Treatment for ovarian cancer hasn't changed much in the last ten years, reflecting the lack of biomarkers and biochemical targets for the disease. Chemotherapy with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel) has therefore formed the bedrock of therapy, along with other options such as gemcitabine or pemetrexed, as illustrated in the latest NCCN Guidelines.
The good news is that the use of paclitaxel-based combination chemotherapy has been shown to increase progression free survival (PFS) and overall survival (OS) in women with primary peritoneal or ovarian cancers.
While a proportion of ovarian cancers have been shown to be highly chemosensitive, a large number unfortunately fail to respond to primary taxane therapy, leading to the emergence of resistant disease.
The big unanswered questions are therefore why does this happen and what can be done about it to improve outcomes and overall prognosis?
It was with great interest that I read about the findings of a new study just published in Cancer Cell from researchers at MD Anderson (see e-link in the references below). According to the MD Anderson news alert:
"For the first time, Salt Inducible Kinase 2 (SIK2) has been found to play a critical role in cell division and to regulate the response of some ovarian cancers to chemotherapy."
It's not often when you see the mention of both a potential target and prognostic/predictive biomarker mentioned in the same sentence as ovarian cancer, so this is huge news! The press release went on to claim:
"Researchers found that depleting SIK2 from ovarian cancers sensitized the cancer cells to paclitaxel, a commonly prescribed chemotherapeutic agent that inhibits cell division, making the drug more effective in stopping the cancer's growth. Levels of the SIK2 protein are increased in approximately 30 percent of ovarian cancers and are associated with poorer survival in women with the disease."
The researchers analysed nearly 780 pools of siRNAs to identify proteins that alter sensitivity to paclitaxel. They found that SIK2 regulates sensitivity to paclitaxel and prevents cell division. This means that SIK2 may offer a useful therapeutic target for pipeline drugs to be developed in ovarian cancer.
What was even more fascinating was that another related article on ovarian cancer from Bast's group appeared in the same journal. In essence, they used siRNA-loaded nanoparticles to stifle a protein, Zeste homolog 2 (EZH2), which is associated with poor survival. This resulted in inhibition of angiogenesis (formation of new blood vessels) to the tumour and caused a steep reduction in the tumour burden in a mouse model of ovarian cancer.
In this study, the authors looked at human 180 ovarian cancer tumours and found that the protein was overexpressed in the tumour samples (66%) and in the endothelial cells (67%). It is relevant to note that endothelial cells line the inside of blood vessels and play a crucial role in angiogenesis.
In practice, they found that women with increased EZH2 levels in their tumours had a median survival of 2.5 years compared to 7.33 years for those without. Looking at overexpression in the endothelial cells, the difference was 2.33 years versus 8.33 years for those with normal levels.
Like me, you're probably wondering how these nanoparticles work. According to MD Anderson:
"The nanoparticles accumulate in the cancer cell and vasculature passively as they circulate in the blood stream. Chitosan nanoparticles are so small that they can flow through tiny holes in the tumor vasculature. They also accumulate in other organs, so the researchers are working to add a targeting molecule that will limit nanoparticle uptake to tumors and their vasculature."
Targeting EZH2 may have application beyond ovarian cancer, since it been associated with the progression and spread of bladder, breast, prostate and gastric cancers and cancer of the pharynx.
All in all, a really interesting pair of papers from Bast's group, which may have clinical promise and real application to the future treatment of ovarian cancer.
Ahmed, A., Lu, Z., Jennings, N., Etemadmoghadam, D., Capalbo, L., Jacamo, R., Barbosa-Morais, N., Le, X., Vivas-Mejia, P., & Lopez-Berestein, G. (2010). SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer Cancer Cell, 18 (2), 109-121 DOI: 10.1016/j.ccr.2010.06.018
Lu, C., Han, H., Mangala, L., Ali-Fehmi, R., Newton, C., Ozbun, L., Armaiz-Pena, G., Hu, W., Stone, R., & Munkarah, A. (2010). Regulation of Tumor Angiogenesis by EZH2 Cancer Cell, 18 (2), 185-197 DOI: 10.1016/j.ccr.2010.06.016