Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

Sunitinib malate is a small multi‐targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high‐grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high‐grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression‐free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high‐grade glioma. Most adverse events were of mild‐to‐moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high‐grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.

Importance This study provides the first objective data documenting neurocognitive impairment in long-term survivors of childhood osteosarcoma. Objective To examine neurocognitive, neurobehavioral, emotional and quality of life outcomes in long-term survivors of childhood osteosarcoma treated with intravenous high-dose methotrexate. Design Cross-sectional cohort study, with prospective treatment and chronic health predictors. Outcome data was collected from June 2008 to August 2014. Setting Academic research hospital. Participants Survivors of osteosarcoma (n=80; mean [SD] age = 38.9 [7.6] years; time since diagnosis = 24.7 [6.6] years; 42% female) recruited from the St. Jude Lifetime Cohort Study and compared to community controls (n=39; age = 39.03 [11.71] years; 56.4% female). Main Outcome Measures Objective tests of neurocognitive function. Subjective report of neurobehavioral symptoms, emotional distress and quality of life. Within survivors, outcomes were examined in relation to pharmacokinetic indices of methotrexate exposure and current chronic health conditions, which were assessed through medical examination and coded according to Common Terminology Criteria for Adverse Events v4.03. Results Compared to community controls, survivors demonstrated lower reading (p=0.012), attention (p=0.002), memory (p=0.019), processing speed (p<0.001) and executive function (p=0.006). Survivors also fell below national norms on these outcomes. Results of pharmacokinetic analysis showed high-dose methotrexate maximum plasma concentration, median clearance, and median/cumulative exposure were not associated with neurocognitive outcomes. Any grade 3 or 4 Common Terminology Criteria for Adverse Events cardiac, pulmonary or endocrine condition was associated with poorer memory (p=0.006) and slower processing speed (p=0.002). Survivor-reported poor general health was associated with decreased sustained attention (p=0.05) and processing speed (p=0.006). Conclusions Long-term survivors of osteosarcoma are at risk for neurocognitive impairment, which, nearly 25 years post-diagnosis, is related to current chronic health conditions and not to original treatment with HDMTX. Prospective longitudinal studies are needed to identify onset and progression of impairment to inform optimal interventions.

Telomerase activation is critical in many cancers including central nervous system (CNS) tumors. Imetelstat is an oligonucleotide that binds to the template region of the RNA component of telomerase, inhibiting its enzymatic activity. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor telomerase activity and sustained responses by imetelstat in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, high-grade glioma (HGG) or ependymoma undergoing resection received one dose of imetelstat as a 2-hour intravenous infusion at 285mg/m2, 12–24 hours before surgery. Telomerase activity was evaluated in fresh tumor from surgery. Post-surgery and in the phase II study, patients received imetelstat IV (days 1 and 8 q21-days) at 285mg/m2. Imetelstat pharmacokinetic and pharmacodynamic studies were performed. Of 2 evaluable patients on the MB trial, intratumoral telomerase activity was inhibited by 95% compared to baseline archival tissue in one patient and was inevaluable in one patient. Forty-two patients (40 evaluable for toxicity) were enrolled: 9 medulloblastomas, 18 HGG, 4 ependymomas, 9 diffuse intrinsic pontine gliomas. Most common grade 3/4 toxicities included thrombocytopenia (32.5%), lymphopenia (17.5%), neutropenia (12.5%), ALT (7.5%) and AST (5%) elevation. Two patients died of intratumoral hemorrhage secondary to thrombocytopenia leading to premature study closure. No objective responses were observed. Telomerase inhibition was observed in peripheral blood mononuclear cells (PBMCs) for at least 8 days. Imetelstat demonstrated intratumoral and PBMC target inhibition; the regimen proved too toxic in children with recurrent CNS tumors.

Increased vascular endothelial growth factor (VEGF) expression in osteosarcoma correlates with a poor outcome. We conducted a phase II trial to evaluate the feasibility and efficacy of combining bevacizumab, a monoclonal antibody against VEGF, with methotrexate, doxorubicin and cisplatin (MAP) in patients with localized osteosarcoma. Eligible patients received 2 courses of MAP chemotherapy before definitive surgery at week 10. Bevacizumab (15 mg/kg) was administered 3 days before starting chemotherapy then on day 1 of weeks 3 and 5 of chemotherapy. After surgery, patients received MAP for a total of 29 weeks; bevacizumab was added every 2 or 3 weeks on day 1 of chemotherapy at least 5 weeks after surgery. Group sequential monitoring rules were used to monitor for unacceptable bevacizumab-related targeted toxicity (grade 4 hypertension, proteinuria, or bleeding, grade 3 or 4 thrombosis/embolism, and grade 2–4 major wound complications). Thirty-one patients (median age 12.8 years) with localized osteosarcoma were enrolled. No unacceptable targeted toxicities were observed except for wound complications (9 minor and 6 major), which occurred in 15 patients; none required removal of prosthetic hardware or amputation. The estimated 4-year event-free survival (EFS) rate and overall survival rate were 57.5%±10.0% and 83.4%±7.8%, respectively. Eight (28%) of 29 evaluable patients had good histologic response (< 5% viable tumor) to preoperative chemotherapy. The addition of bevacizumab to MAP for localized osteosarcoma is feasible but frequent wound complications are encountered. The observed histologic response and EFS do not support further evaluation of bevacizumab in osteosarcoma.

Lead discovery in osteosarcoma has been hampered by the lack of new agents, limited representative clinical samples and paucity of accurate preclinical models. We developed orthotopic patient-derived xenografts (PDXs) that recapitulated the molecular, cellular and histologic features of primary tumors, and screened PDX-expanded short-term cultures and commercial cell lines of osteosarcoma against focused drug libraries. Osteosarcoma cells were most sensitive to HDAC, proteasome, and combination PI3K/MEK and PI3K/mTOR inhibitors, and least sensitive to PARP, RAF, ERK and MEK inhibitors. Correspondingly, PI3K signaling pathway genes were up-regulated in metastatic tumors compared to primary tumors. In combinatorial screens, as a class, HDAC inhibitors showed additive effects when combined with standard-of-care agents gemcitabine and doxorubicin. This lead discovery strategy afforded a means to perform high-throughput drug screens of tumor cells that accurately recapitulated those from original human tumors, and identified classes of novel and repurposed drugs with activity against osteosarcoma.

Background and Objective Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients, and developed new equations for estimated glomerular filtration rate (GFR) in these patients. Methods A retrospective analysis was conducted on patients comparing the estimated GFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from 99mTechnetium-DPTA (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared to doses calculated by GFR estimating equations. Results Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict mGFR in our pediatric oncology patient population. Using a subset of the data, we developed a 5-covariate equation, which included the covariates of height, serum creatinine, age, BUN, and gender, and a simplified version (2-covariates), which only contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of the mGFR values. The equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation. Conclusions Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.

Despite significant improvement in outcomes for patients with hematological malignancies and solid tumors over the past 10 years, patients with primary or metastatic brain tumors continue to have a poor prognosis. A primary reason for this is the inability of many chemotherapeutic drugs to penetrate into the brain and brain tumors at concentrations high enough to exert an antitumor effect due to unique barriers and efflux transporters. Several studies have been published recently examining the CNS pharmacokinetics of various anticancer drugs in patients with primary and metastatic brain tumors. To summarize recent advances in the field, this review will critically present studies published within the last 9 years examining brain and cerebrospinal fluid penetration of clinically available anticancer agents for patients with CNS tumors.