Our studies are aimed at understanding mechanisms of cancer initiation in children and using this information to develop more effective and less toxic treatments that will increase the cure rate and improve quality of life for cancer survivors.
Research Project A
Signaling pathways in childhood sarcoma
Our earlier studies have identified insulin-like growth factor (IGF) signaling as maintaining proliferation of sarcoma cells, and to be involved in angiogenesis by regulating vascular endothelial cell response to VEGF. The current studies, supported through a Program Project Grant from NCI, are aimed at identifying mechanisms of resistance to therapeutics that target the IGF-axis. These studies integrate IGF, STAT3 and NFκB signaling pathways in childhood sarcoma models both in vitro and in vivo.
Research Project B:
The Pediatric Preclinical Consortium (PPTC)
The PPTC builds upon 10 years testing of novel agents against panels of cell lines in vitro and tumor xenografts models in mice that represent childhood solid tumors, brain tumors and acute lymphoblastic leukemias. Over 80 drugs or drug combinations have been tested in 83 models of childhood cancer (kidney cancers, sarcomas, neuroblastoma, brain cancers and acute lymphoblastic leukemia). These studies have identified novel drugs and drug combinations that are now in clinical trial.
Research Project C:
Low-Grade Glioma – Brain tumors
Low-Grade gliomas are ‘driven’ by an activated mutant protein ‘BRAF’. We identified a drug that inhibits a kinase (MEK) downstream in the signaling cascade and causes death of these cancer cells. The drug, selumetinib, has recently completed phase I testing through the Pediatric Brain Tumor Consortium (PBTC), and shows promising activity. This project builds upon our initial work to develop effective therapies that prevent or retard emergence of drug resistant cells, and to explore the therapeutic value of combining selumetinib (or alternate MEK inhibitors) with radiation therapy.
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:
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