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Researchers in the translational programs at St. Jude are bridging the gap between scientific discoveries in the laboratory and the implementation of innovative therapeutic strategies in the clinic by conducting preclinical studies and early clinical trials of molecular target agents, many of which are increasingly targeted to genetically defined tumor subtypes. In this way, novel cutting-edge treatments are being made available in an efficient manner to children with catastrophic diseases.
A variety of preclinical and clinical studies in the Hematological Malignancies Program are investigating new therapies for high-risk acute leukemias. Several of these projects are focused on acute myeloid leukemia (AML), a genetically heterogeneous cancer that frequently exhibits aberrant kinase signaling, which can lead to uncontrolled proliferation and increased survival of tumor cells. In approximately 20% of children with AML, aberrant kinase signaling is a result of mutations in the receptor tyrosine kinase fms-like tyrosine kinase 3 (FLT3).
Sharyn D. Baker, PharmD, PhD (Pharmaceutical Sciences), and colleagues evaluated a treatment strategy combining sorafenib, an FLT3 and multikinase inhibitor, and cytarabine, a key component of standard AML chemotherapy, in a bone marrow xenograft model of AML. At a dose producing a steady-state plasma level of sorafenib in mice that was equivalent to that in humans, sorafenib in combination with cytarabine increased survival over that seen with cytarabine alone. The research, published in the Journal of the National Cancer Institute1, provided the scientific foundation for a Phase I clinical trial in relapsed or refractory (resistant to treatment) leukemia that was led by Hiroto Inaba, MD, PhD (Oncology).
Dr. Inaba and colleagues treated 12 pediatric patients (aged 6-17 years at diagnosis) with relapsed/refractory leukemia: 11 patients had AML, and one had T-cell ALL. The treatment regimen used in the St. Jude protocol consisted of single-agent oral sorafenib for 7 days, followed by sorafenib coadministered with cytarabine and clofarabine for 5 days, and then single-agent sorafenib again for as long as 16 days, if tolerated.
In the Journal of Clinical Oncology2, Drs. Inaba and Baker and colleagues reported that six patients with AML (three with internal tandem duplication mutation in the FLT3 gene [FLT3-ITD] mutations, and three without) entered complete remission. Two patients with FLT3- ITD mutations experienced complete remission with incomplete blood count recovery, and one patient with FLT3 wild-type AML experienced partial remission. The investigators showed that the rate of conversion of sorafenib to its active metabolite, sorafenib N-oxide, is much higher in children with cancer than in adults with cancer (33% vs <10%). They also demonstrated that the metabolite has equipotent kinase-inhibitory activity to that of sorafenib, suggesting that combined exposure to sorafenib and sorafenib N-oxide contributes to overall antileukemic activity.
Pharmacodynamic studies in bone marrow aspirate samples from patients who had received sorafenib revealed that this treatment inhibited the phosphorylation of AKT, 4E-BP1, and S6 ribosomal protein in AML cells. These data suggest that the antileukemic effects of sorafenib include inhibition of protein translation and induction of apoptosis.
Dr. Inaba and colleagues concluded that sorafenib given alone or in combination with other chemotherapy agents induces dramatic responses in patients with childhood AML. The findings from this Phase I trial provide the rationale for further development of sorafenib as a new treatment for pediatric patients with relapsed/refractory AML.
The laboratory of Richard J. Gilbertson, MD, PhD (Developmental Neurobiology, Oncology), has deployed detailed genomic analysis to define new molecular subtypes of several tumors of the central nervous system, including ependymoma, a rare but aggressive childhood tumor. Nearly 40% of childhood ependymoma cases are incurable. In parallel, Dr. Gilbertson’s group has developed a series of mutant mouse strains that model each molecular subtype of the disease and can be used to test novel therapeutic agents.
One subtype of ependymoma is characterized by the overexpression of the receptor tyrosine kinase EPH receptor B2 (EPHB2). In conjunction with the Department of Chemical Biology & Therapeutics, Dr. Gilbertson’s laboratory screened tumor cells from a mouse model of Ephb2-overexpressing ependymoma (mEPEphb2) with a panel of 7,890 unique chemical compounds, including FDA-approved drugs, bioactive agents, kinase inhibitors, and natural products. To identify mEPEphb2-selective agents, the investigators also screened cell lines from non- mEPEphb2 tumors and normal neural progenitor cells. The 634 compounds that resulted in positive hits during the high-throughput screen were further investigated by secondary screening and testing of efficacy in mouse models of mEPEphb2.
A key discovery from Dr. Gilbertson’s study, which was published in Cancer Cell3, was that 5-fluorouracil has selective activity against mEPEphb2. This thymidylate synthase inhibitor has been widely used to treat solid tumors and glioblastoma for many years but has not been tested in ependymoma. Thus, this screen has facilitated the repurposing of 5-fluorouracil.
Preclinical testing and optimization of drug combinations for rare pediatric cancers are essential. Because the patient populations that have these diseases are so small, the number of clinical trials that can be conducted is quite limited. The findings from Dr. Gilbertson’s preclinical screening have resulted in a St. Jude–initiated clinical trial of 5-fluorouracil in pediatric patients with ependymoma.
1Hu S, Niu H, Inaba H, Orwick S, Rose C, Panetta JC, Yang S, Pounds S, Fan Y, Calabrese C, Rehg JE, Campana D, Rubnitz JE, Baker SD. Activity of the multikinase inhibitor sorafenib in combination with cytarabine in acute myeloid leukemia. J Natl Cancer Inst Jun 8;103(11):893-905, 2011. Epub 2011 Apr 12. PubMed PMID: 21487100; PubMed Central PMCID: PMC3110171. Abstract | Full Text
2Inaba H, Rubnitz JE, Coustan-Smith E, Li L, Furmanski BD, Mascara GP, Heym KM, Christensen R, Onciu M, Shurtleff SA, Pounds SB, Pui CH, Ribeiro RC, Campana D, Baker SD. Phase I pharmacokinetic and pharmacodynamic study of the multikinase inhibitor sorafenib in combination with clofarabine and cytarabine in pediatric relapsed/refractory leukemia. J Clin Oncol Aug 20;29(24):3293-300, 2011. Epub 2011 Jul 18. PubMed PMID: 21768474; PubMed Central PMCID: PMC3158600. Abstract | Full Text
3Atkinson JM, Shelat AA, Carcaboso AM, Kranenburg TA, Arnold LA, Boulos N, Wright K, Johnson RA, Poppleton H, Mohankumar KM, Féau C, Phoenix T, Gibson P, Zhu L, Tong Y, Eden C, Ellison DW, Priebe W, Koul D, Yung WK, Gajjar A, Stewart CF, Guy RK, Gilbertson RJ. An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell Sep 13;20(3):384-99, 2011. doi: 10.1016/j.ccr.2011.08.013. PubMed PMID: 21907928; PubMed Central PMCID: PMC3172881. Abstract | Full Text