Peter J Houghton

Nationwide Children's Hospital, Columbus, Ohio, United States

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Publications (321)1291.89 Total impact

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    ABSTRACT: Purpose: While the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (~50%). Mutations in the p53 tumor suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design:Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell cycle arrest and apoptosis in vivo was evaluated. Results:Gene expression analysis revealed that MLL-ALL, B-lineage ALL and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be over-expressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly up-regulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 up-regulation, cell cycle arrest and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusions:The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. Copyright © 2015, American Association for Cancer Research.
    Clinical cancer research : an official journal of the American Association for Cancer Research. 01/2015;
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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: Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28 day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. Results: Thirty-nine patients, median age 11.8 years (range, 1-21.5), with recurrent solid or CNS tumors were enrolled of who 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (1) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (2) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (3) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2 and (4) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included: hypercholesterolemia, fatigue, thrombocytopenia, and increased ALT. Target inhibition (decreased p-S6K1 and p-Akt) in PBMNCs was noted at all dose levels. Marked interpatient variability in temsirolimus PK parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2946 ng•h/mL (range, 937-5536) with a median sirolimus AUC of 767 ng•h/mL (range, 245-3675). Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; · 8.19 Impact Factor
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    ABSTRACT: Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called “fusion-positive” tumors) carries exclusive chromosomal translocations that join the DNAbinding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 (previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in ,30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusionpositive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.
    Cold Spring Harbor Perspectives in Medicine 11/2014; · 7.56 Impact Factor
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    Shile Huang, Mary-Ann Bjornsti, Peter J Houghton
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    ABSTRACT: Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties. The parent compound, rapamycin, is approved as an immunosup-pressive agent for preventing rejection in patients receiving organ transplantation. Two analogues, CCI-779 and RAD001 are currently being investigated as anticancer agents. Rapamycins first bind a cyclophilin FKBP12, and this complex binds and inhibits the function of mTOR (mammalian target of rapamycin) a serine/threonine (Ser/Thr) kinase with homology to phosphatidylinositol 3' kinase. Currently, as mTOR is the only identified target, this places rapamycins in a unique position of being the most selective kinase inhibitor known. Consequently these agents have been powerful tools in elucidating the role of mTOR in cellular growth, proliferation, survival and tumorigenesis. Increasing evidence suggests that mTOR acts as a central controller sensing cellular environment (nutritional status or mitogenic stimulation) and regulating translation initiation through the eukaryotic initiation factor 4E, and ribosomal p70 S6 kinase pathways. Here we review the conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent.
    Cancer biology & therapy 10/2014; 2(3):222-32. · 3.63 Impact Factor
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    ABSTRACT: Signal Transducers and Activators of Transcription 3 (STAT3) signaling is persistently activated and could contribute to tumorigenesis of medulloblastoma. Numerous studies have demonstrated that inhibition of persistent STAT3 signaling pathway results in decreased proliferation and increased apoptosis in human cancer cells, indicating that STAT3 is a viable molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable small molecule, named as LY5 to target STAT3 in medulloblastoma cells. LY5 inhibited persistent STAT3 phosphorylation and induced apoptosis in human medulloblastoma cell lines expressing constitutive STAT3 phosphorylation. The inhibition of STAT3 signaling by LY5 was confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, Bcl-XL, Survivin, and microRNA-21. LY5 also inhibited the induction of STAT3 phosphorylation by Interleukin-6 (IL-6), IGF-1, IGF-2, and LIF in medulloblastoma cells, but did not inhibit STAT1 and STAT5 phosphorylation stimulated by interferon-γ(IFN-γ) and EGF respectively. In addition, LY5 blocked the STAT3 nuclear localization induced by IL-6, but did not block STAT1 and STAT5 nuclear translocation mediated by IFN-γ and EGF respectively. Combination of LY5 with Cisplatin or X-ray radiation also showed more potent effects than single treatment alone in the inhibition of cell viability in human medulloblastoma cells. Furthermore, LY5 demonstrated a potent inhibitory activity on cell migration and angiogenesis. Taken together, these findings indicate LY5 inhibits persistent and inducible STAT3 phosphorylation and suggest that LY5 is a promising therapeutic drug candidate for medulloblastoma by inhibiting persistent STAT3 signaling.
    Journal of Biological Chemistry 10/2014; · 4.60 Impact Factor
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    ABSTRACT: Approval of new cancer drugs for paediatric patients generally occurs after their development and approval for treating adult cancers. As most drug development occurs in the industry setting, the relatively small market of paediatric oncology does not provide the financial incentives for companies to actively pursue paediatric oncology solutions. Indeed, between 1948 and January 2003 the FDA approved 120 new cancer drugs, of which only 30 have been used in children. This slow rate of development must be addressed in a meaningful way if we are to make progress in the most pressing settings in childhood cancer. In this Viewpoint article, the key opinion leaders in the field weigh in and offer practical advice on how to address this issue.
    Nature Reviews Clinical Oncology 09/2014; · 15.03 Impact Factor
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    ABSTRACT: BackgroundBMN 673 is a potent inhibitor of poly-ADP ribose polymerase (PARP) that is in clinical testing with a primary focus on BRCA-mutated cancers. BMN 673 is active both through inhibiting PARP catalytic activity and by tightly trapping PARP to DNA at sites of single strand breaks.ProcedureBMN 673 was tested in vitro at concentrations ranging from 0.1 nM to 1 μM and in vivo at a daily dose of 0.33 mg/kg administered orally twice daily (Mon-Fri) and once daily on weekends (solid tumors) for 28 days.ResultsThe median relative IC50 (rIC50) concentration against the PPTP cell lines was 25.8 nM. The median rIC50 for the Ewing cell lines was lower than for the remaining cell lines (6.4 vs. 31.1 nM, respectively). In vivo BMN 673 induced statistically significant differences in EFS distribution in 17/43 (39.5%) xenograft models. Three objective regressions were observed: a complete response (CR) in a medulloblastoma line (BT-45), a maintained CR in a Wilms tumor line (KT-10), and a maintained CR in an ependymoma line (BT-41). BMN 673 maintained its high level of activity against KT-10 with a threefold reduction in dose. KT-10 possesses a truncating mutation in PALB2 analogous to PALB2 mutations associated with hereditary breast and ovarian cancer that abrogate homologous recombination (HR) repair.Conclusions The PPTP results suggest that single agent BMN 673 may have limited clinical activity against pediatric cancers. Single agent activity is more likely for patients whose tumors have defects in HR repair. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2014; · 2.35 Impact Factor
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    ABSTRACT: In an effort to establish new candidates with enhanced anticancer activity of 5-hydroxy-7-methyl-1,4-naphthoquinone scaffold (7-methyljuglone) previously isolated from the root extract of Euclea natalensis, a series of 7-methyljuglone derivatives have been synthesized and assessed for cytotoxicity on selected human cancer lines. These compounds were screened in vitro for anticancer activity on MCF-7, HeLa, SNO and DU145 human cancer cell lines by MTT assay. Most of them exhibited significant toxicity on cancer cell lines with lower IC50 values. The most potent derivative (19) exhibited the toxicity on HeLa and DU145 cell lines with IC50 value of 5.3 and 6.8 μM followed by compound (5) with IC50 value of 10.1 and 9.3 μM, respectively. Structure-activity relationship reveals that the fluoro substituents at position C-8 while hydroxyl substituents at C-2 and C-5 positions played an important role in toxicity.
    Bioorganic & Medicinal Chemistry 09/2014; · 2.95 Impact Factor
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    ABSTRACT: BackgroundCPX-351, a liposomal formulation of cytarabine and daunorubicin co-encapsulated at an optimized synergistic 5:1 molar ratio, has demonstrated improved clinical outcomes over conventional cytarabine/daunorubicin treatment in a randomized phase 2 trial in patients with AML as well as superior efficacy against preclinical leukemia models when compared to the free drugs in combination.ProceduresGiven the promising phase 2 data, limited toxicities observed, and the known clinical activities of cytarabine/daunorubicin, we assessed the efficacy of CPX-351 against a panel of childhood ALL xenograft models. Plasma pharmacokinetics of cytarabine and daunorubicin following CPX-351 treatment were determined by HPLC in order to correlate efficacy with drug exposure.ResultsCPX-351, at a dose of 5 units/kg (corresponding to 5 mg/kg cytarabine and 2.2 mg/kg daunorubicin), was highly efficacious against all xenografts tested, inducing complete responses in four B-lineage xenografts and partial response in one T-lineage xenograft. These therapeutic responses were achieved with CPX-351 doses that provided drug exposures (based on Cmax and AUC) comparable to those observed in patients with AML.Conclusions These results suggest that CPX-351 may be a promising chemotherapeutic to be utilized in the treatment of ALL and support its testing in pediatric patients with leukemia. Pediatr Blood Cancer 2014;9999:1–7. © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 09/2014; · 2.35 Impact Factor
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    ABSTRACT: BackgroundAZD1480 is an ATP competitive inhibitor of Janus kinases 1 and 2 (JAK1, 2) that has been shown to inhibit the growth of solid tumor models. This agent was selected for testing the putative role of JAK/STAT signaling in the standard PPTP solid tumor models.ProceduresAZD1480 was tested against the PPTP in vitro cell line panel at concentrations from 1.0 nM to 10 μM and against the PPTP in vivo solid tumor xenograft panels at (60 mg/kg once daily (SID) × 5) for three consecutive weeks. Additional studies evaluated 5 to 20 mg/kg BID × 5 with SID dosing at 7–30 mg/kg at weekends for three consecutive weeks.ResultsIn vitro the median relative IC50 (rIC50) for the PPTP cell lines was 1.5 µM, with a range from 0.3 µM to 5.9 µM. The two cell lines with rIC50 values of 0.3 µM both had ALK activating genomic alterations. AZD1480 demonstrated statistically significant differences (P < 0.05) in EFS distribution compared to control in 89% of the solid tumor xenografts. AZD1480 induced intermediate (EFS T/C > 2) or high-level growth inhibition in 15 of 30 (50%) solid tumor xenografts. Tumor regressions were observed in three of six Wilms tumor models at doses that induced inhibition of Stat3(Y705) phosphorylation.ConclusionsAZD1480 demonstrated significant tumor growth inhibition against most PPTP solid tumor xenografts, similar to that observed for antiangiogenic agents tested by the PPTP. Tumor regressing activity was noted for Wilms tumor xenografts. Pediatr Blood Cancer 2014;XX:XX–XX. © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 08/2014; · 2.35 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; · 2.56 Impact Factor
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    Changxian Shen, Peter J Houghton
    Oncotarget 06/2014; · 6.63 Impact Factor
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    ABSTRACT: mTOR is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR-inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 18F-FLT-PET scans showed a remarkable decrease in 18F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after one week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and 18F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although 18F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of 18F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2014; · 6.20 Impact Factor
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    ABSTRACT: We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies. MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence. Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) . The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied. Pediatr Blood Cancer 2014;9999:1-6. © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2014; · 2.35 Impact Factor
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    ABSTRACT: Medulloblastoma is the most common type of pediatric brain tumor. Although numerous factors influence patient survival rates, more than 30% of all cases will ultimately be refractory to conventional therapies. Current standards of care are also associated with significant morbidities, giving impetus for the development of new treatments. We have previously shown that oncolytic measles virotherapy is effective against medulloblastoma, leading to significant prolongation of survival and even cures in mouse xenograft models of localized and metastatic disease. Because medulloblastomas are known to be highly vascularized tumors, we reasoned that the addition of angiogenesis inhibitors could further enhance the efficacy of oncolytic measles virotherapy. Toward this end, we have engineered an oncolytic measles virus that express a fusion protein of endostatin and angiostatin, two endogenous and potent inhibitors of angiogenesis. Oncolytic measles viruses encoding human and mouse variants of a secretable endostatin/angiostatin fusion protein were designed and rescued according to established protocols. These viruses, known as MV-hE:A and MV-mE:A respectively, were then evaluated for their anti-angiogenic potential and efficacy against medulloblastoma cell lines and orthotopic mouse models of localized disease. Medulloblastoma cells infected by MV-E:A readily secrete endostatin and angiostatin prior to lysis. The inclusion of the endostatin/angiostatin gene did not negatively impact the measles virus' cytotoxicity against medulloblastoma cells or alter its growth kinetics. Conditioned media obtained from these infected cells was capable of inhibiting multiple angiogenic factors in vitro, significantly reducing endothelial cell tube formation, viability and migration compared to conditioned media derived from cells infected by a control measles virus. Mice that were given a single intratumoral injection of MV-E:A likewise showed reduced numbers of tumor-associated blood vessels and a trend for increased survival compared to mice treated with the control virus. These data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.
    BMC Cancer 03/2014; 14(1):206. · 3.32 Impact Factor
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    ABSTRACT: STAT3 is well-corroborated preclinically as a cancer therapeutic target, but tractable translational strategies for its blockade by small molecule inhibitors have remained elusive. In this study, we report the development of a novel class of bi-functional STAT3 inhibitors, based on conjugation of a diarylidenyl-piperidone (DAP) backbone to an N-hydroxypyrroline (-NOH) group, which exhibit minimal toxicity against normal cells and good oral bioavailability. Molecular modeling studies of this class suggested direct interaction with the STAT3 DNA binding domain. In particular, the DAP compound HO-3867 selectively inhibited STAT3 phosphorylation, transcription and DNA binding without affecting the expression of other active STATs. HO-3867 exhibited minimal toxicity toward noncancerous cells and tissues but induced apoptosis in ovarian cancer cells. Pharmacological analysis revealed greater bioabsorption and bioavailability of the active (cytotoxic) metabolites in cancer cells compared to normal cells. The selective cytotoxicity of HO-3867 appeared to be multifaceted, eliciting differential activation of the Akt pathway in normal versus cancer cells. RNAi attenuation experiments confirmed the requirement of STAT3 for HO-3867-mediated apoptosis in ovarian cancer cells. In vivo testing showed that HO-3867 could block xenograft tumor growth without toxic side effects. Further, in primary human ovarian cancer cells isolated from patient ascites, HO-3867 inhibited cell migration/invasion and survival. Our results offer preclinical proof-of-concept for HO-3867 as a selective STAT3 inhibitor to treat ovarian cancer and other solid tumors where STAT3 is widely up-regulated.
    Cancer Research 03/2014; · 9.28 Impact Factor
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    ABSTRACT: PF-03084014, a γ-secretase inhibitor, was tested against the PPTP in vitro cell line panel (1.0 nM to 10 μM) and against the in vivo xenograft panels (administered orally twice daily on Days 1–7 and 15–21). PF-03084014 demonstrated limited in vitro activity, with no cell line achieving ≥50% inhibition. PF-03084014 induced significant differences in EFS distribution in 14 of 35 (40%) solid tumor xenografts, and 1 of 9 ALL xenografts (which lacked a NOTCH1 mutation), but objective responses were not observed. PF-03084014 demonstrated limited single agent activity in vitro and in vivo against the pediatric preclinical models studied. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 03/2014; · 2.35 Impact Factor

Publication Stats

9k Citations
1,291.89 Total Impact Points


  • 2010–2014
    • Nationwide Children's Hospital
      Columbus, Ohio, United States
    • Chiba University
      Tiba, Chiba, Japan
  • 2008–2014
    • University of Pretoria
      • Department of Plant Science
      Πρετόρια/Πόλη του Ακρωτηρίου, Gauteng, South Africa
    • National Botanical Research Institute - India
      Lakhnau, Uttar Pradesh, India
    • The Children’s Hospital at Montefiore (CHAM)
      New York City, New York, United States
    • National Cancer Institute (USA)
      • Cancer Therapy Evaluation Program
      Maryland, United States
  • 1992–2014
    • St. Jude Children's Research Hospital
      • Department of Pharmaceutical Sciences
      Memphis, Tennessee, United States
  • 2011–2013
    • The Children's Hospital of Philadelphia
      Philadelphia, Pennsylvania, United States
    • Texas Tech University Health Sciences Center
      El Paso, Texas, United States
    • Ballarat Cancer Research Centre
      Ballaarat, Victoria, Australia
    • Montefiore Medical Center
      • The Children's Hospital at Montefiore
      New York City, New York, United States
    • The University of Tennessee Health Science Center
      • Department of Pediatrics
      Memphis, Tennessee, United States
  • 2009–2013
    • Children's Cancer Institute Australia
      Randwick, New South Wales, Australia
    • South African National Blood Service
      Πρετόρια/Πόλη του Ακρωτηρίου, Gauteng, South Africa
    • Children's Hospital Los Angeles
      Los Angeles, California, United States
  • 2011–2012
    • NCI-Frederick
      Maryland, United States
  • 2008–2012
    • University of New South Wales
      • Children’s Cancer Institute of Australia
      Kensington, New South Wales, Australia
  • 2003–2012
    • Royal Botanic Gardens, Kew
      • Jodrell Laboratory
      TW9, England, United Kingdom
  • 1989–2012
    • King's College London
      • Department of Pharmacy
      Londinium, England, United Kingdom
  • 2009–2011
    • ICL
      Londinium, England, United Kingdom
  • 2008–2011
    • Nemours
      Jacksonville, Florida, United States
    • Hospital of the University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 2003–2011
    • Duke University Medical Center
      • Department of Surgery
      Durham, North Carolina, United States
  • 2008–2010
    • Kwame Nkrumah University Of Science and Technology
      • Faculty of Pharmacy and Pharmaceutical Sciences
      Coomassie, Ashanti, Ghana
  • 2004–2010
    • Università della Calabria
      • Department of Pharmacy, Health and Nutritional Sciences
      Rende, Calabria, Italy
    • University of Mysore
      Mahisūr, Karnātaka, India
    • Chinese Academy of Medical Sciences
      Peping, Beijing, China
    • Chulalongkorn University
      • Faculty of Pharmaceutical Sciences
      Bangkok, Bangkok, Thailand
  • 2007–2008
    • Jadavpur University
      • Department of Pharmaceutical Technology
      Calcutta, Bengal, India
    • The Kings College
      Eidson Road, Texas, United States
  • 2005–2008
    • Aga Khan University Hospital, Karachi
      • Department of Medicine
      Kurrachee, Sindh, Pakistan
    • Western Illinois University
      • Chemistry
      Macomb, IL, United States
    • Bristol-Myers Squibb
      • Clinical Discovery
      New York City, NY, United States
  • 2003–2005
    • University of Maryland, Baltimore
      • Greenebaum Cancer Center
      Baltimore, Maryland, United States
  • 1991–2004
    • King College
      Franklin, Tennessee, United States
  • 2002
    • University of London
      • The School of Pharmacy
      London, ENG, United Kingdom
  • 2000
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 1999–2000
    • University of Tennessee
      Knoxville, Tennessee, United States