Mechanisms and targeting of TP63-rearrangements in lymphoma
Dana-Farber Cancer Institute
Project Term: July 1, 2019 - June 30, 2022
Chromosomal rearrangements involving a gene called TP63 have been found in 5-10% of several subtypes of lymphomas and patients with TP63-rearrangements have dismal outcomes, with nearly 0% of patients surviving 5 years after diagnosis. We investigate the oncogenic mechanisms of TP63-rearrangements to find the unique cancer cell vulnerabilities to this rearrangement using different models. Our study will develop an effective therapeutic strategy for patients with TP63-rearranged lymphomas.
Non-Hodgkin lymphomas (NHL) are cancers of lymphocytes, a type of white blood cell that helps the body fight infection. NHL is the 7th most common type of cancer and approximately 20,000 people die each year in the United States. Recurrent chromosomal rearrangements are a kind of mutation in which two separate genes are fused together and are common across cancers and are critical mediators in the molecular pathogenesis of hematologic neoplasms. Chromosomal rearrangements involving a gene called TP63 have been found in 5-10% of several subtypes of aggressive NHLs. Patients with TP63-rearrangements have dismal outcomes, with 0-17% of patients surviving 5 years after diagnosis, depending on the NHL subtype. The oncogenic mechanisms of TP63-rearrangements are poorly understood, and as a result, attempts to treat these patients to date have been largely empiric. Thus, there is an urgent need to better understand how these rearrangements function and develop new treatment options for these patients. Our laboratory focuses on NHL oncogenic mechanisms and therapy. We recently identified TP63-rearrangements in human lymphoma cell lines and found a dependence on the TP63 fusion, the protein product of TP63-rearrangements, and demonstrated its role as an oncogene. We are now clarifying the oncogenic role of TP63-rearrangements in lymphoma initiation and progression. To TP63 fusion-mediated oncogenic mechanisms, we will use integrative genome-wide CRISPR/Cas9 gene editing technology combined with next-generation sequencing, RNA-sequencing analysis, protein-protein interaction analysis and extensive bioinformatics analyses. These approaches will help us define the cellular processes that are affected by the TP63 rearrangements, which may then allow us to find unique cancer cell vulnerabilities to this rearrangement and develop new drugs based on the unique vulnerabilities. We will also develop animal models for testing new drugs that target the unique vulnerability in TP63-rearrangements lymphomas. This effort could lead directly to the development of an effective therapeutic strategy for the patients with TP63-rearrangements lymphomas, which can be rapidly advanced to a clinical trial. These studies are aligned with my central career goal, which is to leverage mechanistic insights to improve the outcomes for patients with lymphomas that harbor high-risk genetic alterations.