Dana-Farber Cancer Institute
Project Term: October 1, 2021 - September 30, 2026
We focus on blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer with limited treatment options and poor outcomes. We want to understand what causes the disease, develop laboratory tools, and identify new treatments and ways to overcome therapy resistance. We have translated our discoveries to clinical trials. Our goal is to continue this bench to beside approach to develop the next generation of BPDCN therapies that improve survival and minimize treatment toxicity.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive blood cancer desperately in need of new therapies. Survival for patients with BPDCN is under 2 years, and for many, less than one year. Since the majority die from their disease, BPDCN kills more people than many blood cancers that are better studied. There is only one drug approved for BPDCN, tagraxofusp-erzs (TAG), but even with that, there is no standard approach to treatment. Patients with BPDCN are unique: the disease can behave like a leukemia or a lymphoma, half of patients initially only have skin tumors, and males are 4 times more likely to get the disease. I have dedicated my career to studying BPDCN. We established a BPDCN Center at Dana-Farber in 2017, the first its kind, for basic and clinical research. There were few laboratory tools to study BPDCN when we started. We have made mouse models, cell lines, and >15 patient-derived xenografts (PDXs). PDXs are patient BPDCNs that grow in animals and allow us to test new treatments. We have taken our laboratory discoveries to two clinical trials in the last 3 years. My goal is to figure out what makes BPDCN tick and translate that knowledge to new therapy. We co-led the clinical trial that resulted in approval of TAG. However, only some patients respond to TAG and it has a potentially fatal side effect called capillary leak syndrome. We want to develop new treatments that are more effective and less toxic by studying BPDCN in the lab. We will analyze how single BPDCN cells from patients are different from normal blood cells. We will use gene editing to ask what makes BPDCN cells live or die, and how male and female cells are different. We will test how BPDCNs become resistant to the therapies we use in the clinic. After we make laboratory discoveries, it is equally important for us to bring them back to patients quickly. For example, we found that BPDCN is sensitive to a drug called venetoclax and now have two clinical trials testing it in patients. We discovered how BPDCNs become resistant to TAG and now have a trial combining drugs that reverse resistance. We will use this LLS Award to continue to ask: What is BPDCN? Why does it affect men more than women? What are its unique weaknesses? Why does it respond to certain drugs? How can we improve survival and minimize side effects using more targeted therapies? Our BPDCN Center and laboratory have unique tools and a path for rapidly translating discoveries to new clinical trials.