Merkel Cell Carcinoma (MCC) is a highly aggressive cancer of the skin. It is characterized by a high recurrence rate and a very poor five-year prognosis. Drugs targeting the programmed cell death protein 1 (PD1) have had recent success as an FDA approved drug. However, fifty percent of patients do not respond to this treatment. A new method utilizing a two-pronged approach has been proposed; using immunotherapy and targeted drug therapy together as a treatment. Unfortunately, MCC does not have any FDA targeted therapies yet.
One possibility for a targeted therapy that has seen success in other cancers is using a phosphoinositide-3-kinase (PI3K) inhibitor. The PI3K/Akt/mTOR pathway is critical in many cellular processes such as cellular proliferation and survival. They are often de-regulated in many cancers, and can promote unregulated tumor growth. Genomic studies have revealed that this pathway is abnormally activated in MCC. PI3K has several isoforms, or variants, and pan-PI3K inhibitors have been shown to have toxic side effects. The PI3K-delta isoform targeting idelalisib has had surprising success in treating stage IV MCC in one instance. A team from Arkansas decided to follow up on this finding and see if any other isoform targeting PI3K inhibitors could be used to treat MCC.
The team analyzed the expression of the different isoforms of PI3K in several MCC archived tissues from their library and found that PI3K-delta was the most common isoform showing up in 52% of the tissues tested. The next closest was PI3K-alpha, found in 30% of the tissues. Choosing four MCC cell lines, each with a different isoform expression. The team then applied one of four PI3K isoform inhibitors to identify the effects they would have on growth. Each MCC cell line had a slightly different response, but the PI3K alpha/delta inhibitor copanlisib produced the best and most consistent suppression of proliferation. Examining the effect of the inhibitors on apoptosis of the MCC cell lines showed that while all inhibitors induced apoptosis to some degree, copanlisib again produced the most robust response. Copansilib continued to outperform even the successful idelalisib. A final mouse experiment using xenografts or MCC cell lines or patients into mice showed that copansilib managed to impair tumor growth with no apparent signs of toxicity.
The need for alternative therapies for MCC is clear, with the poor prognosis and high recurrence if the current available PD1 treatment. Inhibitors of the PI3K/Akt/mTOR pathway have exhibited potential in several other studies in other cancers, and early work continues this trend. Copansilib is shown to be more effective than other inhibitors at low concentrations, effectively impairing the growth of MCC tumors in mice. The mechanism of action still needs to be investigated, but never-the-less PI3K isoform inhibitors have proven themselves to be effective against cancer growth.