It started with a clinical observation: Why do so many ovarian cancer patients have such high levels of circulating platelets? As it turns out, this characteristic of cancer patients in general has been noted one way or another since 1867. But no one had explained it until now.
In this week's New England Journal of Medicine, Anil Sood, M.D., professor in MD Anderson's departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, and colleagues report the details of a vicious cycle: Tumors set off a chain reaction that spurs production of platelets, which in turn feed tumor growth, and so on and on.
"Our collaborative study not only identified a mechanism that explains platelet count elevation, but also connects this state, called thrombocytosis, to the severity of ovarian cancer," Sood said. "This suggests drugs that interfere with coagulation might be a useful addition to conventional therapies."
Of 619 ovarian cancer patients, 192 (31 percent) had thrombocytosis. Importantly, less than 2 percent of those had an iron deficiency or a non-cancerous inflammatory condition, the two most common causes of elevated platelet levels.
Patients with thrombocytosis survived for a median of 2.62 years, compared to 4.65 years for those with normal platelet counts.
Drawing on clinical data from ovarian cancer patients and following up with mouse model experiments and a clinical trial, Sood and colleagues discovered:
· Ovarian cancers produce the inflammatory cytokine interleukin-6 (IL-6);
· Triggering creation of the platelet-production regulating hormone thrombopoietin (TPO) in the liver;
· Causing platelet counts to soar to more than 450,000 per cubic millimeter in the blood, the threshold for thrombocytosis, and
· Stimulating tumor growth and continuation of the cycle.
Subsequent mouse model experiments showed that blocking either IL-6, TPO, or both reduced platelet levels steeply reduced tumor burden in mouse models of cancer.
In a clinical trial conducted at the Barts Cancer Institute, Queen Mary, University of London, the team also found that treatment of 18 ovarian cancer patients in a phase I/II clinical trial with siltuximab, an antibody to IL-6, sharply reduced platelet counts over a three-week period.
There's more research to be done to understand the connection and perhaps take advantage of it to treat people. Platelet levels may also serve as biomarkers for ovarian and other cancers, Rebecca Stone, M.D., clinical fellow in gynecologic oncology and the first author of the study, noted. "If you see high platelets, absent inflammation or iron deficiency, it would be important to look for cancer."
MD Anderson news release
Interesting perspective from Pharma Strategy Blog.
Related paper by Barts Cancer Center group in Clinical Cancer Research: Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer