2024
Project 1: $100K Pediatric Cancer Research Grant
Project 2: $100K funding to COG Solid Malignancy (SM) Integrated Translation Science Center (ITSC)
Project 1
Research Grant Summary
Project Title: Studies of DNA methylation and other genomic features in pediatric undifferentiated/unclassified soft tissue sarcomas
Principal Investigator: Dr. Frederic Barr of the National Cancer Institute and Dr. Erin Rudzinski of Riley Hospital for Children/Indiana University.
Grant Amount: $100,000
More about the Research Grant
Undifferentiated/unclassifiable sarcoma (UDS/UCS) is a problematic group of soft tissue sarcomas that cannot be further categorized into a specific diagnostic (or therapeutic) type. Scientific advances have discovered genetic changes characteristic of certain sarcoma types, allowing a specific diagnosis to be made when that genetic change is identified in a UDS/UCS case. However, many types of sarcoma still do not have any known defining genetic change, and there may be new sarcoma types that have not yet been recognized.
DNA methylation profiling is a recently developed test that can identify a pattern of changes within a cancer that is related to the specific cell type from which the cancer arose. This methodology thus provides a novel way of classifying soft tissue sarcomas that may help to better categorize UDS/UCS cases that lack defining genetic changes. Our studies of the rhabdomyosarcoma (RMS) family of soft tissue sarcomas used DNA methylation profiling to propose the existence of several previously unknown types within the larger RMS family, including cases that may not actually be RMS. Recently, we have also used DNA methylation profiling to show that an initial set of UDS/UCS cases is heterogeneous and consists of several distinct subtypes.
In the proposed research project, a group of investigators from the Children’s Oncology Group (COG) Soft Tissue Sarcoma committee will use data from the NCI Molecular Characterization Initiative to identify a large number of UDS/UCS cases. We will further add to the size of this group with another set of cases identified by the SPPRITEs consortium of pediatric pathologists representing institutions across the United States. This combined group of UDS/UCS cases will be examined by DNA methylation profiling and the results compared with a group of well characterized sarcoma types to better understand the composition of the UDS/UCS category and determine the similarity of some subsets to known sarcoma types. Clinical and microscopic features will then be compared between UDS/UCS subsets. The UDS/UCS subsets identified by this DNA methylation profiling will be further studied by various molecular techniques to determine whether there are genetic changes enriched in these subsets that may be useful for diagnosis or treatment.
In summary, the proposed studies will use the power of modern epigenetic and genetic technologies to characterize a large group of UDS/UCS cases and ultimately identify classifiable types within this previously unclassifiable category.
Research Grant Specific Aims
The objectives of the research are two-fold:
1) To assess heterogeneity and define subsets in a large cohort of pediatric undifferentiated or unclassifiable sarcoma (UDS/UCS) by unsupervised analyses of DNA methylation data and comparison with DNA methylation databases of well-annotated soft tissue sarcoma (STS) cases.
2) To analyze point mutations, copy number changes and gene fusions in a large cohort of UDS/UCS cases, and to associate these findings with the UDS/UCS subsets from Aim 1.
Project 2
ITSC Funding
ITSC works to identify and remove bottlenecks in the process of developing new drugs, diagnostics, and medical devices. ITSC works to speed the translation of scientific discoveries from clinical trials into effective medical treatments.
Clinical trials are a powerful mechanism to understand if novel therapies or treatment plans are superior. With hundreds or thousands of patients participating in clinical trials, there are incredible opportunities to test and understand more about the enrolled patients and their tumors – and there are important scientific questions that can be asked and answered beyond the scope the of the defined clinical trial.
The funding allows ITSC, as mechanism, to effectively expand the scope of SM research with high scientific value.
More about ITSC
So, what is the ITSC?
NCI has chosen Integrated Translational Centers (ITCs) funded to increase translational research done in clinical trials.
This structure has been super critical to achieve scientific aims that can be bootstrapped onto clinical trials.
In other words, clinical trials are this powerful mechanism to understand if novel therapies or treatment plans are superior. And the process of enrolling hundreds and thousands of patients on this trial is the laborious and costly part. There are incredible opportunities to test and understand more about their tumors or the patients that enroll, and there are important scientific questions that can be asked and answered.
However, the clinical trial, as funded by COG or the NCI, will only fund certain questions that are germane to the clinical trials outcome and some adjacent questions.
However, it’s a unique and in some ways the only opportunity to test some ancillary scientific aims. But these scientific aims will not be funded by COG of the NCTN (NCI).
But NCI realized many years ago that there are incredibly important questions that can be answered. That is why they created the ITSC mechanism. In the early 2010s. Individual NCTN consortia or groups within consortia can apply for these impactful grants.
COG has been successful in applying for and securing some of these grants. COG has broken their ITSC grant applications into Leukemia/ Lymphoma (L+L) and Solid Malignancy (SM).
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However, the funding no longer exists for both groups.
Given their importance for the science and discovery in pediatric cancer - the dollars that go to these scientific questions have very high scientific value.
The SM-ITSC Committee within COG (in charge of prioritizing which questions are highest priority/ yield) was led by Dr. Stephen Skapek, Division Chief at UTSW (University of Texas Southwestern (Dallas)), and leader of their solid tumor program and a leading researcher in sarcoma, he will be handing the baton to Dr. Meredith Irwin who is a leading researcher who focuses on neuroblastoma from Sick Kids (Toronto).
For example of a seriously important project that was only possible through ITSC funding, Dr. Brian Crompton utilized SM-ITSC funding to bootstrap his sarcoma (rhabdomyosarcoma, in this case) circulating tumor DNA (ctDNA) onto recent COG rhabdomyosarcoma phase III clinical trial. (For results see attachment – JCO (Journal of Clinical Oncology) is one of the preeminent cancer journals, not just of pediatric cancer, but oncology overall)
