From the cloud to the clinic, wide range of St. Jude research presented at AACR 2018
Cloud computing, "exhausted" T cells, breast cancer risk in childhood cancer survivors and clinical trial design for CAR-T therapy in solid tumors are among the topics St. Jude Children's Research Hospital investigators will discuss at the five-day American Association for Cancer Research annual meeting that begins Saturday, April 14, in Chicago.
Secure sharing and collaborative analysis of huge datasets are essential in the quest to discover cures for pediatric cancer. Scott Newman, Ph.D., group lead for bioinformatics analysis in the St. Jude Department of Computational Biology, will present St. Jude Cloud, a new publicly available data-sharing and collaboration platform. His talk is set for 3:05 p.m., Sunday, April 15, in Room N228, Level 2 of McCormick Place North. Abstract: 922
St. Jude Cloud is the world's largest public repository of pediatric cancer genomics data and also provides unique analysis tools and visualizations. The platform was developed by scientists at St. Jude in collaboration with Microsoft and DNAnexus. St. Jude Cloud allows scientists to explore more than 5,000 whole-genome (WGS), 5,000 whole-exome (WES) and 1,200 RNA-Seq datasets from more than 5,000 pediatric cancer patients and survivors. By 2019, 10,000 whole-genome sequences will be available on St. Jude Cloud.
Along with the presentations detailed below, St. Jude faculty and staff will also chair major symposiums, give educational talks and participate in forums and sessions on hereditary cancer surveillance and the regulatory horizon for development of CAR-T therapy for solid tumors.
April 14 Education Sessions
Paul Northcott, Ph.D., of the St. Jude Department of Developmental Neurobiology, will give a 1:30 p.m. talk about subgroup-specific enhancer hijacking in the brain tumor medulloblastoma. The talk is part of the "Hijacking the Epigenome in Cancer: Challenges and Opportunities" session set for Room N427, Level 4, McCormick Place North.
Suzanne Baker, Ph.D., of the St. Jude Department of Developmental Neurobiology, will give a 2 p.m. talk about cell context and consequence of oncogenic histone mutations in pediatric gliomas. The talk is part of a session titled "Genetic, Epigenetic and Cellular Context Driving Pediatric Brain Tumor Development," which will be held in Room S402, Level 4, McCormick Place South.
Zoran Rankovic, Ph.D., of the St. Jude Department of Chemical Biology and Therapeutics, will give a 3:15 pm. talk about the challenges and principles of drug design in neuro-oncology. He will speak at a session titled "From Chemistry to the Clinic: Part 3 – Approaches to Drug Design for Neuro-oncology," which will be held in Room S103, Level 1, McCormick Place South.
CAR-T therapy for solid tumors
Scientific and regulatory challenges for developing CAR-T therapy for treatment of solid tumors will feature Stephen Gottschalk, M.D., chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. The session will include an update on CAR-T therapy for sarcoma, brain and other solid tumors. The event is set for 10:30 a.m., Monday, April 16, Room S401bcd, Level 4, McCormick Place South.
Surveillance in hereditary cancer
The National Cancer Institute estimates inherited mutations play a role in 5 to 10 percent of cancers, and more than 50 cancer predisposition syndromes have been identified. The debate continues about how best to monitor individuals with the syndromes, which can affect multiple organs. This session will include Kim Nichols, M.D., a member of the St. Jude Department of Oncology and director of the Cancer Predisposition Division. The forum is set for 5 p.m., Monday, April 16, Room N227, Level 2, McCormick Place North.
Researcher tracks his discovery from the bench to the bedside
More than 25 years ago, research led by Charles Sherr, M.D., Ph.D., yielded a discovery that today is helping cancer patients live longer. Sherr chairs the St. Jude Department of Tumor Cell Biology and is a Howard Hughes Medical Institute investigator. In 1991, Sherr and his colleagues discovered the cyclin D proteins and, one year later, identified cyclin D-dependent kinase 4 (CDK4), a key enzyme that regulates cell proliferation. Cyclin D-dependent CDK6 was discovered in 1994.
Today three FDA-approved CDK4/6 inhibitors are prolonging survival of patients with advanced breast cancer and are also in clinical trials for treatment of many other cancers. At the AACR meeting, Sherr will chair a major symposium on CDK inhibitors and will present an overview of how CDK4/6 inhibitors work in cancer therapy. "Combination targeted therapies with CDK4/6 inhibitors and certain other precision medicines durably arrest the proliferation of tumor cells, triggering the immune response that can kill tumor cells," Sherr said. "These combination targeted therapies can significantly prolong progression-free survival for cancer patients."
DATE: Monday, April 16
TIME: 10:30 a.m.
LOCATION: Room N227, Level 2, McCormick Place North
TITLE: CDK4/6 inhibitors: A paradigm shift in cancer treatment
Lethal brain tumor depends on common mutation for continued growth
Suzanne Baker, PhD, a member of the St. Jude Department of Developmental Neurobiology, will present evidence that a mutation carried in about 80 percent of patients with a lethal brain tumor is important for tumor growth. "The mutation causes massive deregulation of the epigenome, but how that contributes to cancer had been unclear," Baker said. "Our models suggest the mutation is very important for ongoing tumor growth." Baker and others had previously identified the point mutation in a family of DNA packaging proteins called histone H3 in most patients with the brain tumor diffuse intrinsic pontine glioma. The tumor has a dismal prognosis. The mutation affects the epigenome, which helps to regulate gene expression. The research reflects an ongoing effort to develop effective chemotherapy and targeted agents. The laboratory models researchers used included patient-derived xenografts, which makes it possible for researchers to study patient tumors growing in the same organ in mice. Baker is chairing the major symposium, where she is presenting the research.
DATE: Monday, April 16
TIME: 2:05 p.m.
LOCATION: Room S102 (Grand Ballroom), Level 1, McCormick Place South
TITLE: Transforming chromatin: Oncogenic histone H3 in diffuse intrinsic pontine gliomas
Research reveals the surprising origins of rhabdomyosarcoma
Researchers led by Mark Hatley, M.D., Ph.D., an assistant member of the St. Jude Department of Oncology, have written a new origin story for rhabdomyosarcoma, the most common soft tissue cancer in children. Under the microscope, rhabdomyosarcoma resembles muscle cells. Scientists have long believed the tumor originates in immature muscle cells, even though the tumor can occur in tissue without skeletal muscle. Using genetic fate mapping in genetically engineered mice, Hatley and his colleagues have determined that rhabdomyosarcoma originates not in immature muscle cells, but in immature cells meant to line the inner surface of blood vessels. Evidence suggests that problems arise when genetic programs meant to drive muscle development are mistakenly activated in non-muscle cells. "Despite aggressive treatment, clinical outcomes have not improved in three decades," Hatley said. "Revealing the molecular underpinnings of this tumor is an important step for developing more effective treatments." Catherine Drummond, Ph.D., a St. Jude postdoctoral fellow, will present the findings.
DATE: Monday, April 16
TIME: 3:05 p.m.
LOCATION: Room S405, Level 4, McCormick Place South
TITLE: Location specificity in fusion-negative rhabdomyosarcoma driven by cell of origin
Researchers rank breast cancer risk for childhood cancer survivors
Researchers know female childhood cancer survivors are at increased risk for developing breast cancer, primarily due to their earlier cancer therapy. Now St. Jude scientists have combined whole-genome sequencing results with clinical risk factors such as prior treatment exposure to measure the breast cancer risk of individual survivors. The approach is an apparent first and calculates breast cancer susceptibility based on the presence of rare, high-risk genetic mutations in any of the well-established breast cancer predisposition genes as well as mutations in 172 genetic variants that individually confer more modest risk. Survivors with high-risk mutations had a 17-fold increased risk of developing breast cancer. The approach also helped to stratify risk among survivors without high-risk mutations. Among those survivors, those with the highest scores were three times more likely to develop breast cancer than survivors with the lowest scores. "Such individual risk profiles will help survivors and their health care providers better understand and manage survivors' risk, not only for breast cancer but possibly for other health risks with a genetic component," said Zhaoming Wang, Ph.D., of the St. Jude Department of Computational Biology. He is presenting the findings. The study involved 1,133 female St. Jude cancer survivors enrolled in the St. Jude Lifetime Cohort study (St. Jude LIFE).
DATE: Monday, April 16
TIME: 3:05 p.m.
LOCATION: Room S101, Level 1, McCormick Place South
TITLE: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)
Progress reported in quest to 'revive' T cells for treatment of solid tumors
Benjamin Youngblood, Ph.D., an assistant member of the St. Jude Department of Immunology, will detail research that suggests reversing DNA methylation may be essential for effective immunotherapy against solid tumors. Researchers discovered that T cell "exhaustion" in mice was epigenetically regulated by DNA methylation, which functions as an off-switch for gene expression. Researchers also identified a chemotherapy drug that reversed the epigenetic process. Investigators checked pediatric solid tumors and found tumor-associated T cells that were similarly exhausted. The exhausted T cells failed to mount an immune response against the tumor. Youngblood and his colleagues are now exploring an epigenetic contribution to T cell exhaustion in cancer patients. "That may lead to combination therapy to enhance the anti-tumor immune response," Youngblood said.
DATE: Wednesday, April 18
TIME: 10:50 a.m.
LOCATION: Room S100 (Grand Ballroom), Level 1, McCormick Place South
TITLE: Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy