors with increased pAkt-MDM2-survivin signaling may predict response to SF1126 alone or in combination with standard chemotherapy regimens that contain anthracyclines.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-010-1486-7) contains supplementary material, which is available to authorized users.

Overview and recent advances in the treatment of neuroblastoma

“…In a large phase II study, 164 patients with relapsed or refractory neuroblastoma were treated with 131 I-MIBG. Approximately one-third of patients (36%) had evidence of clinical response; with approximately one-third (34%) having stable disease for a median of 6 months [117], leading to efforts to include 131 I-MIBG therapy as a part of upfront consolidation treatment for children with high-risk neuroblastoma. Additional clinical trials are ongoing through the New Agents in Neuroblastoma Therapy (NANT) consortium to identify the best of anticancer agents to combine with MIBG therapy (NCT02035137).…”

“…In addition to the ongoing studies of DFMO for extended maintenance therapy (see above), DFMO has been evaluated as a single agent in a phase I clinical trial [130] and is also under investigation in combination with other anticancer agents, including celecoxib (NCT02030964) and the proteasome inhibitor bortezomib (NCT02139397) in clinical trials for children with relapsed neuroblastoma. SF1126, a pan PI-3 kinase inhibitor, was shown to have potent antitumor activity in neuroblastoma preclinical models [131], suggesting the PI3K/mTOR/Akt pathway as a therapeutic target in neuroblastoma, and SF1126 is also currently being tested in a phase I clinical trial through the NANT consortium for children with neuroblastoma (NCT02337309). Nifurtimox is a nitrofuran compound that has been used since the 1970s as a primary form of therapy for Chagas' disease, a parasitic infection caused by Trypanosoma cruzi [132,133].…”

“…Because neuroblastoma tumors arise from neural crest progenitors, nearly 85% of tumors express the norepinephrine transporter on their cell surface, suggesting that the use of benzylguanidine analogs that bind to this transporter would effectively and selectively target these cells. Approximately 90% of neuroblastoma tumors are MIBG-avid, and infusions of 131 I-MIBG allow for the targeted delivery of radiation therapy directly to any sites of active disease. Initial studies showed overall response rates of 21-47% in patients with neuroblastoma [114][115][116], and subsequent studies have used ASCR after MIBG treatment, allowing for the administration of higher radiation doses.…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…SF1126 inhibits tumor growth by blocking the production of PIP2 and PIP3. Ultimately, SF1126 prevents the conversion of inactive Rac1-GDP to active Rac1-GTP, which deregulates actin cytoskeleton polymerization [62] . [62] and multiple myelomas [63] .…”

“…Ultimately, SF1126 prevents the conversion of inactive Rac1-GDP to active Rac1-GTP, which deregulates actin cytoskeleton polymerization [62] . [62] and multiple myelomas [63] . In an ongoing phase I dose escalation study in patients with solid tumors, SF1126 is administered weekly on days 1, 4 weekly by 90-min IV infusions in cycles of 4-week cycles.…”