Targeting MYB in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)
Abstract
We study a blood cancer called blastic plasmacytoid dendritic cell neoplasm (BPDCN). People diagnosed with BPDCN are desperately in need of new treatments. Survival after diagnosis is only around 1 year. So even though BPDCN is rare, affecting 0.04 per 100,000 people yearly, because it is uniformly fatal more patients die with BPDCN than many other blood cancers that are better studied. Like other blood cancers, BPDCN arises from cells that reside in the bone marrow. Their normal job is to make immune cells that fight infection, such as by viruses. But in BPDCN, the normal immune cells turn into a leukemia that circulates in the blood and bone marrow, and invades other tissues, like the skin, lymph nodes, spleen, and the brain and spinal cord. There is only one drug approved for BPDCN, called tagraxofusp (TAG). But even with TAG available in the U.S., there is no real standard approach to treatment. Patients with BPDCN are unique and thus warrant dedicated research, separate from other cancers. For example, the disease can behave like a leukemia or a lymphoma, half of patients initially have only skin tumors without obvious leukemia in the blood, and males are four times more likely to get the disease. The average age at diagnosis is approximately 65, but it also affects young adults and children. The affected population is therefore highly representative of military personnel and Veterans, and therefore particularly relevant to military health and well-being. 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 new mouse models, cell lines, and more than 15 patient-derived xenografts (PDXs). PDXs are patient BPDCNs that grow in special research animals and allow us to test new treatments. We have taken our discoveries in BPDCN from the lab 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. After we make discoveries, it is equally important for us to bring them to patients quickly. As evidence that we have the capacity to rapidly translate discoveries from this project to people in need, we previously found that BPDCN is sensitive to a drug called venetoclax and now have clinical trials testing it in patients. We also discovered how BPDCNs become resistant to TAG and now have a trial combining drugs that reverse resistance. The objective of this project is to study mutations in a gene called MYB. There are many mutations that have been detected in BPDCN cells, but most of them are shared with cancer genes that are important in many other tumor types. However, the MYB mutations in BPDCN are unique – they are not seen in any other blood cancer. Therefore, we believe that understanding how MYB causes BPDCN will lead to important disease knowledge and ultimately to new treatments that may be more specific for patients with BPDCN. This application addresses all three of the Focus Areas for the Rare Cancers Research Program Idea Development Award: (1) Biology and Etiology: We will define the biological effects of MYB in BPDCN; (2) Research Model: We will develop new models of BPDCN with forms of MYB detected from patients; (3) Therapy: We will repurpose drugs from other cancers that may target MYB. This project is innovative and more than an incremental advance as there are currently no therapies targeting a mutation unique to BPDCN. This work will shed light on disease-specific biology and test therapies that could be rapidly translated to clinica
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211007
Entities
People
- Andrew A Lane
Organizations
- Dana–Farber Cancer Institute
- United States Army