Merkel Cell Carcinoma
Our laboratory focuses primarily on Merkel cell carcinoma (MCC), a rare but lethal skin cancer. In about 80% of cases, MCC is caused by the Merkel cell polyomavirus, while in the remaining 20% of cases it is caused by damage from UV light (sunlight). In 2010, our team found that the immune system plays a very important role in determining how well MCC do. Specifically, patients with a robust immune response within the tumor were far more likely to beat their cancer after standard treatment. Based on these findings, our lab has worked to develop immune based therapies to effectively treat MCC. In 2017, immune therapy replaced chemotherapy as the standard of care for MCC patients that cannot be treated with local therapy.
Our team maintains a clinical database of over 1400 patients with MCC, accumulated since 2004. These data inform our clinical studies and trials of MCC and the corresponding clinical samples are used to study the immunobiology of this cancer. This database allowed us to develop a blood test for antibodies to the Merkel virus that accurately tracks disease recurrences and is increasingly used nationwide. Current interests of the lab include: mechanisms by which MCC avoids the immune system, identification of approaches to increase anti-cancer immunity, and new ways to help radiation activate an immune response against cancer.
Our laboratory has created an informative website on this cancer aimed for patients, their families, and physicians: merkelcell.org
- Pembrolizumab (Keytruda; anti-PD-1) in MCC patients with systemic disease had an objective response rate of 56% with progression free survival at 6 months of 67% (Nghiem et al, New England Journal of Medicine, 2016). This study led to the NCCN designating this type of immune drug becoming the preferred therapy for patients with advanced MCC.
- A clinical trial of avelumab (Bavencio; anti-PD-L1) in MCC patients with advanced, chemotherapy-refractory MCC showed a response rate of 33% with 74% of responses lasting greater than one year (Kaufman et al, Lancet Oncology, 2016). This trial led to the FDA approval of Avelumab for MCC.
- An immune stimulating drug called G100 (a TLR4 agonist) led to increased CD4 and CD8 T cell infiltration into tumors and led to responses in 4/10 patients (Bhatia et al, Clinical Cancer Research, 2018).
UV-induced DNA damage
Our lab also studies basic skin cancer biology focused on the replication checkpoint in cells. A particular interest is the molecular mechanism by which the protein kinase ATR mediates an essential cell cycle arrest following DNA damage such as by ultraviolet radiation.
One hour of sunlight (UV) exposure generates ~100,000 DNA lesions per cell, which are mutagenic. In response to UV, cells activate multiple biological processes (primarily via the ATR kinase) to cope with these deleterious lesions. However, chronic UV exposure leads to development of skin cancers, the most prevalent cancers in humans (annual incidence is 3.5 million in the US; exceeding all other cancers combined). Multiple human epidemiological studies showed that caffeine intake reduces the risk of developing skin cancers. We are elucidating the mechanism by which caffeine prevents skin cancers, that may lead to novel approaches to treat the most prevalent cancers.
This work is now mostly led by Dr. Masaoki Kawasumi. More information can be found at https://kawasumilab.org
To view an animation of how ATR works, click here