Feasibility of implementing molecular‐guided therapy for the treatment of patients with relapsed or refractory neuroblastoma

Abstract

The primary objective of the study was to evaluate the feasibility and safety of a process which would utilize genome-wide expression data from tumor biopsies to support individualized treatment decisions. Current treatment options for recurrent neuroblastoma are limited and ineffective, with a survival rate of <10%. Molecular profiling may provide data which will enable the practitioner to select the most appropriate therapeutic option for individual patients, thus improving outcomes. Sixteen patients with neuroblastoma were enrolled of which fourteen were eligible for this study. Feasibility was defined as completion of tumor biopsy, pathological evaluation, RNA quality control, gene expression profiling, bioinformatics analysis, generation of a drug prediction report, molecular tumor board yielding a treatment plan, independent medical monitor review, and treatment initiation within a 21 day period. All eligible biopsies passed histopathology and RNA quality control. Expression profiling by microarray and RNA sequencing were mutually validated. The average time from biopsy to report generation was 5.9 days and from biopsy to initiation of treatment was 12.4 days. No serious adverse events were observed and all adverse events were expected. Clinical benefit was seen in 64% of patients as stabilization of disease for at least one cycle of therapy or partial response. The overall response rate was 7% and the progression free survival was 59 days. This study demonstrates the feasibility and safety of performing real-time genomic profiling to guide treatment decision making for pediatric neuroblastoma patients.

Overview and recent advances in the treatment of neuroblastoma

“…Pilot studies have demonstrated the feasibility of generating therapeutic treatment plans based on genomic profiling in less than 12 days [137], and a follow-up national, multi-institutional phase I trial showed clinical benefit in 64% of patients (defined as disease stabilization for at least one cycle of therapy or partial response), with an overall response rate of 7% and progression free survival time of 59 days [138]. A subsequent separate single-institution study demonstrated that incorporation of tumor DNA sequencing data into clinical management of patients was feasible, revealed potentially actionable findings in nearly half of patients, and directly led to changes in treatment and family genetic counseling for some patients [139].…”

Suberoylanilide hydroxamic acid sensitizes neuroblastoma to paclitaxel by inhibiting thioredoxin‐related protein 14‐mediated autophagy

“…The effective chemotherapy regimens for NB primarily include cyclophosphamide, ifosfamide, adriamycin, vincristine, etoposide, and platinum. However, few effective drugs are available for patients who are resistant to front‐line chemotherapy . Paclitaxel (PTX), which is a cytotoxic agent that can bind to the spindle microtubules of tumor cells, causes mitotic arrest and cell death, and has been widely used to treat many adult tumors .…”

mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM

“…Considering this conundrum and the high incidence of recurrence in advanced stages of neuroblastoma (stage III and IV) (4, 6), defining appropriate strategies for treating this cancer particularly in advanced stages is a priority. Presently, we evaluated a broad-spectrum anti-tumor protein MDA-7/IL-24 (11, 12, 16) delivered by a tropism-modified chimeric cancer terminator virus (Ad.5/3- CTV ) (23, 26) in neuroblastoma cells.…”

“…Presentation of tumors at advanced stages combined with the absence of surgical options culminates in very poor patient prognosis. Although some improvements in the overall cure rate of neuroblastomas have been realized using intensive multimodality therapies these therapies promote significant short- and long-term toxicities (1, 3, 4). Only about 2% of neuroblastoma patients with stage III or IV remain disease free with relapse occurring shortly after completing chemotherapy, indicating a negligible effect of these agents long-term (5).…”