Neuroblastoma (NB) is a frequently lethal tumor of childhood. MYCN amplification accounts for the aggressive phenotype in a subset while the majority have no consistently identified molecular aberration but frequently express MYC at high levels. We hypothesized that activated Wnt/b-catenin (CTNNB1) signaling might account for this as MYC is a b-catenin transcriptional target and multiple embryonal and neural crest malignancies have oncogenic alterations in this pathway. NB cell lines without MYCN amplification express higher levels of MYC and b-catenin (with aberrant nuclear localization) than MYCNamplified cell lines. Evidence for aberrant b-catenin-TCF transcriptional activity was demonstrated using expression profiles from 73 primary NBs. Findings included increased WNT ligands (WNT1, WNT6, WNT7A, WNT10B), DVL1 and TCF7 expression in high-risk NBs without MYCN amplification, consistent with canonical b-catenin signaling. More directly, Patterns of Gene Expression and Gene Set Enrichment Analyses demonstrated b-catenin target genes (for example, MYC, PPARD, NRCAM, CD44, TCF7) as coordinately upregulated in high-risk NBs without MYCN amplification in comparison to high-risk MYCN-amplified or intermediate-risk NBs, supporting pathway activation in this subset. Thus, high-risk NBs without MYCN amplification may deregulate MYC and other oncogenic genes via altered b-catenin signaling providing a potential candidate pathway for therapeutic inhibition.

To outline an outpatient-based treatment for children with relapsed solid tumors, who already have been extensively pretreated, we defined a 4-drug protocol named COMBAT (combined oral maintenance biodifferentiating and antiangiogenic therapy). Using this protocol, we performed a pilot study to determine its feasibility in children with relapsed and/or high-risk pediatric solid tumors. Patients and Methods: 22 children received the COMBAT protocol. Treatment consisted of daily celecoxib administration along with daily 13-cisretinoic acid (2 weeks on / 2 weeks off) and cycles of metronomic temozolomide (90 mg/m2 for 42 days) and low-dose etoposide (21 days). The treatment was scheduled for a period of 1 year. Results: 9 of the 14 patients assessable for response demonstrated evidence of treatment benefit manifested as prolonged disease stabilization or response. The protocol medication was well tolerated with very good compliance. Only minimal side effects where observed which responded to dose modification or local therapy. Conclusions: The COMBAT regimen is well tolerated by patients with intensive prior therapy including myeloablative regimens. Favorable responses observed in this cohort of patients support the further exploration of this and/or similar strategies in the treatment of pediatric solid tumors.

Background: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. Methods: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. Results: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3–69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. Conclusion: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.

For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.