Welcome to the Science Spotlight, where we highlight the scientific advancements made possible by our consortia and data commons.
In this Science Spotlight, MaGIC highlights three Department of Defense grants they have recently received in their core areas of research: clinical research, clinical trial development, and biologic research. Each grant is an example of the collaborative innovation and team science made possible by participation in MaGIC. The clinical and genomic data resulting from all of these projects will, of course, be fed back into the GCT data commons, which continues to grow thanks to the hard work of MaGIC members and the PCDC team.
Advances in Clinical Research
DoD Translational Team Science Award
Measurement and Impact of Body Composition Using CT Imaging in Patients With Germ Cell Tumors Undergoing Chemotherapy on the NCTN Phase 3 Study AGCT1531
Principal Investigator: Tyler Ketterl, Seattle Children’s Research Institute
Co-Investigators: Christina Dieli-Conwright, Dana-Farber Cancer Institute; Rod Rassekh, University of British Columbia
Reducing both short and long term treatment-related toxicity has consistently been a priority for MaGIC’s research agenda. Patients with germ cell tumors have a high likelihood of cure, and hence there is compelling rationale to take the long view and try to prevent life-long toxicities. This grant aims to test the hypothesis that body composition at diagnosis and changes during treatment predict an increased number of adverse events due to chemotherapy. Body composition (i.e., the percentage of the body that is fat, skeletal muscle, and bone) will be measured over the course of treatment for patients enrolled on COG protocol AGCT1531, a randomized trial of carboplatin vs cisplatin for standard-risk pediatric and adult patients. Using measurements obtained from the staging CT scans already being collected as part of the trial, the team will determine how baseline lean muscle mass and muscle attenuation is related to the development of ototoxicity, neurotoxicity, and hematologic toxicity. The team will replicate these analyses looking at changes in these parameters and development of these toxicities.
Advances in Clinical Trials
DoD Impact Award
Targeting hypermethylation to overcome cisplatin resistance in patients with relapsed/refractory germ cell tumors
Principal Investigator: Darren Feldman, Memorial Sloan-Kettering Cancer Center
Co-Investigators: Mike Spinella, University of Illinois; Lindsay Frazier, Dana-Farber Cancer Institute; Rachana Shah, Children’s Hospital of Los Angeles
No new drug has been approved for germ cell tumors in over 4 decades. Patients with relapsed and refractory germ cell tumors have no curative options. Understanding and overcoming cisplatin resistance is one avenue to improve these odds.
This grant funds the development of a protocol utilizing ASTX727, a hypomethylating agent which has proven effective in pre-clinical data, and which has already been FDA-approved for myelodysplastic syndrome and chronic myelomonocytic leukemia, making its path to clinical adoption much more straightforward.
The grant funds the development of a Phase I/II study, as well as biomarker analyses that will help facilitate interpretation of the clinical responses. This grant is part of a larger initiative within MaGIC to establish a Phase I consortium, entitled Germ Cell Tumor Research Acceleration through Collaboration of Experts (GRACE), which will be led by Darren Feldman at the Memorial Sloan-Kettering Cancer Center.
Advances in Biologic Research
DoD Impact Award
Exploring the Regulatory Landscape of Pediatric vs. Adult Germ Cell Tumors in a Developmental Framework to Gain New Therapeutic Insights
Principal Investigator: Lindsay Frazier, Dana-Farber Cancer Institute
Co-Investigators: Michelle Nuno, University of Southern California; Alyaa AlIbraheemi, Boston Children’s Hospital; James Amatruda, Children’s Hospital of Los Angeles
Identifying and exploring the biological differences between Type 1 (pre-pubertal) and Type 2 (post-pubertal) germ cell tumors has been a focus of MaGIC since the consortium’s inception in 2010. One of MaGIC’s most significant assets has been the growing collaborative work and cross-talk between the medical and pediatric germ cell tumors providers, which has given us the opportunity to further explore these questions by increasing access to biospecimens.
The grant will support genomic analysis of pediatric vs. adult yolk sac tumors, one of the malignant histologies that occur in germ cell tumors and typically one of the most chemo-resistant. The grant also supports a broad look at the changes in the genomics of GCT between diagnosis and relapse, across all ages and histologies. Finally, the grant also supports the use of AI and machine learning to assist in the pathologic assessment of germ cell tumors, both to improve detection of all histologies present but also to identify pathologic features that promote recurrence.
This work will be incremental in moving the field forward in terms of understanding the biologic changes that occur in germ cell tumors across the spectrum of pediatric and adult oncology.