Molecular approaches to personalizing management of ovarian cancer

Abstract

Cytoreductive surgery and empirical combination chemotherapy have improved 5-year survival for ovarian cancer patients, but have not increased the overall rate of cure. Poor outcomes relate, at least in part, to late diagnosis and to the persistence of dormant ovarian cancer cells that have resisted conventional drugs. Increased understanding of the molecular, cellular and clinical biology of ovarian cancer must be translated into personalized therapy with conventional and targeted agents as well as personalized detection of high-grade cancers in early stages. Different strategies will be required to treat low-grade and high-grade serous cancers as well as other histotypes. Activating mutations of Ras and Raf can be targeted in low-grade cancers. Activation of the PI3K pathway-PI3Kness-and inactivation of BRCA function-BRCAness-can be targeted in high-grade lesions. Inhibition of multiple pathways will be required. Sensitivity of primary cancers to paclitaxel and platinum can be modulated by inhibiting kinases and other molecules that regulate the cell cycle. Dormant ovarian cancer cells may depend upon autophagy, cytokines and growth factors for survival. Early detection can utilize two stage strategies where rising serum biomarker levels prompt imaging in a small fraction of women. Screening can be personalized by taking into account each woman's baseline biomarker levels.

Figure 1.

The challenge for translational research. Over the last two decades of cancer research, progress in the laboratory has been exponential, whereas progress in the clinic has been more gradual. Through translational research we have the opportunity to accelerate progress in the clinic (courtesy of Dr Gordon Mills).

Figure 2.

Synthetic lethality produced by inhibiting the PI3K and MEK signaling pathways. Inhibition of PI3K or MEK signaling individually fails to exert toxicity, whereas inhibiting both pathways kills cancer cells (courtesy of Dr David Gershenson). RTK, receptor tyrosine kinase.

Figure 3.

Impact of targeted therapy in the Gynecologic Oncology Group (GOG) 170 trials. When the fraction of responses and the fraction of patients with stable disease for 6 months are considered, treatment with bevacizumab has the best outcome (courtesy of Dr Robert Coleman).