lunes, 3 de octubre de 2016

Fueling Progress Against Childhood Leukemia - National Cancer Institute

TARGET Initiative Fueling Progress Against Childhood Leukemia

09/30/2016

Research from an NCI-funded program studying a group of rare and hard-to-treat childhood cancers has set the stage for two Children’s Oncology Group-led clinical trials that are evaluating new treatment options for children with acute lymphoblastic leukemia (ALL).

The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative is a large, multinational, collaborative effort to conduct comprehensive genomic analyses of select pediatric cancers. The TARGET initiative’s goal is to identify the molecular changes that drive these cancers and, consequently, to lay the foundation for the development of new therapies or approaches that target these molecular alterations.

TARGET Initiative Fueling Progress Against Childhood Leukemia

September 30, 2016 by NCI Staff

The Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative is a large, multinational, collaborative effort to conduct comprehensive genomic analyses of select pediatric cancers. The TARGET initiative’s goal is to identify the molecular changes that drive these cancers and, consequently, to lay the foundation for the development of new therapies or approaches that target these molecular alterations.

“The TARGET ALL project started as a proof-of-concept for genomic investigations of pediatric cancer,” said Daniela Gerhard, Ph.D., NCI co-director of TARGET. “It has since evolved into a highly productive collaboration that resulted in extensive genomic analyses which help explain much of the genomic underpinnings of this childhood cancer.”

Genomic analyses of tumors from children with high-risk ALL led TARGET researchers to identify a distinct subtype of this cancer, called Philadelphia chromosome-like (or Ph-like) ALL. Subsequent studies revealed that Ph-like ALL tumors often contain specific genetic alterations that may make them susceptible to existing targeted therapies.

Two clinical trials are now accruing patients to evaluate two of these targeted therapies in children with this ALL subtype.

“TARGET is an example of how genomic analysis and collaborative science can contribute to precision oncology approaches to better treat childhood cancers,” said Malcolm Smith, M.D., Ph.D., NCI co-director of TARGET.

Team Science Approach

TARGET was initiated approximately 10 years ago with two pilot projects to study genomic alterations in high-risk subtypes of childhood ALL and neuroblastoma. The success of the pilot projects allowed the program to expand to include additional subtypes of these cancers, as well as new projects focused on subtypes of childhood acute myeloid leukemia(AML), select childhood kidney tumors, and osteosarcoma.

The program’s expansion coincided with a “technological revolution” in genomic sequencing, said Stephen Hunger, M.D., of the Children’s Hospital of Philadelphia, principal investigator of the TARGET ALL project. The availability of more comprehensive sequencing techniques allowed scientists to generate and analyze data from patients’ entire genomes instead of just a few hundred genes, he explained.

TARGET project teams include clinicians, pathologists, scientists, and bioinformaticists from NCI, universities, cancer centers, and children’s hospitals across the country. Many of the investigators are members of COG, a large NCI-funded pediatric and adolescent cancer clinical trials group.

Patient samples for TARGET projects are obtained primarily from children enrolled in COG clinical trials or standard treatment protocols. The high quality of samples, paired with detailed clinical information, enhances the ability of TARGET researchers to perform integrated analyses. In addition, the connection with COG “greatly accelerates clinical translation of TARGET-supported research,” said Jaime Guidry Auvil, Ph.D., scientific program manager for TARGET.

“Without this group effort, everybody bringing complementary skills to the table, we never could have been this successful. To me that’s a great model, because I don’t think one can succeed in a vacuum,” agreed Dr. Hunger.

Lessons on Childhood ALL

TARGET and other genomic studies have highlighted the fact that “pediatric and adult cancers are often different at the molecular level, even when they occur in the same organ,” said Dr. Guidry Auvil. A major difference is that pediatric cancers have fewer overall mutations than adult cancers, and the mutations may occur in different genes or at varying frequencies, she explained.

For example, TARGET researchers reported that variations in outcome and treatment response among young adults, adolescents, and children with ALL may be attributable to critical differences in the underlying biology of their tumors.

“Because of their distinct genomic characteristics, pediatric cancers require a different treatment approach than adult cancers, one that includes the application of precision medicine principles,” said Dr. Smith.

Even though most pediatric cancers have a small number of mutations, TARGET researchers have demonstrated that identifying genetic drivers of these cancers can provide a better understanding of their underlying biology and can potentially lead to the discovery of precision treatment strategies.

Their studies of the Ph-like ALL subtype is a perfect example, Dr. Hunger said. In 2009, he and his colleagues discovered Ph-like ALL, a high-risk subtype of ALL marked by a gene expression pattern similar to that of another subtype, Philadelphia chromosome positive (Ph+) ALL. Unlike Ph+ ALL, however, Ph-like ALL lacks the characteristic gene fusion—which results from shifts in DNA that join parts of two different genes—called the Philadelphia chromosome.

But, their subsequent analyses revealed that several different fusion genes are present in Ph-like ALL tumors. “That discovery opened up the opportunity for targeted therapy,” Dr. Hunger said.

Using laboratory tests, the team showed that tumor cells carrying the proteins produced by these fusion genes grew at a much faster rate and could be killed with FDA-approved drugs that target the hybrid proteins, including ruxolitinib (Jakafi®) and dasatinib (Sprycel®).

Through the collaboration with COG, these findings have led to the development of two clinical trials. COG is using a diagnostic test to identify pediatric patients with Ph-like ALL and subsequent tests to determine if certain targetable fusion genes are present in the patient’s cancer. The presence of certain fusion genes could make a patient eligible for participation in a trial testing the combination of chemotherapy and dasatinib, or througha different trial, chemotherapy with ruxolitinib.

Continued Learning

These discoveries about pediatric ALL “are just the tip of the iceberg of what we’ve learned from TARGET,” said Dr. Gerhard. The other TARGET projects are in their final stages, and their respective research teams will continue to analyze data and publish new findings that could help COG establish new clinical trials and improve patient outcomes, she continued.

The research community can continue to build off of these findings, Dr. Gerhard noted. TARGET has recently released data amassed from each of the disease projects. The data is accessible, in ways that protect patient privacy, through the Genomic Data Commons, Data Matrix, and other sites.

Through the impact of its research and the availability of the associated data, Dr. Smith said, TARGET “has and will continue to influence our understanding and treatment of these pediatric cancers for many years.”