Targeted Drug Discovery for Pediatric Leukemia

Abstract

Despite dramatic advances in the treatment of pediatric leukemia over the past 50 years, there remain subsets of patients who respond poorly to treatment. Many of the high-risk cases of childhood leukemia with the poorest prognosis have been found to harbor specific genetic signatures, often resulting from chromosomal rearrangements. With increased understanding of the genetic and epigenetic makeup of high-risk pediatric leukemia has come the opportunity to develop targeted therapies that promise to be both more effective and less toxic than current chemotherapy. Of particular importance is an understanding of the interconnections between different targets within the same cancer, and observations of synergy between two different targeted therapies or between a targeted drug and conventional chemotherapy. It has become clear that many cancers are able to circumvent a single specific blockade, and pediatric leukemias are no exception in this regard. This review highlights the most promising approaches to new drugs and drug combinations for high-risk pediatric leukemia. Key biological evidence supporting selection of molecular targets is presented, together with a critical survey of recent progress toward the discovery, pre-clinical development, and clinical study of novel molecular therapeutics.

Cell‐ and Tissue‐Based Proteome Profiling and Bioimaging with Probes Derived from a Potent AXL Kinase Inhibitor

“…Target‐based drug discovery (TDD), which comprises drug design, lead compound discovery, target identification and preclinical studies, is an important approach to the discovery of first‐in‐class drugs, especially kinase‐targeting drugs . Of these steps, target identification is critical because target information assists in an understanding of drug action and toxicity, and guides drug redesign .…”

“…Ta rget-based drug discovery (TDD),w hich comprises drug design,l ead compound discovery, target identification and preclinical studies, is an importanta pproach to the discovery of first-in-classd rugs,e specially kinase-targetingd rugs. [1] Of these steps, target identification is criticalb ecause target information assists in an understanding of druga ction and toxicity, and guides drug redesign. [2] Over the past decade, chemical proteomics [3] including affinity-based proteome profiling (AfBP) and bioimaging [4] have been developed as powerful approachest oi nvestigate drug target engagementi ns itu.…”

A Sensitive Luminescent Assay for the Histone Methyltransferase NSD1 and Other SAM-Dependent Enzymes

“…We are particularly interested in evaluating NSD1 inhibitors as therapeutic agents to block pediatric AML driven by NUP98-NSD1 fusion proteins. 1,6 To this end, after we had initially validated the assay using the catalytic domain of NSD1, we obtained a construct that encompasses the entire portion of NSD1 present in NUP98-NSD1 fusions. Use of the longer construct for HTS will enable the possibility of inhibition of the catalytic activity of NSD1 through compound binding to a site outside the catalytic domain.…”

“…Many of the high-risk cases of childhood leukemia with the poorest prognosis have been found to harbor specific genetic signatures, often resulting from chromosomal rearrangements. 1 A major focus of our pediatric cancer research is the discovery of chemical probes to further understanding of the biology of leukemia harboring fusion proteins arising from chromosomal rearrangements, and to develop novel specifically targeted therapies. The NUP98-NSD1 fusion protein ( Fig.…”

New frontiers in pediatric Allo-SCT: novel approaches for children and adolescents with ALL

“…A large number of new agents and immunotherapies have the potential to reduce the risk of relapse after HCT. 55,56 Clinical trials to assess the efficacy of such novel therapies employed either pre-and post-transplant are in development 57 (Table 3). A COG trial for children with relapsed ALL who achieve CR after reinduction will include a randomization between blinatumomab and chemotherapy before HCT-a strategy that is aimed to minimize pre-HCT MRD.…”