Writing the Next Chapter

For many years, St. Jude researchers have been investigating the connection between genetics and pediatric cancer. Those approaches continue to have dramatic implications for clinical care.

by Mary Powers

Writing the next chapter

More than 25 years have passed since a St. Jude Children’s Research Hospital investigator published the first scientific paper describing a genetic abnormality in a childhood cancer. Now a new generation of researchers is hard at work using modern technology to mine the genome for clues about cancer that can be translated into new and better tools for treating these diseases.

The genome is the complete set of instructions needed to assemble and sustain life. In humans this instruction book is written in the four-letter alphabet of the DNA molecule (T-C-G-A). The estimated 3 billion letters of the human genetic code are organized into 23 chromosomes carried in nearly every cell.

Long before the entire human genetic code was first deciphered, St. Jude investigators were focusing on missteps in that code. In the 1980s, the hospital expanded its efforts to understand the role genetic alterations play in cancer, investing in the faculty, equipment and facilities to take advantage of new technologies that made searching the genome easier. Dr. William E. Evans, St. Jude director and CEO, says that by the 1990s the benefits were evident.

St. Jude investigators made a number of key discoveries about childhood cancers and pharmacogenomics that were diagnostically important and potentially therapeutically important as well,” he says.

The list includes Evans’ own research that showed normal genetic variation could dramatically affect how patients responded to certain drugs.

Pinpointing DNA defects

A recently published study from Evans’ laboratory identified a defect in the DNA repair system. That mistake might leave some young leukemia patients less likely to benefit from a key chemotherapy drug and at greater risk of relapse. Knowledge of the defect might eventually be used to help identify a new group of high risk leukemia patients.

The work focused on a protein named MSH2, which is involved in DNA repair. Earlier work had linked low levels of MSH2 to an increased risk of certain cancers. Low MSH2 was also associated with resistance to mercaptopurine, a drug that is a backbone of childhood acute lymphoblastic leukemia (ALL) treatment.

The most recent study identified the cause of low MSH2 levels. Investigators demonstrated that the MSH2 gene contained no errors and the leukemia cells were making MSH2 protein.

When researchers screened DNA from 90 newly diagnosed ALL patients at nearly 1 million spots in the genome, they found ALL cells from patients with low MSH2 protein were missing at least one of four genes that regulate the breakdown of MSH2 in cells. As a result, the MSH2 was being eliminated more rapidly and the DNA repair system in the leukemia cells operated less efficiently.

A check of the cancer cells of another group of St. Jude ALL patients found that about 12 percent were missing at least one of the same genes involved in the breakdown of MSH2. Scientists also found evidence that one or more of the genes that play a role in MSH2 levels in cells are missing in more than 13 percent of adults with a form of colon cancer and 16 percent with adult ALL.

“If confirmed, this suggests a patient’s MSH2 status might someday be used to guide treatment,” says the paper’s first author, Barthelemy Diouf, PhD, a postdoctoral fellow in Evans’ Pharmaceutical Sciences laboratory.

Improving clinical care

Another recent example of how laboratory research aids efforts to improve clinical care involved the work of Suzanne Baker, PhD, and postdoctoral fellow Barbara Paugh, PhD, both of Developmental Neurobiology; Alberto Broniscer, MD, of Oncology; and their colleagues. The investigators led an international study that explored a different tumor’s genome for insight into that tumor’s biology and wound up with promising new treatment targets.

The study was the largest ever of a rare brain tumor known as diffuse intrinsic pontine glioma (DIPG). The results helped launch a Phase I study of an experimental drug against DIPG and related tumors. That is good news, since survival rates for children with this tumor remain low.

For this study, scientists checked for deletions or additions of genetic material at more than 1 million locations across each tumor’s genome. The results revealed that approximately one-third of the tumors included extra copies of a gene that promotes cell division and survival. A clinical trial using a drug designed to specifically counteract the increased activity associated with excess copies of this gene is currently underway at St. Jude. Other genetic changes identified in these tumors will likely provide the basis for planning additional clinical trials.

Across the St. Jude campus, other researchers are also writing chapters in the history of childhood cancer in the 21st century. Those investigators include Richard Gilbertson, MD, PhD, who heads the hospital’s Comprehensive Cancer Center, Kip Guy, PhD, Chemical Biology and Therapeutics chair; Peter McKinnon, PhD, of Genetics; Mary Relling, PharmD, Pharmaceutical Sciences chair; Charles Mullighan, MD, of Pathology; and James Downing, MD, the hospital’s scientific director, who is also leading the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project.

The next chapter

The past few decades of genomic work helped set the stage for the Pediatric Cancer Genome Project. Launched in 2010, the three-year project aspires to sequence the complete normal and cancer genomes of 600 children and adolescents with some of the most challenging and least understood types of leukemia and tumors of the brain, spine and other cancers of the bone, muscle and connective tissue.

The project is on target to meet that goal, with important discoveries already emerging.

“To date we have completed the sequencing of more than 220 pediatric cancer samples,” Downing says. “A detailed analysis of the data has revealed major new insights into the genetic lesions that underlie some of the most aggressive cancers seen in the pediatric populations, including acute leukemia, brain tumors and solid tumors. These findings will ultimately change the way we diagnose and treat these specific cancers.”

Scientists are using the information to identify changes that play a central role in the tumor’s formation, spread or survival. The answers are revealing new differences between adult and childhood cancers, providing insights into cancer biology and giving clues about novel ways to use existing chemotherapy agents. The lessons learned will likely help lay the foundation for a new era of personalized therapy.

“When it comes to cancer, we still do not know which genes are the bad actors or the most important mutations in genes or even the genes that are mutated in most cancers,” Evans says. In the coming months and years, more exciting discoveries are sure to occur—advancements that will continue to offer patients around the world reasons for hope.

Promise magazine, Winter 2012

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