Massachusetts General Hospital

The Sarcoma Molecular Biology Laboratory (SMBL), is under the direction of Zhenfeng Duan, MD, PhD and Orthopaedic Oncology Service Chief, Francis J. Hornicek, MD, PhD. The focus of the Laboratory’s work is to study the molecular biology of sarcoma and to examine the mechanisms of multidrug resistance, to identify small molecules and targets to reverse drug resistance and to understand the characterization of molecular mechanisms governing growth, and the proliferation of human sarcoma cells.

The overall objectives of the laboratory are to explore biological mechanisms of tumors arising in bone and other tissues. One of the major focuses is to elucidate the mechanisms of the development of drug resistance in cancer. Previously, we have found multidrug resistance could be partially reversed by siRNA targeting of ABCB1 (MDR1) or by combination of nanoparticles with chemotherapy drug. Recently, we have identified two small molecules that can overcome drug resistance in vitro and in vivo. Another significant aim of the research is to define the essential kinases that are responsible for proliferation and survival of human sarcoma cells. In addition translational research into new treatment options for sarcoma patients has been undertaken.

The Sarcoma Molecular Biology Laboratory has published articles pertaining to multiple drug resistance in human cancer. Research projects on sarcoma biology have received funding from a variety of sources including NIH, foundations, corporate sponsors, and benefactors.

Co-Directors:
Zhenfeng Duan
Francis Hornicek

Co-Investigators:
Edwin Choy
Joe Schwab
Henry Mankin

Fellows:
Xianzhe Liu
Eisuke Kobayashi
Linlin Zhang
Zhan Zhang

Current Research Projects:

• Mechanisms of multidrug resistance in human cancer
• Overcome multidrug resistance by nanotechnology and small molecular compound
• Targeting sarcoma with small molecule kinase inhibitors

Doxorubicin, with stains red, has only partially penetrated these drug resistant osteosarcoma cells. The black cell centers indicate low drug levels in the nuclei.	Nanoparticle-packaged doxorubicin has more completely penetrated these drug resistant osteosarcoma cells. The red centers indicate more effective drug uptake.

1. Duan Z, Choy E, Harmon D, Liu X, Susa M, Mankin H, Hornicek FJ. MicroRNA-199a-3p is Down Regulated in Human Osteosarcoma and Regulates Cell Proliferation and Migration. Mol Cancer Ther. 2011 Jun 10. PubMed PMID: 21666078. View PDF.
2. Le LP, Nielsen GP, Rosenberg AE, Thomas D, Batten JM, Deshpande V, Schwab J, Duan Z, Xavier RJ, Hornicek FJ, Iafrate AJ. Recurrent chromosomal copy number alterations in sporadic chordomas. PLoS One. 2011;6(5):e18846. PubMed PMID: 21602918.
3. Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res. 2011 Apr;31(4):1115-23. PubMed PMID: 21508354.
4. Liu X, Choy E, Harmon D, Yang S, Yang C, Mankin H, Hornicek FJ, Duan Z. Inhibition of polo-like kinase 1 leads to the suppression of osteosarcoma cell growth in vitro and in vivo. Anticancer Drugs. 2011 Jun;22(5):444-53. PubMed PMID: 21399492.
5. Liu X, Choy E, Hornicek FJ, Yang S, Yang C, Harmon D, Mankin H, Duan Z. ROCK1 as a potential therapeutic target in osteosarcoma. J Orthop Res. 2011 Aug;29(8):1259-66. doi: 10.1002/jor.21403. Epub 2011 Mar 8. PubMed PMID: 21387396. View PDF.
6. Milane L, Duan Z, Amiji M. Role of hypoxia and glycolysis in the development of multi-drug resistance in human tumor cells and the establishment of an orthotopic multi-drug resistant tumor model in nude mice using hypoxic pre-conditioning. Cancer Cell Int. 2011 Feb 14;11:3. PubMed PMID: 21320311.
7. DeLaney TF, Duan Z, Hornicek FJ. Proteomic profiling of chordoma. J Surg Oncol. 2010 Dec 1;102(7):719. doi: 10.1002/jso.21766. PubMed PMID: 21104921.
8. Milane L, Duan Z, Amiji M. Development of EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine delivery to treat multi-drug resistance in human breast and ovarian tumor cells. Mol Pharm. 2011 Feb 7;8(1):185-203. Epub 2010 Nov 24. PubMed PMID: 20942457.
9. Susa M, Choy E, Liu X, Schwab J, Hornicek FJ, Mankin H, Duan Z. Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking. Mol Cancer Ther. 2010 Dec;9(12):3342-50. Epub 2010 Sep 29. PubMed PMID: 20881269.
10. Guo Y, Nemeth J, O'Brien C, Susa M, Liu X, Zhang Z, Choy E, Mankin H, Hornicek F, Duan Z. Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer. Clin Cancer Res. 2010 Dec 1;16(23):5759-69. Epub 2010 Aug 10. PubMed PMID: 20699329. View PDF.
11. Susa M, Iyer AK, Ryu K, Choy E, Hornicek FJ, Mankin H, Milane L, Amiji MM, Duan Z. Inhibition of ABCB1 (MDR1) expression by an siRNA nanoparticulate delivery system to overcome drug resistance in osteosarcoma. PLoS One. 2010 May 24;5(5):e10764. PubMed PMID: 20520719. View PDF.
12. Susa M, Milane L, Amiji MM, Hornicek FJ, Duan Z. Nanoparticles: a promising modality in the treatment of sarcomas. Pharm Res. 2011 Feb;28(2):260-72. Epub 2010 May 27. PubMed PMID: 20505985.
13. Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells. Cancer Chemother Pharmacol. 2011 Feb;67(2):439-46. PubMed PMID: 20461381.
14. Yang C, Hornicek FJ, Wood KB, Schwab JH, Choy E, Iafrate J, Rosenberg A, Nielsen GP, Xavier RJ, Mankin H, Duan Z. Characterization and analysis of human chordoma cell lines. Spine (Phila Pa 1976). 2010 Jun 1;35(13):1257-64. PubMed PMID: 20461036.
15. Ryu K, Susa M, Choy E, Yang C, Hornicek FJ, Mankin HJ, Duan Z. Oleanane triterpenoid CDDO-Me induces apoptosis in multidrug resistant osteosarcoma cells through inhibition of Stat3 pathway. BMC Cancer. 2010 May 10;10:187. PubMed PMID: 20459702.
16. Yang C, Hornicek FJ, Wood KB, Schwab JH, Choy E, Mankin H, Duan Z. Blockage of Stat3 with CDDO-Me inhibits tumor cell growth in chordoma. Spine (Phila Pa 1976). 2010 Aug 15;35(18):1668-75. PubMed PMID: 20386502.
17. Susa M, Choy E, Yang C, Schwab J, Mankin H, Hornicek F, Duan Z. Multidrug resistance reversal agent, NSC77037, identified with a cell-based screening assay. J Biomol Screen. 2010 Mar;15(3):287-96. Epub 2010 Feb 11. PubMed PMID: 20150589.
18. Duan Z, Ji D, Weinstein EJ, Liu X, Susa M, Choy E, Yang C, Mankin H, Hornicek FJ. Lentiviral shRNA screen of human kinases identifies PLK1 as a potential therapeutic target for osteosarcoma. Cancer Lett. 2010 Jul 28;293(2):220-9. Epub 2010 Feb 9. PubMed PMID: 20144850.
19. van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MM. Augmentation of therapeutic efficacy in drug-resistant tumor models using ceramide coadministration in temporal-controlled polymer-blend nanoparticle delivery systems. AAPS J. 2010 Jun;12(2):171-80. Epub 2010 Feb 9. PubMed PMID: 20143195.
20. 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. J Orthop Res. 2010 Jul;28(7):971-8. PubMed PMID: 20063378.

Sarcoma Molecular Biology Laboratory

Phone: 617-724-3144

Francis Hornicek, MD, PhD Chief, Orthopaedic Oncology Service email: fhornicek@partners.org

Zhenfeng Duan, MD, PhD email: zduan@partners.org