This project will determine the efficacy of tetrathiomolybdate (TM), a potent copper- reducing compound to effectively inhibit angiogenesis and disrupt fatal micro-metastatic progression to vital organs common in human cancers. To evaluate TM's capacity in this role, a clinical trial will be conducted on dogs diagnosed with osteosarcoma (OS) of the leg bone. This species and this cancer type were selected for this trail to take advantage of beneficial factors absent in a mouse model. Advantages of the dog model over the mouse model include spontaneous development of the disease, an intact immune system, similar genetic changes to human OS, and response to traditional chemotherapies. Thus, we propose to use dogs with OS as a model to evaluate the human potential of a novel treatment for the micro-metastatic phase of OS and perhaps other human cancers. All dogs will receive a course of treatment consisting of amputation followed by a 10-week course of doxorubicin chemotherapy (the care presently yielding the best survival outcomes). At the start of doxorubicin therapy, 40 participant dogs will be randomized into equal cohorts of 20, one receiving TM therapy and the other receiving no additional treatment except placebo. Outcomes to be measured are: 1) progression-free survival interval based on the subsequent onset of metastasis on chest x-rays (the most common metastatic site), as well as abdominal ultrasound evaluation for visceral metastasis, and bone scan for skeletal metastasis, that can be seen as a late onset event in chemotherapy treated dogs, and 2) survival without metastasis. It is hypothesized that this study will demonstrate TM's antiangiogenic properties to slow or prevent disease recurrence from micro-metastases and prolong survival with this deadly spontaneous malignancy as compared to standard care, thus providing important evidence of TM's potential efficacy in treating human micrometastatic cancers. This study expects to provide significant proof-of-concept data in a species whose disease mimics the micro-metastatic progression of osteosarcoma, allowing for a significantly compressed timeframe on which to build human studies, and develop and bring to market effective anti-angiogenic drug therapies for human osteosarcoma and other human cancers. Marked inhibition of micro-metastatic growth, shown so strongly by TM in mouse studies, has never been tested in either human or dog studies.
With many cancers it is the metastatic spread of the disease to vital organs after surgical removal of the primary tumor that ultimately kills. Metastases start out as small clusters of cells that if they are going to grow, require the development of a blood supply, or angiogenesis. During this period they are dependent on one or more angiogenic promoters, signaling molecules that stimulate angiogenesis, which if blocked can inhibit metastatic tumor growth. In contrast, most large tumors appear able to recruit many angiogenic promoters, so that blockade of just one or even a few of these promoters is ineffective in stopping tumor growth. It has been established that many angiogenic promoters are copper dependent, including those that are usually involved in promoting initial angiogenesis for small clusters of tumor cells. By lowering copper availability to an intermediate level with a drug we have developed, tetrathiomolybdate (TM), the action of these copper dependent angiogenic promoters is effectively blocked, preventing further tumor growth. This has been proven true in many mouse models. Here we plan to test this concept in a dog model addressing spontaneous osteosarcoma, where lung micro- metastases, by growing to large metastases, not the primary tumor, usually kills. If TM is effective in this model, it sets the stage for trials in human osteosarcoma, which is nearly identical to the canine disease. More broadly, however, if effective against micro- metastatic disease in osteosarcoma, TM may provide a new weapon against micro- metastatic disease in a wide variety of human cancers.