Identifying Novel Therapeutic Targets and Combination Strategies for Patients with BPDCN
Abstract
This proposal addresses the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of Blood Cancers and Rare Cancers. We study a Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), an aggressive cancer with poor outcomes. Patients diagnosed with BPDCN usually die in about one year because the treatments we have are not very effective. This cancer starts in the bone marrow, the place where blood cells grow, and typically spreads to the involved skin and lymph nodes. Notably, males are significantly more frequently affected by BPDCN than females (more than 3:1 male:female incidence). The average age at diagnosis is approximately 65, but the disease also affects young adults and children. The affected population is highly representative of military personnel and Veterans, and therefore particularly relevant to the health and well-being of the military. Historically, BPDCN treatments that we use currently are not adequate, not specific to BPDCN, and have been borrowed from other cancers. Intensive chemotherapy regimens followed by stem cell transplantation are commonly used; however, the vast majority of patients with BPDCN are unable to tolerate this intensive approach. Therefore, we must recognize BPDCN at its own, separate entity, and then discover and test new therapies for this unique cancer. To this end, it was recently discovered that in nearly 100% of BPDCN patients, BPDCN cells are covered by a protein on their surface called CD123. This led us to start a clinical trial of a new targeted drug for BPDCN that attacks CD123, called tagraxofusp. About 70% of patients had major reductions in the amount of cancer, which led to Food and Drug Administration approval of tagraxofusp in December 2018. However, many patients who initially respond to tagraxofusp have their disease come back. Also, 30% of patients with BPDCN don’t respond to tagraxofusp at all. Thus, development of new therapeutic strategies is very important for this highly aggressive tumor. We have assembled a research team of physician-scientists and clinical investigators from three top academic centers specializing in leukemia (MD Anderson Cancer Center, Dana-Farber Cancer Institute, and Memorial Sloan Kettering Cancer Center), to attack this deadly malignancy. All investigators have a longstanding interest in studying BPDCN, have generated research tools and models of this disease in the laboratory, and have unique expertise in the types of science needed to perform this research. Importantly, all members of this team already have a track record of working together to study BPDCN and other leukemias. This group’s prior work has led to new clinical trials that are bringing new therapies to patients. Therefore, this team has a high likelihood of accomplishing the goals of this project and improving survival for patients with BPDCN. This proposal addresses the following FY19 PRCRP Military Health Focus Area: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may impact mission readiness and the health and well-being of military members, Veterans, their beneficiaries, and the general public. We propose to develop novel therapies that target the underlying biology of BPDCN. Our expected outcome is to impact the cure rates and survival for patients with the disease. In Aim 1, we will study how BPDCN cells evade tagraxofusp. Our preliminary findings indicate that BPDCN can turn off a protein that is necessary for the drug to kill the cancer cells. Most importantly, this protein could be turned back on by a drug we already use in patients with other types of leukemia, called azacitidine. This finding leads to strategies using tagraxofusp and azacitidine in combination. In Aim 2, this concept will be developed further by testing a three drug combination: tagraxofusp/azacitidine plus a novel agent called venetoclax that blocks a protein called BCL-2 that keeps cells from dying. O
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010684
Entities
People
- Andrew A Lane
Organizations
- Dana–Farber Cancer Institute
- United States Army