Signaling pathways in childhood sarcoma

Program Goals

 

Approximately 70% of children with sarcoma can be cured using multimodality treatments, but the outcome is still poor for those with advanced or metastatic disease. Specifically, the 5-year event free survival rates are 30 percent or less in children with advanced or metastatic Ewing sarcoma, osteosarcoma or rhabdomyosarcoma, and intensive chemo-radiotherapy has not substantially altered this outcome over the past two decades. As additional cytotoxic drugs alone are unlikely to significantly increase cure rates, alternative and complimentary approaches need to be explored. Further, given the long-term toxicities associated with standard maximum tolerated dose chemotherapy in the pediatric population, new therapies associated with less genotoxicity are needed. This Program centers around three separate but integrated signaling pathways shown to be active in childhood sarcomas.

The overall goals for this Program Project Grant are to comprehensively understand the roles of three signaling pathways (NF-κB, STAT3, and insulin like growth factors [IGFs]) in the maintenance of malignant phenotypes of childhood sarcomas, and to use these findings to develop novel integrated therapies with enhanced efficacy for affected patients. These goals will be achieved through the combined expertise of the principal investigators in childhood sarcoma biology and pediatric cancer drug development, the incorporation of unique small and large animal models of childhood sarcoma, and the broad interactions between Projects 1-3. Together, the projects will characterize the interrelationship of these pathways and identify combinatorial inhibitory approaches most likely to yield biologic activity in the clinical setting.

The Program is unique both for its focus on childhood sarcomas, and for its focus on combinatorial approaches to suppress glycolysis, tumor cell proliferation, survival and angiogenesis through modulating NF-κB/TOR/STAT3/IGF signaling pathways.

 

Project 1 (Project Leader, Denis Guttridge, PhD, Ohio State University): NF-κB Regulation of a Metabolic Shift in Childhood Sarcomas

Project 2 (Project Leaders, Jiayuh Lin, PhD, Nationwide Children’s Hospital; Cheryl London, DVM, Ph.D. Ohio State University): The Role of STAT3 Signaling in Childhood Sarcoma

Project 3 (Project Leader, Peter J. Houghton, PhD, Greehey Children’s Cancer Research Institute, UTHSCSA): Insulin-like Growth Factor Signaling as a Therapeutic Target in Childhood Sarcomas and Angiogenesis The Program is supported by three shared resource cores.

  • Core A (Administration and Biostatistics) coordinates communication, program interactions, and provides a centralized mechanism for biostatistical support.
  • Core B (Xenograft and Cell Line) provides unique mouse models of childhood sarcoma and expertise.
  • Core C (Comparative Animal Core) supplies expertise in histopatholgy, fresh canine tumor specimens, and oversees preclinical evaluation of therapeutics in dogs with spontaneous osteosarcoma.

 

 

The overall goal of this Program Project Grant is to acquire a comprehensive understanding of the interrelationship between NF-κB, STAT3, and IGF signaling pathways in childhood sarcomas (rhabdomyosarcoma, Ewing sarcoma, osteosarcoma) that can be leveraged to develop novel more effective therapies for treating patients. These goals will be achieved through the combined expertise of the principal investigators in childhood sarcoma biology and pediatric cancer drug development, the incorporation of unique small and large animal models of childhood sarcoma, and the broad interactions between Projects 1-3. The basic premise for the work proposed is that each of the three pathways to be studied is important for sarcoma cell proliferation and survival, but that by virtue of the dynamic nature of cellular signaling, these pathways are interactive and combinatorial inhibition may be essential to achieve maximum therapeutic efficacy. A schematic showing Project interactions and specific pathways to be studied in each Project are shown:

 

 

 

The Bromodomain BET Inhibitor JQ1 Suppresses Tumor Angiogenesis in Models of Childhood Sarcoma. Bid HK, Phelps DA, Xaio L, Guttridge DC, Lin J, London C, Baker LH, Mo, Houghton PJ. Mol Cancer Ther. 2016 May;15(5):1018-28. doi: 10.1158/1535-7163.MCT-15-0567. Epub 2016 Feb 23.PMID:26908627

Intrinsic Resistance to Cixutumumab Is Conferred by Distinct Isoforms of the Insulin Receptor. Forest A, Amatulli M, Ludwig DL, Damoci CB, Wang Y, Burns CA, Donoho GP, Zanella N, Fiebig HH, Prewett MC, Surguladze D, DeLigio JT, Houghton PJ, Smith MA, Novosiadly R. Mol Cancer Res. 2015 Dec;13(12):1615-26. doi: 10.1158/1541-7786.MCR-15-0279. Epub 2015 Aug 11.PMID:26263910

Inhibition of MEK confers hypersensitivity to X-radiation in the context of BRAF mutation in a model of childhood astrocytoma. Studebaker A, Bondra K, Seum S, Shen C, Phelps DA, Chronowski C, Leasure J, Smith PD, Kurmasheva RT, Mo X, Fouladi M, Houghton PJ. Pediatr Blood Cancer. 2015 Oct;62(10):1768-74. doi: 10.1002/pbc.25579. Epub 2015 May 15.PMID:25981859

Inhibition of MDM2 by RG7388 confers hypersensitivity to X-radiation in xenograft models of childhood sarcoma. Phelps D, Bondra K, Seum S, Chronowski C, Leasure J, Kurmasheva RT, Middleton S, Wang D, Mo X, Houghton PJ. Pediatr Blood Cancer. 2015 Aug;62(8):1345-52. doi: 10.1002/pbc.25465. Epub 2015 Apr 1. PMID:25832557

Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma. Woods GM, Bondra K, Chronowski C, Leasure J, Singh M, Hensley L, Cripe TP, Chakravarti A, Houghton PJ. Pediatr Blood Cancer. 2015 Sep;62(9):1550-4. doi: 10.1002/pbc.25516. Epub 2015 Mar 19.PMID:25790258

A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report. Fouladi M, Perentesis JP, Wagner LM, Vinks AA, Reid JM, Ahern C, Thomas G, Mercer CA, Krueger DA, Houghton PJ, Doyle LA, Chen H, Weigel B, Blaney SM. Clin Cancer Res. 2015 Apr 1;21(7):1558-65. doi: 10.1158/1078-0432.CCR-14-0595. Epub 2014 Dec 2. PMID:25467181

Rhabdomyosarcoma: current challenges and their implications for developing therapies. Hettmer S, Li Z, Billin AN, Barr FG, Cornelison DD, Ehrlich AR, Guttridge DC, Hayes-Jordan A, Helman LJ, Houghton PJ, Khan J, Langenau DM, Linardic CM, Pal R, Partridge TA, Pavlath GK, Rota R, Schäfer BW, Shipley J, Stillman B, Wexler LH, Wagers AJ, Keller C. Cold Spring Harb Perspect Med. 2014 Nov 3;4(11):a025650. doi: 0.1101/cshperspect.a025650. Review.PMID:25368019

The role of FLI-1-EWS, a fusion gene reciprocal to EWS-FLI-1, in Ewing sarcoma. Elzi DJ, Song M, Houghton PJ, Chen Y, Shiio Y. Genes Cancer. 2015 Nov;6(11-12):452-61. PMID:26807198

A novel small molecular STAT3 inhibitor, LY5, inhibits cell viability, cell migration, and angiogenesis in medulloblastoma cells. Xiao H, Bid HK, Jou D, Wu X, Yu W, Li C, Houghton PJ, Lin J. J Biol Chem. 2015 Feb 6;290(6):3418-29. doi: 10.1074/jbc.M114.616748. Epub 2014 Oct 13. PMID:25313399

Targeting FANCD2 for therapy sensitization. Shen C, Houghton PJ. Oncotarget. 2014 Jun 15;5(11):3426-7. PMID:24913333

FANCD2 is a potential therapeutic target and biomarker in alveolar rhabdomyosarcoma harboring the PAX3-FOXO1 fusion gene. Singh M, Leasure JM, Chronowski C, Geier B, Bondra K, Duan W, Hensley LA, Villalona-Calero M, Li N, Vergis AM, Kurmasheva RT, Shen C, Woods G, Sebastian N, Fabian D, Kaplon R, Hammond S, Palanichamy K, Chakravarti A, Houghton PJ. Clin Cancer Res. 2014 Jul 15;20(14):3884-95. doi: 10.1158/1078-0432.CCR-13-0556. Epub 2014 Apr 30.PMID: 24787670

p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damage. Cam M, Bid HK, Xiao L, Zambetti GP, Houghton PJ, Cam H. J Biol Chem. 2014 Feb 14;289(7):4083-94. doi: 10.1074/jbc.M113.530303. Epub 2013 Dec 23.PMID: 24366874

ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis. Bid HK, Roberts RD, Cam M, Audino A, Kurmasheva RT, Lin J, Houghton PJ, Cam H. Cancer Res. 2014 Jan 1;74(1):320-9. doi: 10.1158/0008-5472.CAN-13-0894. Epub 2013 Oct 23.PMID: 24154873

miR-29 acts as a decoy in sarcomas to protect the tumor suppressor A20 mRNA from degradation by HuR. Balkhi MY, Iwenofu OH, Bakkar N, Ladner KJ, Chandler DS, Houghton PJ, London CA, Kraybill W, Perrotti D, Croce CM, Keller C, Guttridge DC. Sci Signal. 2013 Jul 30;6(286):ra63. doi: 10.1126/scisignal.2004177. Erratum in: Sci Signal. 2013 Sep 10;6(292):er6. Balkhi, Mumtaz Y [corrected to Balkhi, M Y]. PMID: 23901138

The mTOR pathway negatively controls ATM by up-regulating miRNAs. Shen C, Houghton PJ. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):11869-74. doi: 10.1073/pnas.1220898110. Epub 2013 Jul 1.PMID: 23818585

Regulation of FANCD2 by the mTOR pathway contributes to the resistance of cancer cells to DNA double-strand breaks. Shen C, Oswald D, Phelps D, Cam H, Pelloski CE, Pang Q, Houghton PJ. Cancer Res. 2013 Jun 1;73(11):3393-401. doi: 10.1158/0008-5472.CAN-12-4282. Epub 2013 Apr 30.PMID: 23633493

Dual targeting of the type 1 insulin-like growth factor receptor and its ligands as an effective antiangiogenic strategy. Bid HK, London CA, Gao J, Zhong H, Hollingsworth RE, Fernandez S, Mo X, Houghton PJ. Clin Cancer Res. 2013 Jun 1;19(11):2984-94. doi: 10.1158/1078-0432.CCR-12-2008. Epub 2013 Apr 2.PMID: 23549869

Potent inhibition of angiogenesis by the IGF-1 receptor-targeting antibody SCH717454 is reversed by IGF-2. Bid HK, Zhan J, Phelps DA, Kurmasheva RT, Houghton PJ. Mol Cancer Ther. 2012 Mar;11(3):649-59. doi: 10.1158/1535-7163.MCT-11-0575. Epub 2011 Dec 21.PMID: 22188815

Predicting IGF-1R therapy response in bone sarcomas: immuno-SPECT imaging with radiolabeled R1507. Fleuren ED, Versleijen-Jonkers YM, van de Luijtgaarden AC, Molkenboer-Kuenen JD, Heskamp S, Roeffen MH, van Laarhoven HW, Houghton PJ, Oyen WJ, Boerman OC, van der Graaf WT. Clin Cancer Res. 2011 Dec 15;17(24):7693-703. doi: 10.1158/1078-0432.CCR-11-1488. Epub 2011 Oct 28.PMID: 22038993

Preclinical characterization of OSI-027, a potent and selective inhibitor of mTORC1 and mTORC2: distinct from rapamycin. Bhagwat SV, Gokhale PC, Crew AP, Cooke A, Yao Y, Mantis C, Kahler J, Workman J, Bittner M, Dudkin L, Epstein DM, Gibson NW, Wild R, Arnold LD, Houghton PJ, Pachter JA.Mol Cancer Ther. 2011 Aug;10(8):1394-406. doi: 10.1158/1535-7163.MCT-10-1099. Epub 2011 Jun 14. PMID: 21673091

Combination testing (Stage 2) of the Anti-IGF-1 receptor antibody IMC-A12 with rapamycin by the pediatric preclinical testing program. Kolb EA, Gorlick R, Maris JM, Keir ST, Morton CL, Wu J, Wozniak AW, Smith MA, Houghton PJ. Pediatr Blood Cancer. 2012 May;58(5):729-35. doi: 10.1002/pbc.23157. Epub 2011 May 31. PMID: 21630428

mTORC1 signaling under hypoxic conditions is controlled by ATM-dependent phosphorylation of HIF-1α. Cam H, Easton JB, High A, Houghton PJ.Mol Cell. 2010 Nov 24;40(4):509-20. doi: 10.1016/j.molcel.2010.10.030. PMID: 21095582

Protection from rapamycin-induced apoptosis by insulin-like growth factor-I is partially dependent on protein kinase C signaling. Thimmaiah KN, Easton JB, Houghton PJ.Cancer Res. 2010 Mar 1;70(5):2000-9. doi: 10.1158/0008-5472.CAN-09-3693. Epub 2010 Feb 23.PMID: 20179209

The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Kurmasheva RT, Dudkin L, Billups C, Debelenko LV, Morton CL, Houghton PJ.Cancer Res. 2009 Oct 1;69(19):7662-71. doi: 10.1158/0008-5472.CAN-09-1693. Epub 2009 Sep 29.PMID: 19789339

 

Rhabdomyosarcoma: current challenges and their implications for developing therapies. Hettmer S, Li Z, Billin AN, Barr FG, Cornelison DD, Ehrlich AR, Guttridge DC, Hayes-Jordan A, Helman LJ, Houghton PJ, Khan J, Langenau DM, Linardic CM, Pal R, Partridge TA, Pavlath GK, Rota R, Schäfer BW, Shipley J, Stillman B, Wexler LH, Wagers AJ, Keller C. Cold Spring Harb Perspect Med. 2014 Nov 3;4(11):a025650. doi: 10.1101/cshperspect.a025650. Review.PMID: 25368019

Regulation of mammalian target of rapamycin complex 1 (mTORC1) by hypoxia: causes and consequences. Cam H, Houghton PJ. Target Oncol. 2011 Jun;6(2):95-102. doi: 10.1007/s11523-011-0173-x. Epub 2011 Apr 16. Review.PMID: 21499767

Targeting angiogenesis in childhood sarcomas. Bid HK, Houghton PJ. Sarcoma. 2011;2011:601514. doi: 10.1155/2011/601514. Epub 2010 Dec 9. PMID: 21197468

Everolimus. Houghton PJ. Clin Cancer Res. 2010 Mar 1;16(5):1368-72. doi: 10.1158/1078-0432.CCR-09-1314. Epub 2010 Feb 23. Review.PMID: 20179227