Retinoids in Pediatric Onco-Hematology: the Model of Acute Promyelocytic Leukemia and Neuroblastoma

Abstract

Retinoids are lipophilic compounds derived from vitamin A, which have been extensively studied in cancer prevention and therapy. In pediatric oncology, they are successfully used for the treatment of acute promyelocytic leukemia (APL) and high-risk neuroblastoma (HR-NBL). APL is a subtype of acute myeloid leukemia (AML) clinically characterized by a severe bleeding tendency with a highrisk of fatal hemorrhage. The molecular hallmark of this disease is the presence of the promyelocytic leukemia (PML)-retinoic acid receptor-α (RAR α) gene fusion that plays a critical role in promyelocytic leukemogenesis and represents the target of retinoid therapy. The introduction in the late 1980s of all-trans retinoic acid (ATRA) into the therapy of APL radically changed the management and the outcome of this disease. Presently, the standard front-line therapeutic approach for pediatric APL includes anthracycline-based chemotherapy and ATRA, leading to a complete remission in almost 90% of the patients. Neuroblastoma (NBL) is an aggressive childhood tumor derived from the peripheral neural crest. More than half of patients have a high-risk disease, with a poor outcome despite intensive multimodal treatment. Although the exact mechanism of action remains unclear, the introduction of 13-cis-retinoic acid (13-cis-RA) in the therapy of NBL has improved the prognosis of this disease. Currently, the standard treatment for HR-NBL consists of myeloablative therapy followed by autologous hematopoietic stem cell transplantation (HSCT) and maintenance with 13-cis-RA for the treatment of minimal residual disease, leading to a 3-year disease-free survival rate (DFS) of about 50%. In this paper the authors provide a review of the peer-reviewed literature on the role of retinoids in the treatment of pediatric APL and HR-NBL, summarizing the most relevant clinical trial results of the last decades, analyzing the ongoing trials, and investigating future therapeutic perspectives of children affected by these diseases.

Premature Epiphyseal Closure of the Lower Extremities Contributing to Short Stature after <b><i>cis</i></b>-Retinoic Acid Therapy in Medulloblastoma: A Case Report

“…13-c is -RA is used in advanced therapies for neuroblastoma, acute promyelocytic leukemia [13], and high-risk medulloblastoma [11]. …”

Human Marrow Stromal Cells Downsize the Stem Cell Fraction of Lung Cancers by Fibroblast Growth Factor 10

“…In acute myeloid leukemia (AML), treatment with granulocyte colony-stimulating factor (G- CSF) made AML stem cells susceptible to chemotherapy by inducing them to divide (22). Such pharmacological action controlling cancer stemness is now shared with retinoic acids that have been efficaciously used for patients of acute promyelocytic leukemia and high-risk neuroblastoma (23,24). In this context, we have identified FGF10 as a stemness regulator specific for lung cancer cells in conditioned medium from MSC, with evidence supporting the view that FGF10 could be successfully applied for induction of lung cancer stem cells out of quiescence and making them more susceptible to antiproliferative chemotherapy.…”

Trial Watch: Lenalidomide-based immunochemotherapy

“…Finally, lenalidomide is being evaluated: (1) as a second-line standalone therapeutic intervention in advanced hepatocellular carcinoma patients (NCT01545804); in combination with gemcitabine (a potentially immunogenic nucleoside analog) 218 , 219 in individuals with pancreatic carcinoma (NCT01547260); (3) as a single agent in children affected by recurrent, refractory or progressive pilocytic astrocytoma or optic pathway glioma (NCT01553149); (4) together with isotretinoin (a retinoid) 220 and/or Ch14.18 (a monoclonal antibody directed against ganglioside GD2) 221 - 223 in children with refractory or recurrent neuroblastoma (NCT01711554); and (5) combined with ipilimumab (an FDA-approved monoclonal antibody that inhibits the immunological checkpoint mediated by cytotoxic T lymphocyte-associated protein 4, CTLA4) 224 , 225 in patients affected by advanced tumors (NCT01750983).…”