Despite multiple changes in adujvant chemotherapy, the 2-year metastasis-free survival in osteosarcoma (OS) has remained stagnant at 65-70% for the past 10 years. The lung is the most common and often the only site of metastases. Our laboratory has focused on understanding the mechanisms involved in OS metastasis to the lung and in identifying novel ways to treat OS pulmonarymetastases. Using our experimental humanOS lung metastasis nude mouse model we demonstrated that Fas expression correlates inversely with metastatic potential. We hypothesized that because FasL is constitutively expressed in the lung, that OS cells expressing high levels of Fas will be eliminated upon migration into the lung, whereas those with low or no Fas expression will evade this form of host resistance. We also demonstrated that IL-12 upregulated tumor Fas expression in vitro, altered metastatic potential and that the IL-12 gene could be delivered by aerosol using polyethyinemine (PEI) as a vector delivery system. Aerosol PEI:IL-12 upregulated tumor Fas in vivo and induced regression of established microscopic pulmonary metastases. We also demonstrated that aerosol delivery of liposome-encapsulated 9-nitrocamptothecin (L-9NC) upregulated tumor Fas expression and resulted in eradication of OS lung metastases. A phase I trial in adults using aerosol L-9NC demonstrated the feasibility of aerosol chemotherapy. No children or adolescents were treated in this phase I trial. We now propose to (1) perform a phase I/II clinicaltrial with aerosol L-9NC in patients 10-25 years old with metastases in the lung;(2) determine whether inhibiting Fas signalling impacts tumor cell clearance, cell proliferation and the metastatic potential of OS cells to the lung;(3) determine whether the Fas pathway is critical for both aerosol IL-12 and L-9NC activity in vivo. Together these investigations should give an indication of the importance of the Fas pathway in the metastatic process of OS and in the therapeutic efficacy of both aerosol L-9NC and PEI:IL-12 gene therapy. The long term objectives are to develop aerosol therapy for metastatic OS and other tumors that relapse in the lung.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042992-24
Application #
7751217
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Timmer, William C
Project Start
1986-08-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2011-12-31
Support Year
24
Fiscal Year
2010
Total Cost
$263,918
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Guma, Sergei R; Lee, Dean A; Yu, Ling et al. (2014) Natural killer cell therapy and aerosol interleukin-2 for the treatment of osteosarcoma lung metastasis. Pediatr Blood Cancer 61:618-26
Rao-Bindal, Krithi; Rao, Chethan K; Yu, Ling et al. (2013) Expression of c-FLIP in pulmonary metastases in osteosarcoma patients and human xenografts. Pediatr Blood Cancer 60:575-9
Rao-Bindal, Krithi; Koshkina, Nadezhda V; Stewart, John et al. (2013) The histone deacetylase inhibitor, MS-275 (entinostat), downregulates c-FLIP, sensitizes osteosarcoma cells to FasL, and induces the regression of osteosarcoma lung metastases. Curr Cancer Drug Targets 13:411-22
Hollomon, Mario G; Gordon, Nancy; Santiago-O'Farrill, Janice M et al. (2013) Knockdown of autophagy-related protein 5, ATG5, decreases oxidative stress and has an opposing effect on camptothecin-induced cytotoxicity in osteosarcoma cells. BMC Cancer 13:500
Huang, Gangxiong; Yu, Ling; Cooper, Laurence Jn et al. (2012) Genetically modified T cells targeting interleukin-11 receptor ?-chain kill human osteosarcoma cells and induce the regression of established osteosarcoma lung metastases. Cancer Res 72:271-81
Rao-Bindal, K; Zhou, Z; Kleinerman, E S (2012) MS-275 sensitizes osteosarcoma cells to Fas ligand-induced cell death by increasing the localization of Fas in membrane lipid rafts. Cell Death Dis 3:e369
Huang, Gangxiong; Nishimoto, Kazumasa; Zhou, Zhichao et al. (2012) miR-20a encoded by the miR-17-92 cluster increases the metastatic potential of osteosarcoma cells by regulating Fas expression. Cancer Res 72:908-16
Koshkina, Nadezhda V; Rao-Bindal, Krithi; Kleinerman, Eugenie S (2011) Effect of the histone deacetylase inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metastases. Cancer 117:3457-67
Gordon, Nancy; Kleinerman, Eugenie S (2010) Aerosol therapy for the treatment of osteosarcoma lung metastases: targeting the Fas/FasL pathway and rationale for the use of gemcitabine. J Aerosol Med Pulm Drug Deliv 23:189-96
Rodriguez Jr, Carlos O; Crabbs, Torrie A; Wilson, Dennis W et al. (2010) Aerosol gemcitabine: preclinical safety and in vivo antitumor activity in osteosarcoma-bearing dogs. J Aerosol Med Pulm Drug Deliv 23:197-206

Showing the most recent 10 out of 78 publications