Grant: Operating Grant

One of the most frustrating aspects of cancer research is the disparity between preclinical therapy results - almost always obtained using tumors transplanted or developed in mice - with those later observed in clinical trials of the same therapy. It is not uncommon to obtain dramatic results in the preclinical models, which then fail completely in patients. One reason postulated for this discrepancy by Dr. Kerbel is the failure of basic researchers to mimic the common clinical situation of advanced metastatic disease. Advanced visceral metastatic disease is extremely challenging to treat successfully and yet has rarely been modeled. Five years ago Dr. Kerbel began developing therapy models of advanced disease in mice beginning with breast cancer. More recently he has extended this strategy to ovarian cancer. Using such models, a remarkably effective treatment was developed consisting of daily low 'metronomic' doses of an oral chemotherapy drug, topotecan, combined with an 'antiangiogenic' drug (pazopanib). Topotecan is approved for 'second line' treatment of ovarian cancer where it is usually given intravenously at toxic maximum tolerated doses. Pazopanib targets new blood vessels in tumors which are necessary for their relentless growth. This therapy can be given every day for over six months (about 1/4-1/5 a mouse's lifespan) with 100% survival and minimal toxicity. However, resistance eventually develops to the therapy. The purpose of Dr. Kerbel's research is not only to understand the basis for the therapy's remarkable results but if it also works on refractory disease, and why tumors eventually stop responding to it. Of considerable interest in this regard is that this drug combination is showing excellent preclinical efficacy when treating other types of cancer, e.g. breast and kidney cancer, and childhood neuroblastoma. Hence, the proposed studies could have far reaching clinical implications beyond ovarian cancer.