Issue 7 : June, 2012

Supported in part by the National Cancer Institute (NCI), the Children’s Oncology GroupOpens in a New Tab (COG) is the world’s largest organization dedicated to pediatric cancer research. Since 1955, the COG has made tremendous advances in reducing pediatric cancer mortality through highly-collaborative translational and clinical research. The Office of Cancer Genomics (OCG) is currently working with COG investigators through the Therapeutically Applicable Research to Generate Effective TreatmentsOpens in a New Tab (TARGET) initiative. For this issue of OCG’s e-News, we asked the Chair of COG, Dr. Peter Adamson, to comment on the current status of pediatric cancer research and what COG is doing to build upon its successes over the last 50 years in childhood cancer cure rates.

About Dr. Peter Adamson

Aside from his COG Chair responsibilities, Dr. Peter Adamson is a pediatric oncologist and investigator at the Children's Hospital of Philadelphia (CHOP). Dr. Adamson currently heads a clinical pharmacology laboratory at CHOP that seeks to find new drugs for childhood cancers using pre-clinical and early-phase clinical trial research. Prior to his election to COG Chair in 2011, he served as the Director of the Office for Clinical and Translational Research and Chief of the Division of Clinical Pharmacology and Therapeutics at CHOP. Dr. Adamson received an M.D. from Cornell University Medical College before he received his pediatric oncology training, as well as his research training in drug development and clinical pharmacology, at the NCI. Read his interview below.

Can you describe the childhood cancer clinical trial process and how it compares to the adult cancer process?

What is distinctive about pediatric oncology is that the large majority of children with cancer participate in clinical research. Over 60 percent of children who are newly-diagnosed with cancer will enroll in a clinical trial, in contrast to only 2-3 percent of newly-diagnosed adults. Pediatric oncology is a unique subspecialty where close partnerships with children and their families go hand-in-hand with clinical practice and research.

Despite its widely collaborative approach to clinical trials research, the COG faces many specific challenges. To begin, childhood cancers occur infrequently when compared to adult cancers, so they are considered to be rare tumors. Furthermore, the majority of childhood cancers are curable, leaving a small population of children with cancers that are resistant to treatment and who are appropriate for early phase clinical trials of novel agents. The low frequency of these particularly serious cancers makes studying them especially difficult, despite needing the greatest improvements in outcome.

Phase III trials are largely available to most newly-diagnosed patients. However, with few exceptions, Phase I and II trials primarily enlist children with relapsed or resistant cancers. The cooperative infrastructure of the COG allows us to maximize our ability to conduct these studies, but small cohorts remain a challenge.

Additionally, drug companies develop novel drugs almost exclusively for adult rather than childhood cancers, which is an understandable market-based decision. We get around this limitation by using adult clinical trials to inform the design of pediatric trials. Even though drugs behave differently in children than adults, we can learn from adult Phase I trials which new drugs have the most potential to be efficacious in treating childhood cancers as well. Of note, developing appropriate dosages for children of various sizes and stages of development is not a trivial task. Growth and development of children have considerable impact on the clinical pharmacology of a drug, how we dose that drug and what interactions we might see.

There are many shared challenges among pediatric and adult cancer research, especially in Phase II clinical trials. In general, we study new drugs in patients whose tumors have recurred and are, therefore, more likely to be resistant to multiple forms of therapy. In treating these cancers, some drugs may be efficacious only when combined with other cytotoxic drugs or other targeted agents, making the design of those trials much more difficult.

Are targeted therapies having an impact on treating pediatric cancers?

Imatinib (Gleevec) has made a dramatic impact on the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), but we are still evaluating the efficacy of most targeted therapies in the pediatric population, particularly in the Phase I/II trial stage. Consequently, it’s too early to know if others will significantly reduce mortality, but I do think there will be subsets of patients that will benefit.

How does COG work with TARGET and other genomics research programs to fulfill its mission?

Programs like TARGET are accelerating our ability to hone our clinical trial decisions and prioritize new therapeutic agents in the treatment of certain pediatric cancers. COG is so tightly integrated with TARGET that any new discoveries are quickly translated into clinical trials. The most recent advances include the identification of a subpopulation of ALL patients with mutations in the Janus kinase (JAK) pathway, where JAK inhibitors may prove successful in treating that disease. When the JAK story broke from TARGET, COG was well-positioned to rapidly begin pediatric Phase I testing of the first JAK inhibitor already available in the clinic for adult cancers. TARGET research is helping to define both biologically compelling and druggable targets.

Genomics research has proven useful in understanding, classifying and treating many cancers, but now we are finding many genomic alterations don’t lead to obvious treatments (either no known drugs are available or they don’t provide a straightforward targeting strategy). How is COG addressing this issue?

We do not have a magical solution. Fortunately, the prevalence of mutation in many pediatric cancers (especially those arising early in development) is low, making development of targeted agents against childhood cancers easier than in adult cancers, where the mutation rate is usually high. However, there are some childhood cancers, such as osteosarcoma, with very complicated genomic abnormalities, and therapeutic targeting is therefore more complicated. Despite this hurdle, we think there is likely to be continued value in these genomic studies. Some insights and discoveries that emerge from childhood cancer research are applicable in the adult population. The classic example is retinoblastoma and the Rb gene. Aside from its involvement in an extremely rare childhood cancer, we now know it also plays a role in the malignant transformation of a number of adult cancers.

Genomic research is uncovering the immense molecular complexities of cancer, sub-dividing each cancer type into ever smaller subtypes. How is the discovery of smaller molecular subtypes affecting clinical outcomes and the projected rate of decline of pediatric cancer mortality? What is COG doing to address this challenge in the design of its clinical trials research?

In order to make advances, we must balance the need for improved efficiency with the potential for risk to the patient. Our strategy is to have platforms and protocols that allow for continuous evaluation of novel therapeutics. To that end, we are comparing the efficacy of new targeted therapies in combination with standard cytotoxic drugs to that of standard drugs alone. So, in evaluating treatment of a number of relapsed cancers, we begin with the standard cytotoxic “backbone” of chemotherapies and then integrate a range of targeted agents either in a randomized or sequential fashion. We keep these backbone studies open and ongoing, so that whenever a new targeted therapy arises, we are ready to implement it into a clinical trial. This trial design gives us the flexibility to evaluate different types of agents as quickly as possible for their effect on clinical outcome.

We are also beginning to look at approaches that others have taken with adult cancers. One good example is I-SPY 2 (investigation of serial studies to predict therapeutic response with imaging and molecular analysis) and its application of the Bayesian predictive probability model. The goal of the I-SPY 2 trial is to improve the efficiency in identifying better treatments for patient subpopulations using distinct molecular signatures.

What factors contributed to the success in greatly reducing pediatric cancer mortality over the last 50 years? And, what is COG focusing on now to continue to reduce pediatric cancer mortality, despite the recent plateau in improvement?

The fundamental factors contributing to our success are collaboration and the importance of research. Fifty years ago, the predecessors of the COG set the stage for the field of pediatric oncology by developing a cooperative group system, where a culture of collaborative research flourished. Now, most children diagnosed with cancer today are offered an opportunity to participate in research.

The drugs that we use now to treat most cancers cure approximately 4 out of 5 children. However, most of these drugs were approved in the 1950s – 1970s. We’ve learned how to use these chemotherapies better over time, but I think we’ve gotten as much mileage as we can from them. Now, there is a pressing need to develop novel therapeutics. COG is moving in this direction by studying the biology of tumors and linking that to outcome. At COG sites, we see about 90 percent of newly-diagnosed children in the US. So, in a population-based way, we have an opportunity to capture the biology and outcome through well-annotated clinical biospecimens for every cancer – even rare or relapsed cancers or cancers refractory to current treatment. We are putting our greatest investment into researching the population of tumors in children where current treatments have not proven curative. Through well-annotated biospecimens and translational research of hard-to-treat cancers, we are setting the stage for the next era of discovery.

Dr. Richard Harvey, a TARGET investigator studying high-risk acute lymphoblastic leukemia, is a research professor in the Department of Pathology at the University of New Mexico’s School of Medicine.

The seminal discovery in 1960 of the Philadelphia chromosomeOpens in a New Tab (Ph+) in chronic myelogenous leukemia was a catalyst for decades of research that has resulted in the discovery of hundreds of unique genomic alterations in human cancer. In Ph+ patients with the tumor-specific BCR-ABL1 fusion product, the aberrant expression of the fused Abl tyrosine kinase has proven to be an initiating genomic event in the development of leukemia.^[1] Similar gene perturbations, whether by deregulation or modification (e.g., rearrangement, alternative splicing or mutation), have subsequently been shown to be recurring events in many leukemias.^[2] Successful therapies directed against these initiating genomic events (such as the tyrosine kinase inhibitor, imatinib, for BCR-ABL1) have begun to refocus the field from simply identifying genomic alterations as potential screening tools, to understanding their functional consequences and applying appropriate targeted therapies. In parallel with developing these new therapies, it remains crucial that we continue to focus our efforts on identifying effective diagnostic markers. Predicting an accurate prognosisOpens in a New Tab and assigning an appropriate treatment regimen through diagnostic screening tools can reduce both the burden of uncertainty and cost in cancer management. Together, diagnostic markers and targeted therapies will help to revolutionize cancer outcomes.

As part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)Opens in a New Tab high-risk acute lymphoblastic leukemiaOpens in a New Tab (ALL) project, our research group seeks to cure pediatric high-risk ALL by employing and integrating a variety of molecular approaches. Our initial gene chip analysis in these patients revealed clearly distinct signatures of gene expressionOpens in a New Tab, several of which were characteristic of previously identified chromosomal translocationsOpens in a New Tab (e.g., TCF3-PBX1, MLL, ETV6-RUNX1). We also observed a novel signature comprised of a group of highly expressed genes that had previously been identified as overexpressed in many Ph+ ALL patients.^[3] Curiously, none of the patients in our high-risk ALL patient cohort harbored the Ph+ translocation, yet patients with this signature had a similarly poor prognosis. Concurrent with the expression analysis, our colleagues in this project performed a detailed analysis of the DNA in these patients and found they also exhibited deletions within the IKZF1 gene, another hallmark of ALL patients with Ph+ translocations.^[4] Because of the extensive molecular similarities with Ph+ patients, we refer to this group of ALL patients as Philadelphia chromosome-like, or “Ph-like.”

With these results in hand, we performed more in depth genomic analysis of the Ph-like ALL patients in order to uncover the inherent biology and to identify, if possible, candidate therapeutic targets. Our analysis revealed that this subset of patients had an overall similar gene expression signature, yet was comprised of numerous subgroups with different underlying genomic features. Approximately half of the Ph-like patients harbor a cryptic translocation or rearrangement of the type I cytokine receptor subunit gene (CRLF2), with about half of these CRLF2 subtypes also harboring activating mutations of JAK1 or JAK2 tyrosine kinasesOpens in a New Tab.^[5] Most recently, sequencing of RNA and DNA from a dozen of these Ph-like cases has shown that essentially all of them have cryptic translocations involving tyrosine kinases (ABL1, JAK2), tyrosine kinase receptors (PDGFRB), cytokine receptors (CRLF2, EPOR) and/or deletions involving IKZF1 and mutations of JAK2.^[6] Recurrence testing is ongoing to determine the relative frequency of each of these other translocations, however it is quite apparent that the vast majority of the Ph-like cases share a common underlying theme of tyrosine kinase gene/pathway deregulation.

Despite the absence of the BCR-ABL1 fusion, the repeated involvement of tyrosine kinase genes in Ph-like cases (including other translocations of ABL1 itself) strongly suggest they will be amenable to similar therapeutic approaches targeting their aberrant tyrosine kinase pathways. As mentioned previously, adding the kinase inhibitor, imatinib, to an intensive chemotherapy regimen in children with Ph+ ALL dramatically improved their outcomes.^[7] Recently, we have begun pre-clinical studies using xenograftOpens in a New Tab mouse models that mimic a variety of Ph-like cases in an effort to identify therapeutic agents that might be effective in patients with the Ph-like signature. In parallel with these studies, we continue to focus on developing and improving screening methods to identify these patients at the time of diagnosis. Although their full characterization required gene expression, copy number analysis, cytogenetic analysis and sequencing, identification of the Ph-like gene expression signature alone appears to be sufficient as an initial first screening.^[8] Because the core of the signature is comprised of just a couple of dozen genes, it is quite amenable to rapid and relatively inexpensive clinical platforms for quantitative gene expression analysis. Subsequent characterization of the exact underlying lesions, if necessary, will likely require additional targeted sequencing or PCR analysis.

Through collaborative and integrated molecular evaluations of gene expression, mutations, copy number alterations, functional analysis and related methods, we have found that many of the high-risk pediatric ALL patients with the poorest outcome share perturbations of common pathways. It is imperative that we quickly translate this information into the clinic for the benefit of all patients that suffer from this disease. It is now possible to rapidly identify patients with the Ph-like signature at the time of diagnosis and stratify them into appropriate therapeutic regimens targeted for their particular underlying lesions. The general perturbation of common tyrosine kinase pathways in these patients is encouraging from a therapeutic perspective. Rather than having to target tumor-specific events (such as fusion genes) individually, it bodes well for targeting therapy towards a common aberrant pathway across these poor-outcome leukemias.

References

1. Heisterkamp N, Jenster G, ten Hoeve J, Zovich D, Pattengale PK, Groffen J. Acute leukaemia in bcr/abl transgenic mice. Nature. 1990;344(6263):251-253.
2. Nambiar M, Kari V, Raghavan SC. Chromosomal translocations in cancer. Biochim Biophys Acta. 2008;1786(2):139-152.
3. Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874-4884.
4. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480.
5. Harvey RC, Mullighan CG, Chen IM, et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B-progenitor acute lymphoblastic leukemia. Blood. 2010;115(26):5312-5321.
6. Roberts KG, Morin R, Zhang J, et al. Novel genetic alterations activating kinase and cytokine receptor signaling in high risk acute lymphoblastic leukemia. Cancer Cell. 2012;submitted.
7. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol. 2009;27(31):5175-5181.
8. Czuchlewski DR, Harvey RC, Chen I-M, et al. Quantitative RT-PCR for Expression of a Small Subset of Genes Identifies Novel Prognostic Subgroups in High-Risk Pediatric Precursor B-Cell Acute Lymphoblastic Leukemia (HR-ALL): Clinical Applicability of Gene Expression Microarray Data from Children's Oncology Group Trials. ASH Annual Meeting Abstracts. 2008;112(11):1514-.