In addition to our regular CRI Activities Update, this month’s Research Focus highlights the research and work of Thomas Alexander, MD, MPH, Assistant Professor of Pediatric Hematology-Oncology, and Co-Director of the Pediatric Oncology Developmental Therapeutics and Pharmacology Program

Activities Update:

Congratulations to Toni Darville, MD, for her recent award from the National Institute of Allergy and Infectious Diseases. The NIAID awarded a total of four cooperative research centers, or U19 CRCs, to develop vaccines for sexually transmitted infections, including chlamydia, gonorrhea and syphilis. Dr. Darville and her team were awarded up to $10.7 million to lead the UNC Chlamydia Vaccine Initiative, Sexually Transmitted Infection, Cooperative Research Center, which will also include partners at Blue Willow Biologics in Michigan, the German Cancer Center, Oxford University, N.C. State University, Queensland University of Technology, and the University of Pittsburgh. This collaborative program aims to develop a much-needed Chlamydia trachomatis vaccine by supporting a vaccine development pipeline comprising of vaccine antigen assessment, vaccine testing in animal models, and identification of human correlates of efficacy. Read more >>

We would also like to congratulate Timothy Moran, MD, PhD, for his notice of a K08 award from the National Institute of Environmental Health Sciences! This proposal, “The role of neuropilin-2 in regulating environmental airways injury,” will investigate how the protein neuropilin-2 regulates airway inflammatory responses after exposure to pollutants with the goal of identifying a new therapeutic target or biomarker for environmental airway injury.

Our new address is: 4008 Mary Ellen Jones, 116 Manning Drive, Campus Box 7578. The move continues while we continue to build our virtual presence. We are networking across campus, clinics, and the community to develop clinical research through our Pediatric Clinical Research Unit (Peds CRU). We current have 5 ongoing studies, 2 closing out, 1 entering a contract, and 15 studies where we are assessing feasibility to enter a contract or not. Anyone interested in leading a clinical trial can reach us at our CRI email address: childrensresearch@med.unc.edu. Also, the CRI has a presence on the Program for Precision Medicine in Health (PPMH) Biobanking Working group. This group is currently focusing on potential IRB consent language to obtain prospective consent for leftover samples; interest from investigators across campus in biobanking and research related to biobanked samples; and informatics infrastructure. Please email the CRI if you have questions or interest. Our support of collaborative grant submissions continues with assistance being provided for a UG3/UH3 on Primary Ciliary Dyskinesia Airway Disease led by our Chair, Stephanie Davis, MD, along with Margaret Leigh, MD, Mike Knowles, MD, and Adam Kimple, MD, PhD at UNC in collaboration with several other sites across the country. We are also providing support for a potential collaborative T32 submission with Duke and UNC, led internally by Toni Darville, MD.

Reminder: Thomas Alexander, MD, MPH, will be presenting “Acute Leukemia Genomics Across the Translational Spectrum” at our next CRI luncheon seminar series. This event will be held on Tuesday, June 11, 2019, from 12:15-1:30pm in the Bioinformatics Auditorium (room 1131). Please mark your calendars. We look forward to seeing you there.

Research Focus of the Month:

Thomas Alexander, MD, MPH

Leukemia is the most common form of childhood cancer, accounting for around one-third of cases, with patient outcomes depending on a variety of factors, including response to therapy, age of diagnosis and molecular subtype. Thomas Alexander, MD, MPH, is combining cancer genomic sequencing with early phase clinical trials to enhance understanding of disease response dynamics and improve outcomes in childhood leukemia and other hematological malignancies.

In particular, Dr. Alexander focuses on acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), including high-risk, refractory or relapsed presentations where standard therapies have failed or outcomes are historically poor. Dr. Alexander utilizes a mixture of whole-genome sequencing, whole-exome sequencing, and transcriptome sequencing techniques on biobank samples to further distinguish between rare subtypes and clinical presentations of leukemia that remain poorly understood, which has negative implications for diagnosis and proper treatment decisions. For example, mixed phenotype acute leukemia (MPAL), a high-risk subtype of leukemia that lacks consensus on appropriate therapy, was recently found to be a mix of genetically distinct subtypes. Characterization of these subtypes supports using therapies targeted to the subtype. These findings were published in a Nature article, led by Dr. Alexander. This study, and other studies like it, are made possible through collaboration with multiple groups and partnerships, including St. Jude’s Children’s Research Hospital and the Children’s Oncology Group, and generates data necessary for building a framework for later clinical trials.

Dr. Alexander is also investigating new cancer therapeutics and serves as co-investigator or principal investigator for several multi-institutional early phase clinical trials. Currently, he is involved in testing efficacy of combined venetoclax and navitoclax therapy in patients with relapsed ALL or lymphoblastic lymphoma who are also receiving chemotherapy. A combined regimen of both drugs has shown synergistic effects in preclinical models, as well as potential to lessen dose-limiting side effects of navitoclax therapy alone. In addition, he co-leads the Pediatric Oncology Developmental Therapeutics and Pharmacology Program, along with his division colleague, Patrick Thompson, MD, MS. This program administers individual investigator, cooperative group, and industry led clinical trials at UNC, as well as partnering with the Eshelman School of Pharmacy to monitor traditional cancer regimens and to investigate novel drug delivery mechanisms.

Dr. Alexander works extensively in all of these efforts with collaborators at UNC, including those at the Integrative Program for Biological and Genome Sciences, the Center of Gastrointestinal Biology and Disease, and the Lineberger Comprehensive Cancer Center. He also partners with colleagues outside of UNC, including at St. Jude’s Children’s Research Hospital, the University of Zimbabwe, and the University of Zambia.

Recent publications from Dr. Alexander and related links are below:

Developmental Therapeutics and Pharmacology Program

Alexander TB, Gu Z, Iacobucci I, Dickerson K, Choi JK, Xu B, et al. The Genetic Basis and Cell of Origin of Mixed Phenotype Acute Leukaemia. Nature. 2018 Oct;562(7727):373-379. doi: 10.1038/s41586-018-0436-0. Epub 2018 Sep 12. PMID: 30209392.

Alexander TB, Lacayo NJ, Pullarkat VA, Jabbour EJ, Khaw SL, Mullighan CG, et al. Venetoclax and Navitoclax in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma. Blood. 2018 132;3966; doi: https://doi.org/10.1182/blood-2018-99-113464.

Grande BM, Gerhard DS, Jiang A, Griner NB, Abramson JS, Alexander TB, et al. Genome-Wide Discovery of Somatic Coding and Noncoding Mutations in Pediatric Endemic and Sporadic Burkitt Lymphoma. Blood. 2019 Mar 21; 133(12):1313-1324. doi: 10.1182/blood-2018-09-871418. PMID: 20617194.

Iacobucci I, Web J, Meggendorfer M, Choi JK, Shi L, Pounds SB, et al. Genomic subtyping and therapeutic targeting of acute erythroleukemia. Nat Genet. 2019 Apr;51(4):694-704. doi: 10.1038/s41588-019-0375-1. PMID: 30926971.