Osteosarcoma (OS) is the most common primary malignancy of bone. The 5-year survival for OS patients is 60-70% and virtually all deaths result from pulmonary metastases. There have been no demonstrable improvements in OS prognosis in over twenty years, and the greatest obstacle to advancement is failure to understand and address the biology of OS metastases. Novel treatment strategies focused on metastatic potential are required to improve survival.
We have used related murine OS cell lines to identify factors that may confer metastatic potential. K7M2 cells are vigorously metastatic to the lung, but K12 cells are much less metastatic. We have demonstrated in vitro that aldehyde dehydrogenase (ALDH), Notch1, and mammalian target of rapamycin (mTOR) are differentially expressed in K7M2 and K12 cells. Moreover, we have shown that inhibition of these factors causes decreased motility, proliferation, invasiveness, and resistance to stress in OS cells.
These effects could impact the ability of OS cells to metastatsize. In order to advance this research and investigate the in vivo feasibility of anti-metastatic OS therapy, we propose the following:
SPECIFIC AIM 1: Evaluate the effects of ALDH inhibition with disulfiram, Notch1 inhibition with MK-0752, and mTOR inhibition with ridaforolimus in the mouse model of OS.
SPECIFIC AIM 2: Investigate the in vivo efficacy of combination therapy with specific inhibitors of metastasis-associated factors.
SPECIFIC AIM 3: Evaluate the effects of specific inhibitors and cytotoxic chemotherapy in the mouse model of OS.