Personalized comprehensive molecular profiling of high risk osteosarcoma: Implications and limitations for precision medicine

Oncotarget

Volumn 6, Issue 38, 2015, Pages 40642-40654

  Subbiah, Vivek ^a   Wagner, Michael J ^a   McGuire, Mary F ^c   Sarwari, Nawid M ^c   Devarajan, Eswaran ^b   Lewis, Valerae O ^b   Westin, Shanon ^b   Kato, Shumei ^a   Brown, Robert E ^c   Anderson, Pete ^d  

^a UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^b UNIVERSITY OF TEXAS   (United States)

^c UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^d LERNER RESEARCH INSTITUTE   (United States)

Author keywords

Molecular profiling; Osteosarcoma; Personalized medicine; Precision medicine; Targeted therapy

Indexed keywords

BEVACIZUMAB; CELECOXIB; CISPLATIN; CRIZOTINIB; CYCLOOXYGENASE 2; DNA; DOXORUBICIN; GEMCITABINE; IFOSFAMIDE; MAMMALIAN TARGET OF RAPAMYCIN; MERLIN; METFORMIN; METHOTREXATE; OSTEONECTIN; PACLITAXEL; PLATELET DERIVED GROWTH FACTOR A; PROTEIN KINASE B; RADIOISOTOPE; RADIUM 223; RAPAMYCIN; SCATTER FACTOR RECEPTOR; SOMATOMEDIN C RECEPTOR; SORAFENIB; TEMSIROLIMUS; TYROSINE; UNCLASSIFIED DRUG; ZOLEDRONIC ACID; ANTINEOPLASTIC AGENT; TUMOR MARKER;

ADOLESCENT; ADULT; ARTICLE; CANCER RECURRENCE; CANCER SURGERY; CASE REPORT; CCNE1 GENE; COMPUTER ASSISTED TOMOGRAPHY; DNA EXTRACTION; DNA SEQUENCE; DRUG MEGADOSE; DRUG RESPONSE; DRUG TOLERABILITY; EXOME; EXON; FATIGUE; GENE; GENE AMPLIFICATION; GENE LOSS; GENE MUTATION; GENE REARRANGEMENT; HUMAN; HUMAN TISSUE; INTRON; LEG AMPUTATION; LIMB SALVAGE; LUNG LOBECTOMY; LUNG METASTASIS; MALE; MET GENE; METASTASIS; METASTASIS RESECTION; MOLECULARLY TARGETED THERAPY; MUCOSA INFLAMMATION; MULTIPLE CYCLE TREATMENT; NEXT GENERATION SEQUENCING; NF2 GENE; NUCLEAR MAGNETIC RESONANCE IMAGING; OSTEOSARCOMA; PDGFRA GENE; PERSONALIZED MEDICINE; PIK3CA GENE; PNEUMOTHORAX; PROTEIN EXPRESSION; PTPRD GENE; RADIOISOTOPE THERAPY; THORACOTOMY; TUMOR NECROSIS; TUMOR SUPPRESSOR GENE; YOUNG ADULT; BONE NEOPLASMS; ENZYME IMMUNOASSAY; GENE EXPRESSION PROFILING; GENETICS; HIGH THROUGHPUT SEQUENCING; PATHOLOGY; PROCEDURES; PROTEOMICS;

ADOLESCENT; ADULT; ANTINEOPLASTIC AGENTS; BIOMARKERS, TUMOR; BONE NEOPLASMS; GENE EXPRESSION PROFILING; HIGH-THROUGHPUT NUCLEOTIDE SEQUENCING; HUMANS; IMMUNOENZYME TECHNIQUES; MALE; MOLECULAR TARGETED THERAPY; OSTEOSARCOMA; PRECISION MEDICINE; PROTEOMICS; YOUNG ADULT;

EID: 84951080846     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.5841     Document Type: Article

References (73)

1. Anderson P, Salazar-Abshire M. Improving outcomes in difficult bone cancers using multimodality therapy, including radiation: physician and nursing perspectives. Current oncology reports. 2006; 8:415-422.
2. Egas-Bejar D, Anderson PM, Agarwal R, Corrales-Medina F, Devarajan E, Huh WW, Brown RE, Subbiah V. Theranostic Profiling for Actionable Aberrations in Advanced High Risk Osteosarcoma with Aggressive Biology Reveals High Molecular Diversity: The Human Fingerprint Hypothesis. Oncoscience. 2014; 1:167-179.
3. Grignani G, Palmerini E, Ferraresi V, D'Ambrosio L, Bertulli R, Asaftei SD, Tamburini A, Pignochino Y, Sangiolo D, Marchesi E, Capozzi F, Biagini R, Gambarotti M, Fagioli F, Casali PG, Picci P, et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. The lancet oncology. 2015; 16:98-107.
4. Subbiah V, Anderson P, Rohren E. Alpha Emitter Radium 223 in High-Risk Osteosarcoma: First Clinical Evidence of Response and Blood-Brain Barrier Penetration. JAMA Oncol. 2015; 1:253-255.
5. Anderson PM, Subbiah V, Rohren E. Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: samarium-153-EDTMP and radium-223. Advances in experimental medicine and biology. 2014; 804:291-304.
6. Subbiah V. Prospects and pitfalls of personalizing therapies for sarcomas: from children, adolescents, and young adults to the elderly. Current oncology reports. 2014; 16:401.
7. Zakikhani M, Blouin MJ, Piura E, Pollak MN. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast cancer research and treatment. 2010; 123:271-279.
8. Masri J, Bernath A, Martin J, Jo OD, Vartanian R, Funk A, Gera J. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer research. 2007; 67:11712-11720.
9. Subbiah V, Westin SN, Wang K, Araujo D, Wang WL, Miller VA, Ross JS, Stephens PJ, Palmer GA, Ali SM. Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein. Journal of hematology & oncology. 2014; 7:8.
10. Patane S, Avnet S, Coltella N, Costa B, Sponza S, Olivero M, Vigna E, Naldini L, Baldini N, Ferracini R, Corso S, Giordano S, Comoglio PM, Di Renzo MF. MET overexpression turns human primary osteoblasts into osteosarcomas. Cancer research. 2006; 66:4750-4757.
11. Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M, Comoglio PM. The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene. 1995; 10:739-749.
12. Coltella N, Manara MC, Cerisano V, Trusolino L, Di Renzo MF, Scotlandi K, Ferracini R. Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2003; 17:1162-1164.
13. Liao AT, McCleese J, Kamerling S, Christensen J, London CA. A novel small molecule Met inhibitor, PF2362376, exhibits biological activity against osteosarcoma. Veterinary and comparative oncology. 2007; 5:177-196.
14. Zhou R, Zhang Z, Zhao L, Jia C, Xu S, Mai Q, Lu M, Huang M, Wang L, Wang X, Jin D, Bai X. Inhibition of mTOR signaling by oleanolic acid contributes to its antitumor activity in osteosarcoma cells. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2011; 29:846-852.
15. Moroy T, Geisen C. Cyclin, E. The international journal of biochemistry & cell biology. 2004; 36:1424-1439.
16. Lockwood WW, Stack D, Morris T, Grehan D, O'Keane C, Stewart GL, Cumiskey J, Lam WL, Squire JA, Thomas DM, O'Sullivan MJ. Cyclin E1 is amplified and overexpressed in osteosarcoma. The Journal of molecular diagnostics: JMD. 2011; 13:289-296.
17. Chan TA, Heguy A. The protein tyrosine phosphatase receptor D, a broadly inactivated tumor suppressor regulating STAT function. Cell cycle (Georgetown, Tex). 2009; 8:3063-3064.
18. Subbiah V, Naing A, Brown RE, Chen H, Doyle L, LoRusso P, Benjamin R, Anderson P, Kurzrock R. Targeted morphoproteomic profiling of Ewing's sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures. PloS one. 2011; 6:e18424.
19. Xiao H, Verdier-Pinard P, Fernandez-Fuentes N, Burd B, Angeletti R, Fiser A, Horwitz SB, Orr GA. Insights into the mechanism of microtubule stabilization by Taxol. Proceedings of the National Academy of Sciences of the United States of America. 2006; 103:10166-10173.
20. Zhang D, Sun L, Xian W, Liu F, Ling G, Xiao L, Liu Y, Peng Y, Haruna Y, Kanwar YS. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-beta/Smad activity. Laboratory investigation; a journal of technical methods and pathology. 2010; 90:436-447.
21. Gradishar WJ. Albumin-bound paclitaxel: a next-generation taxane. Expert opinion on pharmacotherapy. 2006; 7:1041-1053.
22. Desai NP, Trieu V, Hwang LY, Wu R, Soon-Shiong P, Gradishar WJ. Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status. Anti-cancer drugs. 2008; 19:899-909.
23. Desai N, Trieu V, Damascelli B, Soon-Shiong P. SPARC Expression Correlates with Tumor Response to Albumin-Bound Paclitaxel in Head and Neck Cancer Patients. Translational oncology. 2009; 2:59-64.
24. Yang Y, Niu X, Zhang Q, Hao L, Ding Y, Xu H. The efficacy of abraxane on osteosarcoma xenografts in nude mice and expression of secreted protein, acidic and rich in cysteine. The American journal of the medical sciences. 2012; 344:199-205.
25. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocrinerelated cancer. 2010; 17:351-360.
26. Vazquez-Martin A, Corominas-Faja B, Cufi S, Vellon L, Oliveras-Ferraros C, Menendez OJ, Joven J, Lupu R, Menendez JA. The mitochondrial H(+)-ATP synthase and the lipogenic switch: new core components of metabolic reprogramming in induced pluripotent stem (iPS) cells. Cell cycle (Georgetown, Tex). 2013; 12:207-218.
27. Cui JJ, Tran-Dube M, Shen H, Nambu M, Kung PP, Pairish M, Jia L, Meng J, Funk L, Botrous I, McTigue M, Grodsky N, Ryan K, Padrique E, Alton G, Timofeevski S, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). Journal of medicinal chemistry. 2011; 54:6342-6363.
28. Rocha GZ, Dias MM, Ropelle ER, Osorio-Costa F, Rossato FA, Vercesi AE, Saad MJ, Carvalheira JB. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011; 17:3993-4005.
29. Schurman L, McCarthy AD, Sedlinsky C, Gangoiti MV, Arnol V, Bruzzone L, Cortizo AM. Metformin reverts deleterious effects of advanced glycation end-products (AGEs) on osteoblastic cells. Experimental and clinical endocrinology & diabetes: official journal, German Society of Endocrinology [and] German Diabetes Association. 2008; 116:333-340.
30. Cortizo AM, Lettieri MG, Barrio DA, Mercer N, Etcheverry SB, McCarthy AD. Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). Molecular and cellular biochemistry. 2003; 250:1-10.
31. Kataoka K, Ono T, Murata H, Morishita M, Yamamoto KI, Sakaguchi M, Huh NH. S100A7 promotes the migration and invasion of osteosarcoma cells via the receptor for advanced glycation end products. Oncology letters. 2012; 3:1149-1153.
32. Curto M, McClatchey AI. Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. British journal of cancer. 2008; 98:256-262.
33. Agarwal R, Liebe S, Turski ML, Vidwans SJ, Janku F, Garrido-Laguna I, Munoz J, Schwab R, Rodon J, Kurzrock R, Subbiah V. Targeted therapy for hereditary cancer syndromes: neurofibromatosis type 1, neurofibromatosis type 2, and Gorlin syndrome. Discovery medicine. 2014; 18:323-330.
34. Laulajainen M, Melikova M, Muranen T, Carpen O, Gronholm M. Distinct overlapping sequences at the carboxy-terminus of merlin regulate its tumour suppressor and morphogenic activity. Journal of cellular and molecular medicine. 2012; 16:2161-2175.
35. McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, Jacks T. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes & development. 1998; 12:1121-1133.
36. Stemmer-Rachamimov AO, Nielsen GP, Rosenberg AE, Louis DN, Jones D, Ramesh V, Gusella JF, Jacoby LB. The NF2 gene and merlin protein in human osteosarcomas. Neurogenetics. 1998; 2:73-74.
37. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V. NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Molecular and cellular biology. 2009; 29:4250-4261.
38. Subbiah V, Slopis J, Hong DS, Ketonen LM, Hamilton J, McCutcheon IE, Kurzrock R. Treatment of patients with advanced neurofibromatosis type 2 with novel molecularly targeted therapies: from bench to bedside. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2012; 30:e64-68.
39. Fletcher JA. Role of KIT and platelet-derived growth factor receptors as oncoproteins. Seminars in oncology. 2004; 31:4-11.
40. Kubo T, Piperdi S, Rosenblum J, Antonescu CR, Chen W, Kim HS, Huvos AG, Sowers R, Meyers PA, Healey JH, Gorlick R. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer. 2008; 112:2119-2129.
41. Sulzbacher I, Birner P, Dominkus M, Pichlhofer B, Mazal PR. Expression of platelet-derived growth factoralpha receptor in human osteosarcoma is not a predictor of outcome. Pathology. 2010; 42:664-668.
42. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes & development. 2008; 22:1276-1312.
43. Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway. Nature reviews Cancer. 2009; 9:862-873.
44. Agarwal R, Liebe S, Turski ML, Vidwans SJ, Janku F, Garrido-Laguna I, Munoz J, Schwab R, Rodon J, Kurzrock R, Subbiah V. Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome. Discovery medicine. 2014; 18:331-339.
45. Said R, Hong DS, Warneke CL, Lee JJ, Wheler JJ, Janku F, Naing A, Falchook GS, Fu S, Piha-Paul S, Tsimberidou AM, Kurzrock R. P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy. Oncotarget. 2013; 4:705-714.
46. Subbiah V, Brown RE, McGuire MF, Buryanek J, Janku F, Younes A, Hong D. A novel immunomodulatory molecularly targeted strategy for refractory Hodgkin's lymphoma. Oncotarget. 2014; 5:95-102.
47. Agarwal R, Koenig K, Rohren E, Subbiah V. Combined Antiangiogenic and Mammalian Target of Rapamycin Inhibitor Targeted Therapy in Metaplastic Breast Cancer Harboring a PIK3CA Mutation. Journal of breast cancer. 2014; 17:287-290.
48. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. The New England journal of medicine. 2015; 373:726-736.
49. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, Doebele RC, Le LP, Zheng Z, Tan W, Stephenson P, Shreeve SM, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. The New England journal of medicine. 2014; 371:1963-1971.
50. Shaw AT, Engelman JA. ALK in lung cancer: past, present, and future. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013; 31:1105-1111.
51. Subbiah V, Berry J, Roxas M, Guha-Thakurta N, Subbiah IM, Ali SM, McMahon C, Miller V, Cascone T, Pai S, Tang Z, Heymach JV. Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases. Lung Cancer. 2015; 89:76-79.
52. Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, Asaka R, Hamanaka W, Ninomiya H, Uehara H, Lim Choi Y, Satoh Y, Okumura S, Nakagawa K, Mano H, Ishikawa Y. RET, ROS1 and ALK fusions in lung cancer. Nature medicine. 2012; 18:378-381.
53. Subbiah IM, Subbiah V. Exceptional responders: in search of the science behind the miracle cancer cures. Future oncology (London, England). 2015; 11:1-4.
54. Subbiah V, Trent JC, Kurzrock R. Resistance to mammalian target of rapamycin inhibitor therapy in perivascular epithelioid cell tumors. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2010; 28:e415.
55. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011; 144:27-40.
56. Le Tourneau C, Delord JP, Goncalves A, Gavoille C, Dubot C, Isambert N, Campone M, Tredan O, Massiani MA, Mauborgne C, Armanet S, Servant N, Bieche I, Bernard V, Gentien D, Jezequel P, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, openlabel, proof-of-concept, randomised, controlled phase 2 trial. The lancet oncology. 2015; 16:1324-1334.
57. Shen JK, Cote GM, Choy E, Yang P, Harmon D, Schwab J, Nielsen GP, Chebib I, Ferrone S, Wang X, Wang Y, Mankin H, Hornicek FJ, Duan Z. Programmed cell death ligand 1 expression in osteosarcoma. Cancer immunology research. 2014; 2:690-698.
58. Shen JK, Cote GM, Choy E, Hornicek FJ, Duan Z. Targeting programmed cell death ligand 1 in osteosarcoma: an auto-commentary on therapeutic potential. Oncoimmunology. 2014; 3:e954467.
59. Brown RE. Morphogenomics and morphoproteomics: a role for anatomic pathology in personalized medicine. Archives of pathology & laboratory medicine. 2009; 133:568-579.
60. Subbiah V, Brown RE, Jiang Y, Buryanek J, Hayes-Jordan A, Kurzrock R, Anderson PM. Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing's sarcoma (EWS/FLI1) and Wilms' tumor(WT1). PloS one. 2013; 8:e68985.
61. Subbiah V, Brown RE, Buryanek J, Trent J, Ashkenazi A, Herbst R, Kurzrock R. Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L/TRAIL (dulanermin), a dual proapoptotic receptor (DR4/DR5) agonist. Molecular cancer therapeutics. 2012; 11:2541-2546.
62. Liu ZL, Wang G, Peng AF, Luo QF, Zhou Y, Huang SH. Fatty acid synthase expression in osteosarcoma and its correlation with pulmonary metastasis. Oncology letters. 2012; 4:878-882.
63. Chu F, Chou PM, Zheng X, Mirkin BL, Rebbaa A. Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. Cancer research. 2005; 65:10183-10187.
64. Tu B, Du L, Fan QM, Tang Z, Tang TT. STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma. Cancer letters. 2012; 325:80-88.
65. Ryu K, Choy E, Yang C, Susa M, Hornicek FJ, Mankin H, Duan Z. Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2010; 28:971-978.
66. Rodriguez NI, Hoots WK, Koshkina NV, Morales-Arias JA, Arndt CA, Inwards CY, Hawkins DS, Munsell MF, Kleinerman ES. COX-2 expression correlates with survival in patients with osteosarcoma lung metastases. Journal of pediatric hematology/oncology. 2008; 30:507-512.
67. Li Y, Gao Q, Yin G, Ding X, Hao J. WNT/beta-cateninsignaling pathway stimulates the proliferation of cultured adult human Sertoli cells via upregulation of C-myc expression. Reproductive sciences. 2012; 19:1232-1240.
68. Iwaya K, Ogawa H, Kuroda M, Izumi M, Ishida T, Mukai K. Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis. Clinical & experimental metastasis. 2003; 20:525-529.
69. Zambo I, Hermanova M, Adamkova Krakorova D, Mudry P, Zitterbart K, Kyr M, Vesely K, Sterba J, Veselska R. Nestin expression in high-grade osteosarcomas and its clinical significance. Oncology reports. 2012; 27:1592-1598.
70. Navid F, Letterio JJ, Yeung CL, Pegtel M, Helman LJ. Autocrine Transforming Growth Factor-beta Growth Pathway in Murine Osteosarcoma Cell Lines Associated with Inability to Affect Phosphorylation of Retinoblastoma Protein. Sarcoma. 2000; 4:93-102.
71. Dennler S, Andre J, Alexaki I, Li A, Magnaldo T, ten Dijke P, Wang XJ, Verrecchia F, Mauviel A. Induction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivo. Cancer research. 2007; 67:6981-6986.
72. Hirotsu M, Setoguchi T, Sasaki H, Matsunoshita Y, Gao H, Nagao H, Kunigou O, Komiya S. Smoothened as a new therapeutic target for human osteosarcoma. Molecular cancer. 2010; 9:5.
73. Dalla-Torre CA, Yoshimoto M, Lee CH, Joshua AM, de Toledo SR, Petrilli AS, Andrade JA, Chilton-MacNeill S, Zielenska M, Squire JA. Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma. BMC cancer. 2006; 6:237.