“...this work has pointed toward new genes that may influence the efficacy of current treatment...”

It is perhaps the first paper to identify gene expression patterns that are different in drug-sensitive and drug-resistant cancers, and we also showed that these patterns were able to forecast ultimate treatment outcome.

The resistance-associated genes we identified help to widen our viewpoints on potential causes of drug resistance in acute leukemia. Further, this study utilized two entirely separate patient populations treated at different institutions in different countries, to first discover and then validate these findings.

Finally, childhood acute lymphoblastic leukemia (ALL) has long served as a paradigm for developing curative treatment of disseminated cancers, so principles from this study are potentially applicable in many human malignancies.

The paper describes the discovery of a relatively small number of genes whose level of expression in leukemia cells differed significantly in drug-sensitive and drug-resistant ALL cells.

This research also showed that the genes associated with drug resistance differed substantially among the four mechanistically different anticancer agents studied, and that no one gene was significant for all four drugs.

In this podcast audio commentary, Dr. William E. Evans of St. Jude Children’s Research Hospital in Memphis, talks about the collaborative effort his hospital has undertaken with Erasmus MC Sophia Children’s Hospital in Rotterdam to identify gene expression patterns in childhood acute lymphoblastic leukemia (ALL) that are different in drug-sensitive and drug-resistant cancers. Podcast formats: mp3 wma

Surprisingly, only 3 of 124 genes that we found to be associated with drug resistance had been previously associated with resistance to any of these medications in any human cancer. This points to a shortcoming of "candidate gene" approaches in pharmacogenomics, illustrating that one may not know a priori many of the important genes to study.

This work has revealed new genetic insights into why some patients with leukemia are not cured by treatment that is curative in over 80% of patients with the same disease and comparable prognostic features.

At the same time, this work has pointed toward new genes that may influence the efficacy of current treatment, thereby providing new leads into potential diagnostics to help clinicians further optimize treatment.

Finally, it is possible that some of the proteins or pathways encoded by genes associated with drug sensitivity can become targets for the development of new medications for this disease.

Our two groups, one based in Memphis and the other in Rotterdam, have been involved for many years in pharmacological and genomics research in order to improve the treatment of childhood ALL.

For many years, the Erasmus group has been focused on defining cellular sensitivity and causes of resistance in acute leukemia, whereas the St. Jude group has a long track record of pharmacogenetics research in childhood ALL.

The current work represents our first major collaborative effort capitalizing on our complementary expertise and resources in undertaking a project that neither of us could have done as well or as expediently if working alone. This collaboration allowed us to more readily deal with the usual obstacles for conducting translational clinical trials, which in the end, were not as great.

There are no obvious social or political implications, beyond the implications our findings have for further improving the cure rate of the most common cancer in children. Perhaps our findings will further enhance the enthusiasm for pharmacogenomics research and for translating genomic discoveries into better treatment of human diseases.

William E. Evans, Pharm.D.
Director and CEO
St. Jude Children’s Research Hospital
Memphis, TN, USA

Monique L. den Boer, Ph.D. 
Department of Pediatric Oncology/Hematology
Erasmus MC/Sophia Children’s Hospital
Erasmus University Medical Center
Rotterdam, the Netherlands

A Closer Look...
	Below are images sent in by William E. Evans & Monique L. den Boer which correspond with the featured paper, or current research.

Figure 1:

Figure 1: An overview of the research strategy used for this research (Holleman et al, NEJM, 2004). Primary acute lymphoblastic leukemia (ALL) cells from a large cohort of patients were subjected to gene-expression analysis and in vitro sensitivity testing to a series of antileukemic agents. These data were used together to identify gene-expression patterns that were related to in vitro drug sensitivity. These gene expression patterns were subsequently shown to discriminate overall treatment outcome among patients with ALL who were treated with these medications. Reproduced with permission from Cheok and Evans, Nat. Rev. Cancer, 6:117-129, 2006. Reprinted by permission from Macmillan publishers Ltd: Nature Reviews Cancer, Cheok MH and Evans WE. Acute lymphoblastic leukemia: a model for the pharmacogenomics of cancer therapy. Nat Rev Cancer, 6:117-129, copyright 2006.