Peer Reviewed Cancer
Posted December 16, 2020
FY19 PRCRP CCAYA Blood Cancer Awards
In 2020, approximately 11,050 children under the age of 15 will be diagnosed with cancer.1 For these children and their families, a cancer diagnosis is devastating and life-altering. For military families, a cancer diagnosis impacts not just the family, but the Service member’s unit and mission. A healthy family unit allows the Service member to focus on his or her role in the overarching military mission.
The Peer Reviewed Cancer Research Program (PRCRP) is tasked by Congress to fund research that is relevant to Service members and their families. Beginning in fiscal year 2017, (FY17), the topic area of Cancer in Children, Adolescents, and Young Adults was included in the congressional language of the Department of Defense appropriation for the PRCRP. Research within this topic area is targeted toward cancers that predominantly affect children (ages 0-14 years), adolescents (ages 15-24 years), and/or young adults (ages 25-39 years).1,2 Overall, cancers in children, adolescents, and young adults are rare, but are the second leading cause of death among these age groups. Blood cancers are the most common type of cancer in children, adolescents, and young adults. Leukemias account for 28% of childhood cancers, begin in the bone marrow, and result in abnormal growth of immature white blood cells. Lymphomas account for about 8% of childhood cancers and result from the abnormal growth of lymphocytes that accumulate in lymph nodes. Most leukemia and lymphoma patients can be cured with standard chemotherapy; however, these treatments can lead to lifelong chronic health conditions, including cardiac disease, hearing or vision loss, cognitive dysfunction, infertility, and secondary cancers later in life.3 Additionally, patients who experience a relapse of their cancer have a poor prognostic outlook. It is important to address knowledge gaps related to cancers in children, adolescents, and young adults to ultimately develop less toxic, more effective, therapeutics.
In FY19, PRCRP invested $7.45 million in the topic area of Cancers in Children, Adolescents, and Young Adults. Three of these projects, summarized below, are focused on blood cancers.
Rational Targeting of Oncogenic Kras and Sos Interaction in JMML
Jing Zhang, Ph.D., University of Wisconsin-Madison
Juvenile myelomonocytic leukemia (JMML) is a rare pediatric blood cancer caused by uncontrolled proliferation of monocytes and myelocytes. Approximately 85% of patients carry mutations in the RAS pathway. There are no effective chemotherapies to treat JMML; allogeneic hematopoietic stem cell transplant is the only treatment option. Dr. Zhang, with a FY19 Impact Award, aims to develop small molecule inhibitors to target mutant KRAS as a treatment for JMML. Specifically, she plans to target Sos1, which interacts with and activates KRAS. This project will combine Dr. Zhang’s expertise in Ras-driven leukemia with the expertise of her two collaborators, Dr. Yi Zheng (Cincinnati Children’s Hospital) in rationally designed small molecules, and Dr. Eric Patron (Moffitt Cancer Center) in JMML animal studies. The outcome of this project will enhance our understanding of the molecular mechanisms of JMML and potentially lead to new therapeutics for treating this rare disease.
A Multi-Omics Approach to Overcome Resistance in Infant Leukemia by Identifying Immune Therapy Failure Mechanisms
Kathrin Bernt, M.D., Children’s Hospital of Philadelphia; Erin Guest, M.D., Children’s Mercy Hospitals and Clinics; Patrick Brown, M.D., Johns Hopkins University
Translational Team Science Award
Infant acute lymphoblastic leukemia (iALL) is an extremely rare form of leukemia diagnosed in children younger than 1 year old. Even with intense chemotherapy regimens, iALL has a poor prognosis, with less than 35% of patients surviving. Immune-based therapies such as chimeric antigen receptor (CAR)-T cells are currently approved for certain types of ALL and lymphoma. CAR-T therapy involves engineering a patient’s own T cells to specifically recognize and target cancer cells. However, there remain significant gaps in understanding the mechanisms of therapeutic resistance and T cell dysfunction in iALL patients. With funding from a FY19 Translational Team Science Award, Drs. Bernt, Guest, and Brown will use systems biology approaches to study both the leukemia cells and T cells in iALL patients. By identifying immune therapy targets on every iALL subpopulation, they can engineer effective CAR-T cells to treat iALL and prevent relapse in these patients.
A Multivalent Epstein-Barr Virus-Like Particle Vaccine Candidate Against EBV+ Lymphomas
Gabriela Escalante, B.S., Pre-Doctoral Candidate, City of Hope Beckman Research Institute
Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis, which affects approximately 100 in 100,000 active duty Service members a year and impacts mission readiness. EBV was the first human virus identified with a proven link to cancer development. Globally, latent EBV infection results in about 200,000 new cases of cancer a year, including several types of lymphoma. Despite its known pathogenesis, there is no vaccine for EBV. Gabriela Escalante was awarded a FY19 Horizon Award to develop a multivalent vaccine that targets five EBV glycoproteins important for viral entry into cells. After generating and characterizing the vaccine, she will then measure the ability of the vaccine to neutralize EBV infection in vitro and in animal models. An EBV vaccine will benefit children, adolescents, and young adults by preventing mononucleosis, and it will reduce the global burden of EBV+ cancers.
1 National Cancer Institute. Cancer in Children and Adolescents. https://www.cancer.gov/types/childhood-cancers/child-adolescent-cancers-fact-sheet.
2 National Cancer Institute. Adolescents and Young Adults with Cancer. https://www.cancer.gov/types/aya.
3 Oeffinger KC, Mertins AC, Sklar CA, et al. 2006. Chronic Health Conditions in Adult Survivors of Childhood Cancer. New England Journal of Medicine 355:1572-1582.
Last updated Wednesday, December 16, 2020