Department of Molecular Medicine
 

phouhton.jpg Peter  HoughtonPh.D.

Professor of Molecular Medicine


Profile and Contact Information | Research | Laboratory


RESEARCH

 

Research Program

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.


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.


GCCRI Profile Page

 

Selected Publications

  1. P53 suppresses ribonucleotide reductase via inhibiting mTORC1. He Z, Hu X, Liu W, Dorrance A, Garzon R, Houghton PJ, Shen C. Oncotarget. 2017 Apr 26. doi: 10.18632/oncotarget.17440. [Epub ahead of print] PMID:28507282

  2. Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells. Zhou X, Liu W, Hu X, Dorrance A, Garzon R, Houghton PJ, Shen C. Sci Rep. 2017 May 8;7(1):1535. doi: 10.1038/s41598-017-01729-w. PMID:28484242

  3. Bioluminescence Imaging Enhances Analysis of Drug Responses in a Patient-Derived Xenograft Model of Pediatric ALL. Jones L, Richmond J, Evans K, Carol H, Jing D, Kurmasheva RT, Billups CA, Houghton PJ, Smith MA, Lock RB. Clin Cancer Res. 2017 Jan 24. doi: 10.1158/1078-0432.CCR-16-2392. [Epub ahead of print] PMID:28119366

  4. Initial testing of VS-4718, a novel inhibitor of focal adhesion kinase (FAK), against pediatric tumor models by the Pediatric Preclinical Testing Program. Kurmasheva RT, Gorlick R, Kolb EA, Keir ST, Maris JM, Lock RB, Carol H, Kang M, Reynolds CP, Wu J, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26304. Epub 2016 Oct 27. PMID:27786412

  5. Initial testing (stage 1) of the curaxin CBL0137 by the pediatric preclinical testing program. Lock R, Carol H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Wu J, Purmal A, Gudkov A, Kurmashev D, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2017 Apr;64(4). doi: 10.1002/pbc.26263. Epub 2016 Sep 21. PMID:27650817

  6. Initial testing (stage 1) of tazemetostat (EPZ-6438), a novel EZH2 inhibitor, by the Pediatric Preclinical Testing Program. Kurmasheva RT, Sammons M, Favours E, Wu J, Kurmashev D, Cosmopoulos K, Keilhack H, Klaus CR, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2017 Mar;64(3). doi: 10.1002/pbc.26218. Epub 2016 Aug 24. PMID:27555605

  7. Evaluation of Alternative In Vivo Drug Screening Methodology: A Single Mouse Analysis. Murphy B, Yin H, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Kurmasheva RT, Dvorchik I, Wu J, Billups CA, Boateng N, Smith MA, Lock RB, Houghton PJ. Cancer Res. 2016 Oct 1;76(19):5798-5809. Epub 2016 Aug 5. PMID:27496711

  8. Hypoxic Proliferation of Osteosarcoma Cells Depends on Arginase II. Setty BA, Jin Y, Houghton PJ, Yeager ND, Gross TG, Nelin LD. Cell Physiol Biochem. 2016;39(2):802-13. doi: 10.1159/000447790. Epub 2016 Aug 1. PMID:27475813

  9. Venetoclax responses of pediatric ALL xenografts reveal sensitivity of MLL-rearranged leukemia. Khaw SL, Suryani S, Evans K, Richmond J, Robbins A, Kurmasheva RT, Billups CA, Erickson SW, Guo Y, Houghton PJ, Smith MA, Carol H, Roberts AW, Huang DC, Lock RB. Blood. 2016 Sep 8;128(10):1382-95. doi: 10.1182/blood-2016-03-707414. Epub 2016 Jun 24. PMID:27343252

  10. Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant. Richmond J, Robbins A, Evans K, Beck D, Kurmasheva RT, Billups CA, Carol H, Heatley S, Sutton R, Marshall GM, White D, Pimanda J, Houghton PJ, Smith MA, Lock RB. Cancer Res. 2016 Aug 1;76(15):4579-91. doi: 10.1158/0008-5472.CAN-16-0523. Epub 2016 Jun 14. PMID:27302164

  11. Initial Testing (Stage 1) of MK-8242-A Novel MDM2 Inhibitor-by the Pediatric Preclinical Testing Program. Kang MH, Reynolds CP, Kolb EA, Gorlick R, Carol H, Lock R, Keir ST, Maris JM, Wu J, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2016 Oct;63(10):1744-52. doi: 10.1002/pbc.26064. Epub 2016 May 30. PMID:27238606

  12. Synergism of FAK and tyrosine kinase inhibition in Ph+ B-ALL. Churchman ML, Evans K, Richmond J, Robbins A, Jones L, Shapiro IM, Pachter JA, Weaver DT, Houghton PJ, Smith MA, Lock RB, Mullighan CG. JCI Insight. 2016;1(4). pii: e86082. Epub 2016 Apr 7. PMID:27123491

  13. Quantitative phosphotyrosine profiling of patient-derived xenografts identifies therapeutic targets in pediatric leukemia. Dolai S, Sia KC, Robbins AK, Zhong L, Heatley SL, Vincent TL, Hochgräfe F, Sutton R, Kurmasheva RT, Revesz T, White DL, Houghton PJ, Smith MA, Teachey DT, Daly RJ, Raftery MJ, Lock RB. Cancer Res. 2016 Mar 9. pii: canres.2786.2015. [Epub ahead of print] PMID:26960974

  14. 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 X, 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

  15. 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

  16. Initial Testing of NSC 750854, a Novel Purine Analog, Against Pediatric Tumor Models by the Pediatric Preclinical Testing Program. Gorlick R, Kolb EA, Keir ST, Maris JM, Lock RB, Carol H, Reynolds CP, Kang MH, Billups CA, Collins J, Kurmashev D, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2016 Mar;63(3):443-50. doi: 10.1002/pbc.25826. Epub 2015 Nov 24. PMID:26797892

  17. Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Attiyeh EF, Maris JM, Lock R, Reynolds CP, Kang MH, Carol H, Gorlick R, Kolb EA, Keir ST, Wu J, Landesman Y, Shacham S, Lyalin D, Kurmasheva RT, Houghton PJ, Smith MA.Pediatr Blood Cancer. 2016 Feb;63(2):276-86. doi: 10.1002/pbc.25727. Epub 2015 Sep 23. PMID:26398108

  18. Preclinical Childhood Sarcoma Models: Drug Efficacy Biomarker Identification and Validation. Geier B, Kurmashev D, Kurmasheva RT, Houghton PJ. Front Oncol. 2015 Aug 26;5:193. doi: 10.3389/fonc.2015.00193. eCollection 2015. Review. PMID:26380223

  19. 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

  20. Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the pediatric preclinical testing program. Reynolds CP, Kang MH, Maris JM, Kolb EA, Gorlick R, Wu J, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2015 Nov;62(11):1897-905. doi: 10.1002/pbc.25611. Epub 2015 Jul 7. PMID:26154614

  21. AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, Hedrick A, Sutton R, Marshall GM, Wilson WR, Kurmasheva RT, Billups C, Houghton PJ, Smith MA, Carol H, Lock RB. Blood. 2015 Sep 3;126(10):1193-202. doi: 10.1182/blood-2014-12-618900. Epub 2015 Jun 26. PMID:26116659

  22. The oncogenic role of the cochaperone Sgt1. Ogi H, Sakuraba Y, Kitagawa R, Xiao L, Shen C, Cynthia MA, Ohta S, Arnold MA, Ramirez N, Houghton PJ, Kitagawa K. Oncogenesis. 2015 May 18;4:e149. doi: 10.1038/oncsis.2015.12. PMID:25985210

  23. 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

  24. 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

  25. Initial testing (stage 1) of the tubulin binding agent nanoparticle albumin-bound (nab) paclitaxel (Abraxane(®)) by the Pediatric Preclinical Testing Program (PPTP). Houghton PJ, Kurmasheva RT, Kolb EA, Gorlick R, Maris JM, Wu J, Tong Z, Arnold MA, Chatterjee M, Williams TM, Smith MA. Pediatr Blood Cancer. 2015 Jul;62(7):1214-21. doi: 10.1002/pbc.25474. Epub 2015 Mar 23. PMID:25809532

  26. 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

  27. Effective targeting of the P53-MDM2 axis in preclinical models of infant MLL-rearranged acute lymphoblastic leukemia. Richmond J, Carol H, Evans K, High L, Mendomo A, Robbins A, Meyer C, Venn NC, Marschalek R, Henderson M, Sutton R, Kurmasheva RT, Kees UR, Houghton PJ, Smith MA, Lock RB. Clin Cancer Res. 2015 Mar 15;21(6):1395-405. doi: 10.1158/1078-0432.CCR-14-2300. Epub 2015 Jan 8. PMID:25573381

  28. Evaluation of the in vitro and in vivo efficacy of the JAK inhibitor AZD1480 against JAK-mutated acute lymphoblastic leukemia. Suryani S, Bracken LS, Harvey RC, Sia KC, Carol H, Chen IM, Evans K, Dietrich PA, Roberts KG, Kurmasheva RT, Billups CA, Mullighan CG, Willman CL, Loh ML, Hunger SP, Houghton PJ, Smith MA, Lock RB. Mol Cancer Ther. 2015 Feb;14(2):364-74. doi: 10.1158/1535-7163.MCT-14-0647. Epub 2014 Dec 10. PMID:25504635

  29. Synergistic activity of PARP inhibition by talazoparib (BMN 673) with temozolomide in pediatric cancer models in the pediatric preclinical testing program. Smith MA, Reynolds CP, Kang MH, Kolb EA, Gorlick R, Carol H, Lock RB, Keir ST, Maris JM, Billups CA, Lyalin D, Kurmasheva RT, Houghton PJ. Clin Cancer Res. 2015 Feb 15;21(4):819-32. doi: 10.1158/1078-0432.CCR-14-2572. Epub 2014 Dec 10. Erratum in: Clin Cancer Res. 2017 Feb 15;23 (4):1118-1119. PMID:25500058

  30. 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

  31. Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program.Kolb EA, Gorlick R, Keir ST, Maris JM, Kang MH, Reynolds CP, Lock RB, Carol H, Wu J, Kurmasheva RT, Houghton PJ, Smith MA. Pediatr Blood Cancer. 2015 Jun;62(6):1106-9. doi: 10.1002/pbc.25329. Epub 2014 Nov 18. PMID:25407467

  32. 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

  33. Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673. Smith MA, Hampton OA, Reynolds CP, Kang MH, Maris JM, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Wu J, Kurmasheva RT, Wheeler DA, Houghton PJ. Pediatr Blood Cancer. 2015 Jan;62(1):91-8. doi: 10.1002/pbc.25201. Epub 2014 Sep 27. PMID:25263539

  34. Initial solid tumor testing (stage 1) of AZD1480, an inhibitor of Janus kinases 1 and 2 by the pediatric preclinical testing program. Houghton PJ, Kurmasheva RT, Lyalin D, Maris JM, Kolb EA, Gorlick R, Reynolds CP, Kang MH, Keir ST, Wu J, Smith MA. Pediatr Blood Cancer. 2014 Nov;61(11):1972-9. doi: 10.1002/pbc.25175. Epub 2014 Aug 17. PMID:25131802

  35. Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. Suryani S, Carol H, Chonghaile TN, Frismantas V, Sarmah C, High L, Bornhauser B, Cowley MJ, Szymanska B, Evans K, Boehm I, Tonna E, Jones L, Manesh DM, Kurmasheva RT, Billups C, Kaplan W, Letai A, Bourquin JP, Houghton PJ, Smith MA, Lock RB. Clin Cancer Res. 2014 Sep 1;20(17):4520-31. doi: 10.1158/1078-0432.CCR-14-0259. Epub 2014 Jul 10. PMID:25013123

  36. 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

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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