World Cancer Day 2014, State of the Science at St. Jude Children’s Research Hospital
Accomplishments at St. Jude Children’s Research Hospital since last World Cancer Day are giving us new insights into the origins and possible treatment of the many and varied cancer subtypes and include published discoveries in genomics, pharmacogenomics, immunology and long-term survivorship. Highlights of research at St. Jude include:
Cancer’s Subtype Complexity
- Efforts to push the overall survival rate beyond 80 percent and improve the quality of life for long-term survivors of childhood cancer depend in part on advancing understanding of the genetic alterations responsible for different pediatric cancer subtypes.
- St. Jude remains a leader in those efforts. Examples from the past year include a study that provided the first evidence of the genetic basis for a high-risk pediatric leukemia subtypes known as hypodiploid acute lymphoblastic leukemia (ALL). Patients with this cancer have fewer than 44 chromosomes, rather than the 46 carried in normal human cells.
- In another study from the Pediatric Cancer Genome Project, researchers identified mutations in two genes that occurred almost exclusively in a subtype of childhood brain tumor with a poor outcome. The study offered the first clues about the alterations that give rise to the brain tumor subtype known as diffuse low grade glioma. Not only did the findings provide important insight into the genetic missteps that give rise to different childhood cancer subtypes, but also pointed investigators to promising new drugs.
- Researchers found that an inherited gene variation is tied to high-risk leukemia and an increased risk of relapse.
- Another study showed that a rare, inherited mutation leaves children susceptible to acute lymphoblastic leukemia.
- Scientists linked inherited variations in a few genes to increased risk of acute lymphoblastic leukemia, which helps explain why Hispanic children have a higher incidence of this cancer.
- Additional research showed that inherited variation in the gene GATA3 explains why some children are at a higher risk of to develop a newly-defined subtype of acute lymphoblastic leukemia (Philadelphia-chromosome-like), and to explain racial and ethnic differences in the frequency of that subtype.
- St. Jude is transforming the understanding of the genetic basis of pediatric cancer and is improving the ability to accurately diagnose, stratify risk and treat children with cancer based on the results from our Pediatric Cancer Genome Project (PCGP). This massive study has completed whole genome sequencing of more than 700 children with cancer, comparing their cancer genome to their healthy DNA. With this new information, St. Jude scientists are now developing a rigorously-tested approach for incorporating this cancer genome sequencing data into routine patient care.
- Gene therapy developed by St. Jude is currently being studied in a clinical trial for treatment of adult patients with hemophilia B and is the first to show long-term correction of a single-gene disorder. This clinical trial, which involves St. Jude and collaborators at the University College London, relies on a vector to deliver the correct version of a gene for making the blood clotting protein Factor IX. The vector was pioneered and until recently produced exclusively at St. Jude in the institution’s GMP facility. The current trial is for adults and is currently open for enrollment.
- St. Jude researchers identified an enzyme that can halt or possibly even reverse the build-up of toxic protein fragments known as plaques in the brains of mice with Alzheimer’s disease. Loss of the neuraminidase 1 (NEU1) activity is associated with plaque building up in the brain. Using gene therapy to increase activity of the NEU1 enzyme, researchers found that the plaques declined dramatically in the brains of treated mice. The results raise hope the enzyme could lead to new methods of diagnosing and treating Alzheimer’s disease in humans.
- The best treatment of some childhood cancers may vary depending on the individual’s inherited genome, the genomic fingerprint of their specific cancer, and the molecular markers that can predict a child’s likelihood of successfully responding to medications or identify those medications potentially deadly to a child.
- While “personalized medicine” has become a buzzword in medicine, St. Jude is laying the scientific foundation to make it a reality through the PCGP and the ongoing PG4KDS study. Blood samples from nearly 1,500 enrolled patients have been checked for variations in 225 genes that play a role in how an individual responds to drugs. The first four genes results are currently reported in St. Jude patient medical records so that clinicians factor those results into prescribing decisions in routine care using computer tools developed for the study.
- The immune system of mammals is composed of a plethora of specialized cell types whose functions are key in protecting the body from invading pathogens and other attacks. These cell types can be broadly categorized by the nature of their immunological response: innate or adaptive immunity. Innate immunity is the first, immediate line of defense against invading pathogens, while adaptive immune responses take longer to develop.
- Scientists identified an immune system marker tied to improved bone marrow transplant outcomes. Researchers found that the risk of death following bone marrow transplantation can be reduced about 60 percent using a new technique to identify bone marrow donors who make the most potent cancer-fighting immune cells.
- Another study outlined how a genetic mutation might lead to a promising new treatment for autoinflammatory diseases. In this study, researchers not only solved the mystery of how mutations in the SHP-1 gene lead to a variety of inflammatory and autoimmune disorders, but have also identified a drug that protected against an inflammatory skin disease in a mouse model, findings which could have significant therapeutic implications for humans.
- One of the great cancer success stories is how scientists and clinicians have vastly improved cure rates for many childhood cancers. But as the number of children who survive cancer age into and through adulthood, we are now identifying the potential adverse long-term effects of those treatments.
- Following more than 1,700 adult survivors of childhood cancers, St. Jude found thesesurvivors experience significant undiagnosed, serious disease as adults. In one landmark study, St. Jude researchers found that by 50 years of age, the vast majority of childhood cancer survivors will have a serious, disabling or life-threatening chronic health condition.
- One recent milestone study found that adult survivors of childhood cancer are much more likely to age prematurely, becoming much more frail than their peers without cancer. This leaves survivors at increased risk of death and chronic disease.
- Another study was one of the first to focus on how certain lifestyle risk factors, such as hypertension, diabetes, obesity and elevated blood lipids contribute to cardiovascular disease specifically in childhood cancer survivors. The research concentrated on risk factors that can often be modified with diet, exercise and other lifestyle changes, offering childhood cancer survivors can take charge of their own health to minimize their chances of developing cardiac problems.
- These studies and findings were possible because St. Jude brings many of its cancer patients back for regular and extensive medical assessments. This continuing follow up provides critical prospective data on the health of childhood cancer survivors and may continue to yield important insights.