A team of researchers at Case Western Reserve University School of Medicine has developed the first "theranostic" agent for the treatment of acute lymphoblastic leukemia (ALL). ALL is the most common type of childhood cancer diagnosed in approximately 5,000 new cases each year in the United States. The findings provide insight into pediatric oncology that specifically focuses on the development of "theranostic" agents-- a treatment platform that combines a selective diagnostic test with targeted therapy based on the test results.
Discovery of this new class of drugs is the first step towards new diagnostic markers and therapeutic approaches in treatments with anti-cancer agents of numerous other cancers in addition to ALL.
"This discovery takes a chemical biology approach to target ALL. Our nucleosides represent a new class of theranostic agents that provide an original approach to achieving personalized treatments against pediatric leukemia," says Anthony J. Berdis, PhD, assistant professor of pharmacology at Case Western Reserve School of Medicine.
"We've developed a non-natural nucleoside that specifically targets this form of childhood leukemia. The combination of therapeutic and diagnostic activities will provide more selective and more expedient ways to treat patients by optimizing the dosages needed to kill the cancer cells without affecting normal cells. This selectivity should minimize the development of adverse side effects typically associated with conventional anti-cancer nucleosides," says Dr. Berdis.
Using an enzyme implicated in the disease, terminal deoxynucleotidyl transferase (TdT) which serves as a biomarker and is overexpressed in 90 percent of ALL patients, Dr. Berdis and his team designed a new selective anti-cancer agent against ALL. By evaluating the anti-leukemia activities of two non-natural nucleotides designated 5-NITP and 3-Eth-5-NITP, the investigators strategically placed novel functional groups on these agents so that they could be tagged with fluorogenic dyes. These taggable nucleotides improve the accuracy of dosing regiments and could accelerate clinical decisions regarding therapeutic intervention. The next steps will be validation in animal studies and toxicology testing, leading to clinical trials.
This study appears online this week in ACS Chemical Biology. In addition to Dr. Berdis, co-authors on the paper include Edward A. Motea and Dr. Irene Lee, in the Department of Chemistry and Department of Pharmacology at Case Western Reserve.
Acute lymphoblastic leukemia (ALL) is a form of leukemia, or cancer of the white blood cells characterized by excess lymphoblasts. Acute refers to the relatively short time course of the disease (being fatal in as little as a few weeks if left untreated). This disease is caused when malignant, immature white blood cells continuously multiply and are overproduced in the bone marrow. ALL causes damage and death by crowding out normal cells in the bone marrow and by spreading to other organs. Although ALL is most common in childhood with a peak incidence at 2-5 years of age, this type of leukemia is also prevalent in people over the age of 60.
Funding for this research was provided by the NIH and the National Cancer Institute Training Programs in Cancer Pharmacology.
This research was supported by the Developmental Therapautics Program at the Case Comprehensive Cancer Center, a National Cancer Institute (NCI) - designated Comprehensive Cancer Center located at Case Western Reserve University in Cleveland, Ohio. NCI-designated cancer centers are characterized by scientific excellence and the capability to integrate a diversity of research approaches to focus on the problem of cancer. Lead by Stanton Gerson, MD, Asa and Patricia Shiverick- Jane Shiverick (Tripp) Professor of Hematological Oncology, director of the Case Comprehensive Cancer Center, and director of the Seidman Cancer Center at UH Case Medical Center. The Case Comprehensive Cancer Center, now in its 22nd year of funding, integrates the cancer research activities of the largest biomedical research and health care institutions in Ohio – Case Western Reserve University, University Hospitals Case Medical Center, Cleveland Clinic and MetroHealth Medical Center.
About Case Western Reserve University School of Medicine
Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the school of medicine.
Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report "Guide to Graduate Education."
The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu.
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