CDCN Funds Four High-Impact Grants

The CDCN is excited to announce funding for four high-impact research proposals! Each research project was awarded an individual grant of $42,000.

3/27/2018 Dr. David Fajgenbaum, Co-Founder and Executive Director of the CDCN and Assistant Professor of Medicine at the University of Pennsylvania, commented on how the recent grants demonstrate the organization’s collaborative, accelerated research model. “This wave of strategic research leverages funds raised by the Castleman Warriors community of patients, our partnership with the Penn Orphan Disease Center, the talent of high caliber researchers, and tissue samples generously donated by patients fighting Castleman disease. These important projects will help to unlock the mysteries of Castleman disease and move towards new life-saving treatments.”

Functional Validation of Genomic Hits

The grants awarded to Drs. Byun, Ohgami, and Xiao will fund research investigating genetic variants observed in their prior genetic sequencing studies of patients with Castleman disease. The genetic code is the blueprint used by every cell to produce the proteins that allow cells to function. Variants in the sequence of this genetic code may lead to the production of faulty proteins that do not function correctly and lead to diseases like Castleman disease. However, many genetic variants are harmless, so scientists must perform functional validation studies to determine how a genetic variant impacts protein function and cellular behavior to determine whether a variant is actually disease causing.

Prior research conducted separately by Dr. Byun and Dr. Ohgami identified genetic abnormalities in the gene DNMT3A in select patients with Castleman disease. DNMT3A is of particular interest because it has been previously associated with diseases similar to Castleman disease, such as cancers of the blood. However, abnormalities in DNMT3A are also commonly found in people with no known disease. Drs. Byun and Ohgami will be using their grants to determine whether or not abnormalities in DNMT3A play a role in Castleman disease.

Dr. Byun originally discovered this variant using funds from a 2016 CDCN/Penn Orphan Disease Center funded project involving 16 Castleman Disease patients. Now, Dr. Byun, whose grant was provided with funds raised by the Castleman Warriors community of patients, will be using induced pluripotent stem cells (adult cells that are transformed into a stem cell like state) to further characterize her team’s earlier findings. “We performed whole-genome sequencing of patients with idiopathic Multicentric Castleman Disease (iMCD). In one of the patients, an acquired mutation in DNMT3A gene was identified. The goal of this research project is to functionally characterize this mutation and to investigate the role of DNMT3A in the pathogenesis of idiopathic MCD with an emphasis on T cell biology.”

Per Dr. Ohgami, his team will use their funding, which is provided jointly by the Penn Orphan Disease Center and CDCN, to perform laser microdissection and look for genetic variants in precisely selected lymph node cells.  He hopes that this research will help to “identify and understand the neoplastic cell of origin in iMCD, and the dynamic relationship with the immune system.”

Previous work by Dr. Xiao identified a mutation in the MAP2K2 gene in a patient with TAFRO (Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis of the bone marrow, Organomegaly) subtype of iMCD. His team will use their grant to “study if this mutation leads to increased production of cytokines that play an important role in the pathogenesis of this disease. Also, we will look for the specific cell type that has this mutation.”

While the previously identified genetic variants being studied now were not seen in all patients with Castleman disease, a validated genetic variant would be an important clue in characterizing the disease process. Such findings could allow for new diagnostic tools and targeted therapies in the future.

Identification of Cytokine Producing Cells

The fourth grant awarded by the CDCN will investigate cytokine producing cells in the lymph node tissue of patients with Castleman disease. Immune system hyperactivation and systemic inflammation in Castleman disease have been shown to be associated with increased levels of certain cytokines, such as IL-6 and VEGF; however, the cells responsible for increased production of these cytokines remain unknown. Describing the project, Dr. Pillai said his goal is to “determine which cells in the lymph nodes are responsible for producing cytokines and amplifying the immune response.” Identifying the cells responsible for cytokine production in Castleman disease is a critical step to understanding how the immune system malfunctions and could be used to identify new treatment targets.

Warriors Fight Back

The Castleman Warriors are a group of patients and loved ones who work to advance the search for a cure by raising awareness, fundraising, and supporting newly diagnosed patients. Mileva Repasky, whose daughter has Castleman disease, volunteers as Director of the Castleman Warrior Program. Mileva explained that “Each year the warriors aim to raise enough funds to enable a new research project. We are excited to support Dr. Byun’s research this year; providing the grant is a huge achievement for the Warriors and shows what patients and loved ones battling Castleman disease can accomplish! I could not be more proud to be apart of such an amazing team fighting back!”

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