The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, only moderate improvements in survival have been made for patients with advanced disease. Retinoic acid is a differentiation agent that has shown some antitumor efficacy in RMS cells in vitro; however, the effects are of low magnitude. E23-(4 0 -hydroxyl-3 0 -adamantylbiphenyl-4-yl) acrylic acid (ST1926) is a novel orally available synthetic atypical retinoid, shown to have more potent activity than retinoic acid in several types of cancer cells. We used in vitro and in vivo models of RMS to explore the efficacy of ST1926 as a possible therapeutic agent in this sarcoma. We found that ST1926 reduced RMS cell viability in all tested alveolar (ARMS) and embryonal (ERMS) RMS cell lines, at readily achievable micromolar concentrations in mice. ST1926 induced an early DNA damage response (DDR), which led to increase in apoptosis, in addition to S-phase cell cycle arrest and a reduction in protein levels of the cell cycle kinase CDK1. Effects were irrespective of TP53 mutational status. Interestingly, in ARMS cells, ST1926 treatment decreased PAX3-FOXO1 fusion oncoprotein levels, and this suppression occurred at a post-transcriptional level. In vivo, ST1926 was effective in inhibiting growth of ARMS and ERMS xenografts, and induced a prominent DDR. We conclude that ST1926 has preclinical efficacy against RMS, and should be further developed in this disease in clinical trials.Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma, and the third most common solid tumor in children. 1 It accounts for 6% of all childhood cancers and approximately 40% of soft tissue sarcomas. 2,3 RMS likely arises from primitive mesenchymal progenitors that have undergone a limited program of myogenic differentiation, because of the expression of skeletal myogenic proteins in RMS tumors. 1,4 Rhabdomyosarcoma occurs in two major histological subtypes: embryonal (ERMS) and alveolar (ARMS) histologies. 1,4 ARMS is associated with a chromosomal translocation between the PAX3 or PAX7 and FOXO1 genes in approximately 55 and 22% of cases, respectively. 5 Patients presenting with ARMS tumors usually have a worse prognosis as compared to ERMS. The PAX-FOXO1 fusion transcript has been shown to exhibit a more potent transcriptional activation function than the PAX proteins alone, 6 and contributes to the invasive phenotype of ARMS, 7,8 making it an interesting target for therapeutic intervention. 9 Despite multiple attempts at intensifying chemotherapeutic approaches to treatment, limited improvements in survival have been made for patients with advanced-stage disease or recurrent RMS over the past 10 years. [10][11][12] This underlies the need for novel therapeutic approaches. 10,13 Retinoic acid is a morphogen and a major regulator of cellular proliferation, apoptosis and differentiation, 14 and has been investigated as differentiation therapy in multiple types of cancer, contributi...

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