Investigation Of Novel Anti-Metastatic Therapies For Osteosarcoma
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. In this Aim we will assess the ability of specific inhibitors of metastasis-associated factors to alter the in vivo metastatic biology of OS. Primary endpoints will be time from tumor implantation to metastasis-associated morbidity, and gross pulmonary disease burden. SPECIFIC AIM 2: Investigate the in vivo efficacy of combination therapy with specific inhibitors of metastasis-associated factors. Based on the results of Aim 1 we will test various combinations of the most effective doses of disulfiram, MK-0752, and ridaforolimus in the animal model of OS. We will assess the ability of these combinations to further decrease the metastatic potential of OS cells. Identical experimental endpoints to Aim 1 will be evaluated, with attention to possible combination therapy-related toxicities. SPECIFIC AIM 3: Evaluate the effects of specific inhibitors and cytotoxic chemotherapy in the mouse model of OS. It is likely that novel OS treatments will be used in concert with the current standard of care: cytotoxic chemotherapy. In this Aim we will combine doxorubicin treatment with the specific inhibitor doses/combinations determined from Aims 1 and 2. Experimental endpoints will be identical to Aims 1 and 2. It is our expectation that these experiments will uncover novel strategies that improve the prognosis of OS. We will accomplish this through the specific inhibition of molecular pathways that fundamentally affect OS metastatic biology. Furthermore, as pulmonary metastases represent the deadliest aspect of all sarcomas, we hypothesize that the treatment regimens discovered from these experiments will benefit patients with other sarcomas besides