In 1962, St. Jude Children’s Research Hospital opened its doors amid an emotionally charged debate regarding how to treat childhood cancer. At that time, few children with the most common form of childhood cancer survived, and many physicians believed treatment was futile.

St. Jude physicians and researchers took a radically different approach, and these efforts proved pivotal in changing the way the world treats childhood cancer. St. Jude is recognized for playing a significant role in improving overall survival rates for childhood cancer, which have increased from 20 percent in 1962 to 80 percent today.

In recognition of this impact over the past 50 years, Tennessee Gov. Bill Haslam declared February “St. Jude Month” in the state of Tennessee. Founded by the late entertainer Danny Thomas, the hospital opened February 4, 1962.

“In the nearly four decades I’ve been at St. Jude, I’ve had the privilege of watching the organization grow from one star-shaped building to a sprawling campus of about 2.5 million square feet of research, clinical and administrative space,” said Dr. William E. Evans, St. Jude director and CEO.

“When I started, there were a few hundred people on staff. Now we have more than 3,700 employees. Driven by our patients, and thanks to our employees, our colleagues at ALSAC and the public support they generate, St. Jude will only continue to grow and flourish in the years to come.”

The history of St. Jude is marked with milestones in the treatment of pediatric cancer and other childhood illnesses. In 1971, St. Jude investigators showed that the combination of chemotherapy and radiation cured at least half of all children with acute lymphoblastic leukemia (ALL).

The most common form of childhood cancer, ALL, was previously considered almost universally fatal. Today, St. Jude patients with ALL have a 94 percent survival rate. In 1984, a St. Jude patient with sickle cell disease was the first to be cured with a bone marrow transplant.

St. Jude is currently engaged in the largest effort in the world to do whole genome sequencing of pediatric cancer tumors. The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project collaboration has already produced significant new findings related to aggressive forms of pediatric leukemia, eye tumors and brain tumors.

“St. Jude has a legacy of taking on the toughest of pediatric cancer questions, and that focus won’t change,” said James R. Downing, M.D., scientific director and deputy director at St. Jude. “We’re uniquely positioned as an institution to move research and treatment ahead. From the genetic data we collect from the genome project, we’re creating the foundation of knowledge to deliver the next decades’ childhood cancer discoveries and treatments.”

Throughout its five decades, St. Jude research has included work in cancer biology and genomics, pharmacogenomics, gene therapy, bone marrow transplant, drug discovery, radiation treatment, blood diseases and infectious diseases, integrated into a long series of innovative clinical trials.

According to Joseph Laver, M.D., St. Jude clinical director, “the unsurpassed family-centered care that is provided at St. Jude stems from the multidisciplinary team approach that has been a hallmark of St. Jude since the doors opened in 1962.”

“Looking toward the future, St. Jude is a national resource with a global mission and will continue to enhance its leadership as a resource for children with cancer and other catastrophic diseases,” Evans said. “Even though we’ve grown significantly, our mission has never wavered.

We’ve created a collaborative culture whose team members demonstrate unceasing compassion for our patients and families, innovation in our treatment and research, and quality in everything we do.”

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Researchers have discovered that a subtype of leukemia characterized by a poor prognosis is fueled by mutations in pathways distinctly different from a seemingly similar leukemia associated with a much better outcome. The findings from the St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project highlight a possible new strategy for treating patients with this more aggressive cancer.

The work provides the first details of the genetic alterations fueling a subtype of acute lymphoblastic leukemia (ALL) known as early T-cell precursor ALL (ETP-ALL). The results suggest ETP-ALL has more in common with acute myeloid leukemia than with other subtypes of ALL. The study appears in the January 12 edition of the journal ‘Nature’.

ALL is the most common childhood cancer and about 12 percent of patients have T-ALL. T-ALL arises from T-lineage white blood cells that make up one branch of the immune system. ETP-ALL was discovered by St. Jude researchers and accounts for about 12 percent of T-cell ALL. Many ETP-ALL patients fail to respond to current therapy and never enter remission. Only 30 to 40 percent of these patients become long-term survivors, compared to about 80 percent of children battling other T-ALL subtypes.

“The mutations and gene expression profile we identified in this study suggest that patients with ETP-ALL might benefit from treatment that includes drugs developed for treatment of acute myeloid leukemia,” said Charles Mullighan, M.D., Ph.D., an associate member of the St. Jude Department of Pathology and one of the study’s corresponding authors.

Mullighan said ETP-ALL was selected for inclusion in the pediatric cancer genome project due to the poor outcome and the lack of information on the genetic lesions that underlie this aggressive subtype of leukemia. “St. Jude is a pioneer in increasing overall ALL survival rates, which today exceed 90 percent for St. Jude patients. Now, we are working toward similar progress against this rare form of the disease,” he said.

The human genome is the complete set of instructions needed to assemble and sustain human life. Leukemia and other cancers develop when normal cells accumulate mutations in the genome that cause the unchecked cell growth that is a hallmark of cancer. The three-year Pediatric Cancer Genome Project is sequencing the genomes of tumor cells and matched normal DNA samples of 600 children with some of the most poorly understood and aggressive cancers. Investigators believe the findings will be the foundation for the next generation of clinical tools.

For this study, researchers sequenced and analyzed the normal and cancer genomes of 12 St. Jude patients with ETP-ALL. Investigators then checked for some of the same mutations in an additional 94 young leukemia patients with either ETP-ALL or other types of T-cell ALL.

“We found mutations unique to ETP-ALL that are not seen in other forms of ALL,” said co-author Richard Wilson, Ph.D., director of The Genome Institute at Washington University. “The results provide new targets for therapy and a way to use genetic tests to identify ETP-ALL patients early and earmark them for more aggressive therapy.”

The pattern of mutations identified in ETP-ALL was reminiscent of changes associated with AML, Mullighan said. The alterations were concentrated in genes in the cytokine receptor and RAS signaling pathways that are involved in the type of cell regulation disrupted in cancer. The mutations, which included NRAS, FLT3, JAK3, IL7R, and other genes, were found in about 67 percent of patients with ETP-ALL, but in only 19 percent of other T-ALL patients.

In addition, mutations in genes known or predicted to disrupt normal development of blood stem cells or lymphocytes were identified in 58 percent of ETP-ALL patients, but in just 17 percent of other T-ALL patients. The affected genes included ETV6, RUNX1, IKZF1, and GATA3. GATA3 helps regulate the early stages of T cell development, and mutations in the gene were found exclusively in ETP-ALL patients.

Epigenetic mutations, which are alterations affecting genes that indirectly influence the activity of other genes, were also more common in ETP-ALL patients. These genes, including EZH2 and SUZ12, were mutated or deleted in 45 percent of ETP-ALL patients, but in just 11 percent of the comparison group. The targeted genes modify proteins known as histones, which control gene activity through DNA binding.

Researchers also showed that ETP-ALL includes recurring mutations in about a half-dozen genes not previously linked to blood cancers. The list includes the genes RELN and DNM2. “The pattern of mutations we found in those genes suggests they function as tumor suppressors and their loss contributes to the malignant transformation of developing blood cells,” Mullighan said.

Mullighan said work is underway to develop laboratory models of human ETP-ALL and to use these models to identify AML drugs that are most likely to benefit ETP-ALL patients. The list of possible drugs includes high-dose cytarabine and targeted chemotherapy agents that inhibit activity in the cytokine receptor and JAK signaling pathways found in this study to be disrupted in ETP-ALL patients, researchers said. Those pathways help regulate cell division and normal development of the blood system.

“This is the first of a series of important discoveries on the genomic basis of childhood cancers that are emerging from the Pediatric Cancer Genome Project, which is on schedule to fully sequence 600 pediatric cancer genomes by 2013,” said Dr. William E. Evans, St. Jude director and CEO.

James Downing, M.D., St. Jude scientific director, St. Jude PCGP site leader and a corresponding author of the study, added, “This study highlights how the genome project is generating new insights into the genetic alterations that underlie some of the most aggressive childhood cancers and in turn is pointing us toward new therapeutic options that may increase the survival rates for children with these cancers.”

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