Researchers at Johns Hopkins Medicine (MD, USA) recently reported in Cancer Cell that combining the experimental SYK inhibitor fostamatinib (not yet US FDA approved) with paclitaxel (standard chemotherapy) may overcome chemoresistance in ovarian cancer.
In the USA, over 21,000 women are expected to be diagnosed with ovarian cancer this year and over 14,000 will die from it. The majority of patients initially respond to the standard first-line treatments for advanced ovarian cancer – paclitaxel and carboplatin; however, most develop treatment-resistant tumors and, according to study lead Ie-Ming Shih (Johns Hopkins), only 10–15% of these patients survive long term.
The researchers implanted paclitaxel-resistant human ovarian cancer cells into mice, and then tested the power of fostamatinib to reduce tumor size, and found that the combination of paclitaxel and fostamatinib reduced tumor size in six mice by up to 87% in 3 weeks, compared with no shrinkage in six untreated animals. Furthermore, after 5 weeks the combination treatment in the six mice shrunk tumor size by up to 66%, compared with six mice that received paclitaxel only.
The researchers had demonstrated in a previous study that resistance to paclitaxel might occur due to higher levels of the enzyme spleen tyrosine kinase (SYK) in ovarian cancer cells – levels of SYK were shown to be higher in recurrent tumors compared with matched primary tumors – and the team confirmed this result in the current study.
The team analyzed 25 different ovarian cancer cell lines and found that the higher the levels of active SYK, the more resistant the cell lines were to paclitaxel treatment. They discovered that treatment of the resistant cells with fostamatinib increased the cell’s sensitivity to paclitaxel.
Paclitaxel stabilizes microtubules, preventing a cell from rapidly growing and dividing. Yu Yu, co-author on the study also of Johns Hopkins, commented that the effect of fostamatinib on microtubules appears to increase the stabilizing effect of paclitaxel, even in resistant cells, which might in turn prevent the proliferation of cancer cells.
Shih commented that, based on what is already known about the toxicity of fostamatinib, the fostamatinib–paclitaxel combination treatment may cause side effects such as nausea, vomiting, diarrhea and low white blood cell counts.
Owing to these findings, the researchers are now planning a Phase I clinical trial to test the combination therapy in individuals with recurrent advanced ovarian cancer.