Sean M. Post, PhD
Dr. Sean M. Post is an Assistant Professor at The University of Texas M.D. Anderson Cancer Center and a recipient of the Lymphoma Research Foundation's Chronic Lymphocytic Leukemia (CLL) Collaborative Grant in 2012. His grant project studied the impact of a mutation on the protein TP53 (p53) in CLL. P53 is part of the short arm of chromosome 17 – which has long been known to be a critical genetic alteration in CLL (17p deletion). As with biomarkers and genetic mutations across lymphoma, identifying patients with 17p deletion can help predict a patient's response to treatment and overall prognosis. However, although 17p deletions are routinely assessed during clinical diagnoses, patients who still possess the 17p chromosome are often not assessed for mutated p53, despite recent research suggesting that mutant p53 is periodically present in cells that expand, rather than respond, to standard chemoimmunotherapies. "Given the limited clinical data that exist for frontline treatment of patients with CLL that harbor TP53 mutations," Dr. Post says, "our goal was to determine the impact of p53 mutations on CLL progression, evaluate the dynamic loss of remaining wild type [unmutated] allele, and identify treatment strategies for this subset of patients."
In December 2015, the results of Dr. Post's research were presented at the Annual Meeting of the American Society of Hematology (ASH), one of the largest conferences for research in the hematologic malignancies, including lymphoma and CLL. Working with a preclinical mouse model of CLL, Dr. Post and his colleagues tested whether the effectiveness of ibrutinib (Imbruvica) was affected by the presence of a p53 mutation. Their results revealed that ibrutinib, which targets the Bruton's tyrosine kinase (BTK) pathway and other gene sets outside of the p53 pathway, was an effective therapy regardless of whether the CLL sample had mutated p53. "These data demonstrate the potent effect of BTK-inhibition in CLL and more importantly, provide evidence that ibrutinib is an effective treatment option for aggressive forms of CLL with TP53 mutation and potentially chemoresistant refractory disease," Dr. Post notes. Dr. Post's research, begun prior to the United States Food and Drug Administration's (FDA) approval of ibrutinib for patients with relapsed/refractory CLL or patients with 17p deletion, provides evidence of the biologic mechanism that makes this therapy an important advance for this population, while identifying the p53 mutation as a contributor to resistance to treatment. Going forward, Dr. Post and his colleagues plan to expand their research, testing combination therapies against p53 mutations in the lab. "If successful," he adds, "this work will guide our clinical collaborators, within our department and institute, in the design of clinical trials for TP53-mutant CLL."
Dr. Post received his PhD in molecular medicine from the University of Texas Health Science Center at San Antonio, before doing postgraduate training at Baylor College of Medicine and MD Anderson, where he has been a member of the faculty since 2011. Although Dr. Post says he has "always had an interest in understanding fundamental scientific questions," it was a research project studying slime mold during his junior year of college that pointed him down his current path. "From that time onward, I have continued to use model organisms to address biological questions." He advises beginning researchers to examine clinical or biological questions in which they have a true interest, and to persevere when grants or manuscripts are rejected. "If you have a passion for what you are doing, you can keep moving forward while refining your studies and approaches."
Dr. Post notes that his Lymphoma Research Foundation grant "has been instrumental in our ability to execute these studies," adding that the grant supported both the supplies and the researchers needed to complete the project. "Having the resources from the Foundation allowed my laboratory to not only address important clinical topics, but interesting basic scientific questions as well," he says. "Receiving funding from a well-established and reputable granting agency like the Lymphoma Research Foundation early in my career has afforded me the ability to become a truly independent researcher."
For more patient resources on CLL, visit FocusOnCLL.org, the Foundation's CLL-specific website.
For additional coverage of the 2015 ASH Annual Meeting, read the Lymphoma Research Foundation's Special ASH Issue of Research Report, available only at lymphoma.org/researchreport.