Osteosarcoma Metastasis: An Unmet Clinical Need and Unique Drug Development Opportunity

The great majority of cancer deaths result from drug-resistant recurrence that has spread from the initial tumor. Consistent with this,
osteosarcoma patients will often develop metastatic disease following primary tumor resection and adjuvant chemotherapy. This latency
can be explained by the presence of undetected, non-dividing disseminated tumor cells (“DTCs”) that have developed mechanisms of long-
term stress adaptation and dormancy to enable their survival until re-awakened to form overt metastasis. Importantly, these mechanisms
are unique and specific to the biology and the circumstances of these DTCs, namely, the conditions of the microenvironment at the secondary
sites. We suggest the term “metastatic endurance” to encompass a combination of the following features of DTCs at secondary sites: stress
adaptation, survival, and dormancy. To date, little progress has been made in the area of DTCs-directed therapies. Our unique perspective on
metastasis biology (i.e., metastatic endurance) both arises from, and delivers, in vitro and ex vivo assays that enable efficient drug discovery
and preclinical efforts that target DTCs. Pet dogs and humans share the biology of osteosarcoma metastasis and late recurrence following
stress adaptation and dormancy of DTCs. Pet canine osteosarcoma drug clinical trials therefore inform human osteosarcoma trials, enabling
novel potential therapies to advance with the support of a community receptive to metastasis-prevention clinical trials. In addition to the
extreme importance of finding better drugs for osteosarcoma patients, this disease serves as an outstanding “model” for recurrence in other
cancers and provides a unique opportunity to develop drugs that target metastatic-progression for various cancers.
Keywords: Circulating tumor cells, disseminated tumor cells, tumor dormancy, metastatic endurance, Comparative oncology