Chemoresistance, dormancy and recurrence in platinum drug therapy of ovarian cancers

Ovarian cancer is the most deadly of gynecological malignancies. Lineage analyses have suggested broadly classifying ovarian cancers into two types: Type I, which includes low grade cancers with intact TP53, and Type II, which comprises high grade cancers with defective TP53. If detected in early stages, surgical resection of ovarian tumors results in a high rate of long-term survival; however, most ovarian cancers are detected at advanced stages. The standard first line treatment for advanced stage ovarian cancer is maximal surgical cytoreduction followed by platinum- based combination chemotherapy. Although the overall prognosis for less aggressive Type I ovarian cancers is better, their response to chemotherapy is generally weaker than that of the Type II ovarian cancers. Despite an initially favorable response of optimally debulked Type II ovarian cancers to platinum-based chemotherapy, the rate of recurrence is high, making the long-term survival rate quite poor. The dynamics of the response of high grade ovarian cancers platinum suggest that the tumors are phenotypically heterogeneous, and that a subpopulation of tumor cells is relatively resistant to chemotherapy. The resistant tumor cell population persists after chemotherapy in a state of dormancy, with recurrent tumors arising upon transformation of the dormant cells back to malignant growth. This chapter will consider how lineage, histological subtype, and grade influence the differential responses of ovarian cancers to platinum-based chemotherapy. In addition, mechanisms contributing ovarian cancer resistance to platinum drugs and to tumor cell entry into and exit from dormancy will be discussed.