Sarcoma and Molecular Biology Laboratory (SMBL)

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

The overall objective of the Laboratory is to explore biological mechanisms of tumors arising in bone and other tissues. One major focus is to elucidate the mechanisms of the development of drug resistance in cancer. Previously, we found multidrug resistance could be partially reversed by siRNA targeting of ABCB1 (MDR1) or by a combination of nanoparticles with chemotherapy drugs. Recently, we identified two small molecules (NSC23925, NSC77037/Tetran¬drine) that can overcome drug resistance in vitro and in vivo. These compounds and their derivatives hold significant therapeutic value in the treatment of MDR-dependent cancers. Another significant aim of the research is to define the essential kinases responsible for the proliferation and survival of human sarcoma cells. We have discovered that several kinases, including CDK11 and PLK1 signaling, are essential in tumor cell growth and survival. In addition, translational research into new treatment options for sarcoma patients has been undertaken.

The Sarcoma Molecular Biology Laboratory has published articles pertaining to sarcoma and multidrug resistance in human cancer. One paper of note is “Systematic Kinome shRNA Screening Identifies CDK11 (PITSLRE) Kinase Expression is Critical for Osteosarcoma Cell Growth and Proliferation,” which was published in Clinical Cancer Research, September 2012. Kinases play an essential role in cancer cell growth and survival; however, the roles of most kinases in osteosarcoma cell growth are largely uncharacterized. In the search for kinases required for osteosarcoma cell growth, we identified CDK11 (PITSLRE) as a potential target using comprehensive human kinome-wide shRNA screening in osteosarcoma cell lines. Furthermore, knockdown of CDK11, either by lentiviral shRNA or by synthetic siRNA-independent confirmation, can inhibit cell growth or induce apoptosis in osteosarcoma cells. Immunohistochemical analysis indicated that osteosarcoma patients with high CDK11 tumor expression levels were associated with significantly shorter survival than patients with osteosarcoma low level of CDK11 expression. Systemic in vivo administration of in vivo ready siRNA of CDK11 reduced tumor growth in an osteosarcoma s.c. xenograft model. These observations show that CDK11 signaling is essential in osteosarcoma cell growth and survival. CDK11 may become a promising therapeutic target in the management of osteosarcoma.

Research projects have received funding from a variety of sources including NIH, foundations, corporate sponsors, and benefactors.