Catherine A Billups

St. Jude Children's Research Hospital, Memphis, Tennessee, United States

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Publications (116)692.8 Total impact

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    ABSTRACT: Background: Inhibitors of poly-ADP ribose polymerase (PARP), an enzyme involved in base excision repair (BER) have demonstrated single agent activity against tumors deficient in homologous repair processes. Ewing sarcoma cells are also sensitive to PARP inhibitors, although the mechanism is not understood. Here we evaluated the stereo-selective PARP inhibitor, talazoparib (BMN 673), combined with temozolomide or topotecan. Procedures: Talazoparib was tested in combination with temozolomide (0.3- 1000 μM) or topotecan (0.003 - 0.1 μM) against the PPTP in vitro and in vivo panels at a dose of 0.1 mg/kg BID x 5 combined with temozolomide (30 mg/kg/daily x 5; Combination A) or 0.25 mg/kg/daily x 5 combined with temozolomide (12 mg/kg/daily x 5; Combination B). Pharmacodynamic studies were undertaken after 1 or 5 days of treatment. Results: In vitro talazoparib potentiated the toxicity of temozolomide up to 85-fold, with marked potentiation in Ewing sarcoma and leukemia lines (30-50-fold). There was less potentiation for topotecan. In vivo, talazoparib potentiated the toxicity of temozolomide, and Combination A and Combination B represent the maximum tolerated doses when combined with low dose or high dose talazoparib, respectively. Both combinations demonstrated significant synergism against 5 of 10 Ewing sarcoma xenografts. The combination demonstrated modest activity against other xenograft models. Pharmacodynamic studies showed a treatment-induced complete loss of PARP only in tumor models sensitive to either talazoparib alone or talazoparib plus temozolomide. Conclusions: The high level of activity observed for talazoparib plus temozolomide in Ewing sarcoma xenografts makes this an interesting combination to consider for pediatric evaluation. Copyright © 2014, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 12/2014;
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    ABSTRACT: Genome-wide studies have identified a high-risk subgroup of pediatric acute lymphoblastic leukemia (ALL) harboring mutations in the Janus kinases (JAKs). The purpose of this study was to assess the preclinical efficacy of the JAK1/2 inhibitor, AZD1480, both as a single agent and in combination with the MEK inhibitor selumetinib, against JAK-mutated patient-derived xenografts. Patient-derived xenografts were established in immune-deficient mice from bone marrow or peripheral blood biopsy specimens, and their gene expression profiles compared with the original patient biopsies by microarray analysis. JAK/STAT and MAPK signaling pathways, and the inhibitory effects of targeted drugs, were interrogated by immunoblotting of phosphoproteins. The anti-leukemic effects of AZD1480 and selumetinib, alone and in combination, were tested against JAK-mutated ALL xenografts both in vitro and in vivo. Xenografts accurately represented the primary disease as determined by gene expression profiling. Cellular phosphoprotein analysis demonstrated that JAK-mutated xenografts exhibited heightened activation status of JAK/STAT and MAPK signaling pathways compared with typical B-cell precursor ALL xenografts, which were inhibited by AZD1480 exposure. However, AZD1480 exhibited modest single-agent in vivo efficacy against JAK-mutated xenografts. Combining AZD1480 with selumetinib resulted in profound synergistic in vitro cell killing, although these results were not translated in vivo despite evidence of target inhibition. Despite validation of target inhibition and the demonstration of profound in vitro synergy between AZD1480 and selumetinib, it is likely that prolonged target inhibition is required to achieve in vivo therapeutic enhancement between JAK and MEK inhibitors in the treatment of JAK-mutated ALL. Copyright © 2014, American Association for Cancer Research.
    Molecular Cancer Therapeutics 12/2014; · 5.60 Impact Factor
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    ABSTRACT: Background:Late relapse and solitary lesion are positive prognostic factors in recurrent osteosarcoma.Methods:We reviewed the records of 39 patients treated at three major centres for recurrent osteosarcoma with a single pulmonary metastasis more than 1 year after diagnosis. We analysed their outcomes with respect to clinical factors and treatment with chemotherapy.Results:Median age at diagnosis was 14.6 years. Relapse occurred at a median of 2.5 years (range, 1.2-8.2 years) after initial diagnosis. At relapse, all patients were treated by metastasectomy; 12 (31%) patients also received chemotherapy. There was no difference in time to recurrence or nodule size between the patients who received or did not receive chemotherapy at relapse. Sixteen patients had no subsequent recurrence, 13 of whom survive without evidence of disease. The 5-year and 10-year estimates of post-relapse event-free survival (PREFS) were 33.0±7.5% and 33.0±9.6%, respectively, and of post-relapse survival (PRS) 56.8±8.6% and 53.0±11.0%, respectively. There was a trend for nodules <1.5 cm to correlate positively with PREFS (P=0.070) but not PRS (P=0.49). Chemotherapy at first relapse was not associated with PREFS or PRS.Conclusion:Approximately half of the patients with recurrent osteosarcoma presenting as a single pulmonary metastasis more than 1 year after diagnosis were long-term survivors. Metastasectomy was the primary treatment; chemotherapy did not add benefit.British Journal of Cancer advance online publication, 25 November 2014; doi:10.1038/bjc.2014.585 www.bjcancer.com.
    British journal of cancer. 11/2014;
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    ABSTRACT: Modular and non-invasive expandable prostheses have been developed to provide a functional knee joint that allows future expansion as growth occurs in the contralateral extremity in children with bone sarcomas that require removal of the growth plate. This study aimed to evaluate the functional outcomes of paediatric patients who received either a non-invasive expandable or modular prosthesis for bone sarcomas arising around the knee. We evaluated clinician-reported, patient-reported and measured function in 42 paediatric patients at least one year (median age at assessment 19.1years) after limb salvage surgery, and compared patients who received modular system prostheses (N=29, median age 15.5), who did not require lengthening procedures to those who received non-invasive expandable prostheses (N=13, median age 11.1) requiring lengthening procedures (median 5). The number of revisions and time to first revision did not differ between the two groups. There were no differences between the two groups in total scores on the Enneking Musculoskeletal Tumor Society Scale, the Toronto Extremity Salvage Scale, and the Functional Mobility Assessment. Children with non-invasive expandable prostheses climbed stairs (11.93±4.83 versus 16.73±7.24s, p=0.02) in less time than those with modular prostheses. Our results suggest that the non-invasive expandable prosthesis produces similar functional results to the more traditional modular prosthesis. Copyright © 2014 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 10/2014; 50(18):3212-3220. · 4.12 Impact Factor
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    ABSTRACT: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. Experimental Design: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts comprised of MLL-, BCP- and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro co-culture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. Results: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro co-culture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). Conclusion: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy.
    Clinical Cancer Research 06/2014; · 7.84 Impact Factor
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    ABSTRACT: Glembatumumab vedotin is an antibody-auristatin conjugate that targets cells expressing the transmembrane glycoprotein NMB (GPNMB, also known as osteoactivin). It has entered clinical evaluation for adult cancers that express GPNMB, including melanoma and breast cancer.
    Pediatric Blood & Cancer 06/2014; · 2.35 Impact Factor
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    ABSTRACT: The addition of immunotherapy, including a combination of anti-GD2 monoclonal antibody (mAb), ch14.18, and cytokines, improves outcome for patients with high-risk neuroblastoma. However, this therapy is limited by ch14.18-related toxicities that may be partially mediated by complement activation. We report the results of a phase I trial to determine the maximum-tolerated dose (MTD), safety profile, and pharmacokinetics of hu14.18K322A, a humanized anti-GD2 mAb with a single point mutation (K322A) that reduces complement-dependent lysis. Eligible patients with refractory or recurrent neuroblastoma received escalating doses of hu14.18K322A ranging from 2 to 70 mg/m(2) per day for 4 consecutive days every 28 days (one course). Thirty-eight patients (23 males; median age, 7.2 years) received a median of two courses (range, one to 15). Dose-limiting grade 3 or 4 toxicities occurred in four of 36 evaluable patients and were characterized by cough, asthenia, sensory neuropathy, anorexia, serum sickness, and hypertensive encephalopathy. The most common non-dose-limiting grade 3 or 4 toxicities during course one were pain (68%) and fever (21%). Six of 31 patients evaluable for response by iodine-123 metaiodobenzylguanidine score had objective responses (four complete responses; two partial responses). The first-course pharmacokinetics of hu14.18K322A were best described by a two-compartment linear model. Median hu14.18K322A α (initial phase) and β (terminal phase) half-lives were 1.74 and 21.1 days, respectively. The MTD, and recommended phase II dose, of hu14.18K322A is 60 mg/m(2) per day for 4 days. Adverse effects, predominately pain, were manageable and improved with subsequent courses.
    Journal of Clinical Oncology 04/2014; · 18.04 Impact Factor
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    ABSTRACT: Most prior studies evaluating subsequent malignant neoplasms (SMNs) in patients with neuroblastoma are restricted to long-term survivors and/or their treatment exposures. This study investigates SMNs in patients diagnosed with neuroblastoma at our institution. Records of 646 patients treated for neuroblastoma at St Jude Children's Research Hospital between 1961 and 2005 were reviewed. Data from patients with SMNs were analyzed and the 20- and 30-year cumulative incidence of SMNs and standardized incidence ratio were calculated. Twenty-one patients had a SMN. The 20- and 30-year cumulative incidences of a SMN were 2.6%±0.7% and 4.6%±1.1%, respectively. The standardized incidence ratio was 8.3 (95% confidence interval, 5.0-13.0). Five patients developed a SMN within 5 years from diagnosis. The median latency for the development of acute myeloid leukemia/myelodysplastic syndrome (n=4), sarcomas (n=7), and carcinomas (n=5) were 3.6, 9, and 24.2 years, respectively. Nine patients died from their SMN, including all with acute myeloid leukemia/myelodysplastic syndrome. Patients with neuroblastoma have an increased risk of secondary neoplasia. Modification of risk-adapted therapies will likely alter the affected patient population and the incidence of SMNs. Future studies are necessary to link SMNs to treatment exposures and to evaluate the risk of SMNs beyond 30 years from diagnosis.
    Journal of Pediatric Hematology/Oncology 03/2014; · 0.97 Impact Factor
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    ABSTRACT: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma. Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated. Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y). Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.
    Journal of Pediatric Hematology/Oncology 02/2014; · 0.97 Impact Factor
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    ABSTRACT: Background: The history, prognostic factors and outcome of young patients with head and neck non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) have not been adequately characterized. Methods: Medical records of 58 patients with head and neck NRSTS treated at St. Jude Children's Research Hospital were reviewed. Results: The majority of tumors were ≤ 5 cm and high grade. Lymph node and/or distant metastases were present in 17% at presentation. Patients received a combination of surgery, chemotherapy and radiotherapy. The 10-year event-free and survival rates were 53.1% ± 7.3% and 63.2% ± 7.1%. Features associated with inferior survival included high histologic grade (p=0.006), tumor diameter > 5 cm (p<0.001), invasiveness (p<0.001), and incomplete resection at diagnosis (p=0.005). Conclusions: Most head and neck NRSTS in young patients are small, high-grade and non-metastatic. The outcome is poor compared to NRSTS at other anatomic sites. Innovative approaches to local control and improved systemic therapy are needed. Head Neck, 2013.
    Head & Neck 12/2013; · 2.83 Impact Factor
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    ABSTRACT: OBJECTIVE. The purpose of this article is to assess the feasibility and utility of PET/CT in distinguishing benign from malignant pulmonary nodules in patients with solid childhood malignancies. SUBJECTS AND METHODS. This prospective study was conducted between March 2008 and August 2010. We enrolled 25 subjects 21 years old or younger with solid childhood malignancies and at least one pulmonary nodule measuring 0.5-3.0 cm. PET/CT was performed within 3 weeks of diagnostic chest CT. Three panels of three reviewers each reviewed diagnostic CT only (panel 1), PET/CT only (panel 2), or diagnostic CT and PET/CT concurrently (panel 3) and predicted each nodule's histologic diagnosis as benign, malignant, or indeterminate. Interreviewer agreement was assessed with the kappa statistic. Using nodule biopsy or clinical follow-up as reference standards, the sensitivity, specificity, and accuracy for each panel was assessed. Logistic regression was used to assess the nodule's maximum standardized uptake value (SUVmax) association with its histologic diagnosis. RESULTS. There were 75 nodules with a median size of 0.74 cm (range, 0.18-2.38 cm); 48 nodules were malignant. Sensitivity was 85% (41/48) for panel 1, 60% (29/48) for panel 2, and 67% (32/48) for panel 3. All panels had poor specificities. Interreviewer agreement was moderate for panel 1 (0.43) and poor for panels 2 (0.22) and 3 (0.33). SUVmax was a significant predictor of histologic diagnosis (p = 0.004). CONCLUSION. PET/CT assessment of pulmonary nodules is feasible in children with solid malignancies but may not reliably improve our ability to predict a nodule's histologic diagnosis. The SUVmax may improve the performance of PET/CT in this setting.
    American Journal of Roentgenology 12/2013; 201(6):W900-W905. · 2.90 Impact Factor
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    ABSTRACT: Volasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP. Volasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels administered IV at a dose of 30 mg/kg (solid tumors) or 15 mg/kg (ALL models) using a q7dx3 schedule. In vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1 nM, (range 6.0-135 nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts. Volasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 08/2013; · 2.35 Impact Factor
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    ABSTRACT: Survival rates for children with medulloblastoma have risen over the past decade, in part due to the addition of cisplatin-containing adjuvant chemotherapy. Total dose of cisplatin required for optimal treatment is unknown. The purpose of this study was to evaluate the survival outcomes based on cumulative cisplatin doses (CCD) in children with newly diagnosed average-risk medulloblastoma. CCD data were reviewed for 363 patients in a prospective study evaluating patients between 3 and 21 years with a newly diagnosed average-risk medulloblastoma and treated with craniospinal radiation and post-radiation cisplatin based adjuvant chemotherapy. Eight-year event-free survival (EFS) and overall survival (OS) estimates were 78.2 ± 2.6% and 83.9 ± 2.4%, respectively. Only 73 patients received the protocol specified CCD of 600 mg/m(2) , primarily due to mandated cisplatin toxicity-related dose reductions. The median CCD given to those without relapse or death on treatment was 487.5 mg/m(2) . CCD, as a time-dependent covariate, was not associated with EFS (P = 0.54) or OS (P = 0.11). The 343 patients who completed chemotherapy failure-free were categorized into four groups according to CCD (n = 10; 75-150 mg/m(2) ), (n = 26; 151-300 mg/m(2) ), (n = 113; 301-450 mg/m(2) ), and (n = 194; 451-600 mg/m(2) ). There were no statistically significant differences in distributions of EFS (P = 0.53) or OS (P = 0.49) among these four groups. CCD is not associated with EFS or OS suggesting that lower doses of cisplatin may be incorporated into future medulloblastoma trials, thereby limiting its toxicity profile without affecting survival. If ototoxicity is encountered, more stringent cisplatin dose modification/cessation rules seem warranted. Pediatr Blood Cancer. © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 08/2013; · 2.35 Impact Factor
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    Annals of Surgical Oncology 05/2013; · 4.12 Impact Factor
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    ABSTRACT: Background Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts. ProceduresSAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14. ResultsIn vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7–24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts. Conclusions Under the conditions evaluated in this study, SAR245408 achieved modest single-agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered. Pediatr Blood Cancer 2013; 60: 791–798. © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 05/2013; 60(5). · 2.35 Impact Factor
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    ABSTRACT: BACKGROUND: Chemotherapy has improved the outcome of patients with newly diagnosed osteosarcoma, but its role in relapsed disease is unclear. METHODS: We reviewed the records of all patients who were treated for relapsed high-grade osteosarcoma at our institution between 1970 and 2004. Postrelapse event-free survival (PREFS) and postrelapse survival (PRS) were estimated, and outcome comparisons were made using an exact log-rank test. RESULTS: The 10-year PREFS and PRS of the 110 patients were 11.8% ± 3.5% and 17.0% ± 4.3%, respectively. Metastasis at initial diagnosis (14%), and relapse in lung only (75%) were not significantly associated with PREFS or PRS. Time from initial diagnosis to first relapse (RL1) ≥18 months (43%), surgery at RL1 (76%), and ability to achieve second complete remission (CR2, 56%) were favorably associated with PREFS and PRS (P ≤ 0.0002). In patients without CR2, chemotherapy at RL1 was favorably associated with PREFS (P = 0.01) but not with PRS. In patients with lung relapse only, unilateral relapse and number of nodules ( ≤ 3) were associated with better PREFS and PRS (P ≤ 0.0005); no patients with bilateral relapse survived 10 years. The median PREFS after treatment with cisplatin, doxorubicin, methotrexate, and ifosfamide was 3.5 months (95% confidence interval, 2.1-5.2), and the median PRS was 8.2 months (95% confidence interval, 5.2-15.1). CONCLUSIONS: Late relapse, surgical resection, and unilateral involvement (in lung relapse only) favorably impact outcome after relapse. Surgery is essential for survival; chemotherapy may slow disease progression in patients without CR2. These data are useful for designing clinical trials that evaluate novel agents. Cancer 2013;. © 2013 American Cancer Society.
    Cancer 04/2013; · 5.20 Impact Factor
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    ABSTRACT: BACKGROUND: Antimitotic agents are essential components for curative therapy of pediatric acute leukemias and many solid tumors. Eribulin is a novel agent that differs from both Vinca alkaloids and taxanes in its mode of binding to tubulin polymers. PROCEDURES: Eribulin was tested against the PPTP in vitro cell line panel at concentrations from 0.1 nM to 1.0 μM and against the PPTP in vivo xenograft panels at a dose of 1 mg/kg (solid tumors) or 1.5 mg/kg (ALL models) using a q4dx3 schedule repeated at Day 21. RESULTS: In vitro eribulin demonstrated cytotoxic activity, with a median relative IC50 value of 0.27 nM, (range <0.1-14.8 nM). Eribulin was well tolerated in vivo, and all 43 xenograft models were considered evaluable for efficacy. Eribulin induced significant differences in event-free survival (EFS) distribution compared to control in 29 of 35 (83%) of the solid tumors and in 8 of 8 (100%) of the ALL xenografts. Objective responses were observed in 18 of 35 (51%) solid tumor xenografts. Complete responses (CR) or maintained CR were observed in panels of Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, glioblastoma, and osteosarcoma xenografts. All eight ALL xenografts achieved CR or MCR. CONCLUSIONS: The high level of activity observed for eribulin against the PPTP preclinical models makes this an interesting agent to consider for pediatric evaluation. The activity pattern observed for eribulin in the solid tumor panels is equal or superior to that observed previously for vincristine. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2013; · 2.35 Impact Factor
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    ABSTRACT: PURPOSE: Pediatric adrenocortical carcinoma (ACC) is a rare, aggressive malignancy. Conventional chemotherapeutic agents have shown limited utility and are largely ineffective in treating children with advanced ACC. The lack of cell lines and animal models of pediatric ACC has hampered the development of new therapies. Here we report the establishment of the first pediatric ACC xenograft model and the characterization of its sensitivity to selected chemotherapeutic agents. EXPERIMENTAL DESIGN: A tumor from an 11-year-old boy with previously untreated ACC was established as a subcutaneous xenograft in immunocompromised CB17 scid-/- mice. The patient harbored a germline TP53 G245C mutation, and the primary tumor showed loss of heterozygosity with retention of the mutated TP53 allele. Histopathology, DNA fingerprinting, gene expression profiling, and biochemical analyses of the xenograft were performed and compared with the primary tumor and normal adrenal cortex. The second endpoint was to assess the preliminary antitumor activity of selected chemotherapeutic agents. RESULTS: The xenograft maintained the histopathologic and molecular features of the primary tumor. Screening the xenograft for drug responsiveness showed cisplatin had a potent antitumor effect. However, etoposide, doxorubicin, and a panel of other common cancer drugs had little or no antitumor activity, with the exception of topotecan, which was found to significantly inhibit tumor growth. Consistent with these preclinical findings, topotecan as a single agent in a child with relapsed ACC resulted in disease stabilization. CONCLUSIONS: Our study established a novel TP53-associated pediatric ACC xenograft and identified topotecan as a potentially effective agent for treating children with this disease.
    Clinical Cancer Research 02/2013; · 7.84 Impact Factor
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    ABSTRACT: Purpose To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Patients and Methods Sorafenib dose was escalated from 90 mg/m2 to 110 mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was 21 days. PK and PD studies were performed during the first course. Results Nineteen patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1 to 23). DLTs during course 1 included grade 3 rash (2), increased lipase (1), anorexia (1), and thrombus (1). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (9), lymphopenia (9), and rashes (4). Five of 17 evaluable patients had partial tumor responses, and 5 had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 ml/min/m2 at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGFR2 was inversely correlated with sorafenib steady-state concentrations (p=0.019). Conclusion The recommended phase II doses are sorafenib, 90 mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.
    Clinical Cancer Research 11/2012; · 7.84 Impact Factor
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    ABSTRACT: BACKGROUND: Locoregional failure is a significant concern in patients with high-risk abdominal neuroblastoma (NB) receiving radiotherapy. Locoregional control outcomes were studied in children with NB receiving intensity modulated radiotherapy (IMRT). PROCEDURE: Twenty children (11 females, 9 males) with NB (median age at diagnosis 3.4 years) receiving IMRT were analyzed for locoregional failure, outcomes, and toxicities. IMRT doses were 23.4 Gy (n = 12), 30 Gy (n = 1), 30.6 Gy (n = 5), and 36.0 Gy (n = 2) based on extent of resection. Five patients had tumors with MYCN amplification, and 19 had metastatic disease. All patients were treated consistently using reproducible immobilization techniques; physiological motion was assessed by 4D-CT, and target localization by cone-beam computed tomography. ICRU 62 volumetric conventions were employed based on institutional data for pediatric target volume and organ motion. RESULTS: No patient developed primary site infield or locoregional failure at a median follow-up of 2.2 years. Distant failure (median time to distant failure 1.6 years) occurred in the brain, lungs, or skeletal sites in eight patients, five of whom died. The 2-year event-free survival was 58.5 ± 13.3% and cumulative incidence of local and distant failures was 0% and 41.5 ± 11.9%, respectively. Asymptomatic loose stool during RT occurred in nearly all patients, but required no intervention. CONCLUSIONS: IMRT is feasible, safe in the short term, and yields excellent locoregional control. Despite subtotal resection in some cases, locoregional control appeared to be increased by conformal radiotherapy with ICRU 62-compliant volumes. Dose escalation beyond 30.6 Gy may be unnecessary with improved target volume coverage. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2012; · 2.35 Impact Factor

Publication Stats

2k Citations
692.80 Total Impact Points

Institutions

  • 2002–2014
    • St. Jude Children's Research Hospital
      • • Department of Oncology
      • • Department of Pharmaceutical Sciences
      Memphis, Tennessee, United States
  • 2013
    • Texas Tech University Health Sciences Center
      El Paso, Texas, United States
  • 2012
    • University of New South Wales
      • Children’s Cancer Institute of Australia
      Kensington, New South Wales, Australia
    • NCI-Frederick
      Maryland, United States
  • 2011–2012
    • Montefiore Medical Center
      • The Children's Hospital at Montefiore
      New York City, New York, United States
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
  • 2010–2011
    • Nationwide Children's Hospital
      Columbus, Ohio, United States
    • Children's Cancer Institute Australia
      Randwick, New South Wales, Australia
  • 2008–2011
    • Nemours
      Jacksonville, Florida, United States
    • The Children’s Hospital at Montefiore (CHAM)
      New York City, New York, United States
  • 2007–2011
    • The University of Tennessee Health Science Center
      • Department of Ophthalmology
      Memphis, TN, United States
  • 2009
    • Children's National Medical Center
      Washington, Washington, D.C., United States
  • 2005
    • KK Women's and Children's Hospital
      • Department of Paediatric Surgery
      Singapore, Singapore
    • Bristol-Myers Squibb
      • Clinical Discovery
      New York City, NY, United States