New anticancer drug discovery and personalized medicine in pediatric cancer

Anchoring comprehensive and coordinated efforts to discover and develop new drugs for pediatric cancer at Cincinnati Children’s, our Childhood Cancer Drug Discovery Laboratory is working in integrated efforts with the University of Cincinnati’s Drug Discovery Center to screen a pharma-grade library of 340,000+ drug-like compounds for activity in a large panel of pediatric and young adult cancers and leukemias. These efforts include high volume screening of new small molecules and biomolecules against pediatric leukemia and other cancer cell lines, and build on our expertise in computational biology and cheminformatics, a unique resource among academic medical centers in the Midwest. In parallel, we are determining the molecular signature of childhood cancers, including the sequencing of high-value druggable targets (e.g., kinases, G-coupled protein receptors) to lead in new drug development for pediatric cancers.

Our laboratory is working to bridge the gap between patients with relapsed and chemotherapy-resistant tumors and the array of novel targeted therapies becoming available. Work is underway in the lab to define the real targets and biological pathways responsible for the responses observed in some but not all patients treated with novel targeted agents. Using focused assays for the PI3K-Akt-mTOR and RAS-MEK-ERK pathways, the lab is expanding our capability to perform real-time tumor signature profiling on patient samples in order to direct patients to protocols offering the most appropriate new targeted agents, to “get the right drugs to the right patients.”

Molecular etiology and pharmacogenetics of childhood leukemias

Individuals with Down syndrome have a 2% cumulative risk for the development of leukemia by the time they reach 30 years of age. In addition, as many as 5 - 10% of infants with Down syndrome may develop a transient myeloproliferative disorder (TMD). The molecular basis for this increased risk of developing hematologic disorders remains unknown. Additional genetic material from the critical Down syndrome locus at 21q22 includes the Cu/Zn superoxide dismutase gene and other genes contributing to high oxidative stress and increased endogenous DNA damage observed in cells from patients with Down syndrome. The additional chromosome 21q22 genetic material thus constitutes a necessary but not sufficient “first hit” for the development of leukemia. Our hypothesis is that functional polymorphic variants in enzymes catalyzing detoxification of oxidants and repair of oxidant-associated DNA damage are associated with an increased risk for the development of myeloid leukemia and TMD in children with Down syndrome.

In what is now the largest study of Down syndrome children with leukemia, the Perentesis Laboratory has recently demonstrated that polymorphic functionally slow detoxifying alleles of oxidant metabolism enzymes (NQO1, p22phox, SOD2 and PON1) and polymorphic DNA repair pathways (FANCA and XRCC1) are highly associated with risk for both transient myeloproliferation and leukemia in children with Down syndrome. This is the first work demonstrating such an effect and is congruent with emerging data revealing the strong influence of deranged oxidant metabolism in acute myeloid leukemia in other patients without Down syndrome. This work provides the foundation for development of a novel predictive “risk score” for transient myeloproliferation and leukemia in children with Down syndrome, which in turn may lead to improved screening and potential chemopreventative strategies. We are currently extending these observations by evaluation of samples from two new national Children’s Oncology Group regimens for the treatment of Down syndrome AML and TMD (AAML-0431 and AAML-0532). We are also studying the molecular progression of AML by characterizing leukemogenic kinase mutations in these patients.

In related work, our lab is using new gene sequencing techniques and gene array technologies to understand how differences in an individual’s ability to metabolize chemotherapy influences cure rates and risk from side effects. We are carrying out this work in children with Down syndrome and leukemia, but also for other children and young adults with leukemia and Hodgkin lymphoma enrolled on national COG treatment studies. We hope to identify easy-to-test-for genetic markers so that we can adjust chemotherapy doses and “personalize” treatment to individual patients’ metabolism to obtain high cure rates with low side effects.

Novel gene discovery

  • Translational elongation factor 2 gene, EFT1 (Saccharomyces cerevisiae): GenBank Data Bank accession M59369.  (Los Alamos National Laboratory, Los Alamos, New Mexico, 1990).
  • Translational elongation factor 2 gene, EFT2 (Saccharomyces cerevisiae): GenBank Data Bank accession M59370.  (Los Alamos National Laboratory, Los Alamos, New Mexico, 1990).

Novel anti-cancer drug discovery

DTctGMCSF: Recombinant granulocyte-macrophage colony stimulating factor receptor – targeted diphtheria fusion toxin anti-leukemia drug (Blood, 82:384a, 1993).