AACR-QuadW Foundation Fellowship for Clinical/Translational Sarcoma Research
The AACR-QuadW Foundation Fellowship for Clinical/Translational Sarcoma Research represents a joint effort to encourage and support a postdoctoral or clinical research fellow to work on mentored sarcoma research and to establish a successful career path in this field. Eligibility is limited to postdoctoral and clinical research fellows within the first five years of their fellowship. The research proposed for funding may be translational or clinical in nature and must have direct applicability and relevance to sarcoma research.
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma, most commonly seen in adolescent and young adult males. DSRCT is defined by a single recurrent mutation, EWS-WT1, a dysregulated transcription factor, that alters the expression of more than 1500 genes. Dr. Gedminas’ previous work defined DSRCT cells as absolutely dependent on EWS-WT1 for survival. Dr. Gedminas’ current work will exploit this dependency as a therapeutic vulnerability using the small molecule lurbinectedin which she has shown to inhibit the expression of EWS-WT1 based on preliminary data. The goal of this study is to elucidate the mechanism of EWSWT1 suppression by lurbinectedin to guide the administration of this compound and identify novel combination therapies. This will be a major step forward for this disease as there are currently no clinical trials for new agents for DSRCT and no accepted effective standard of care.
Dr. Gedminas completed her undergraduate education at the University of Florida and received her MD from the Chicago Medical School at Rosalind Franklin University of Medicine and Science, followed by residency training in pediatrics at Advocate Children’s Hospital. Following completion of her fellowship in pediatric hematology and oncology at Helen DeVos Children’s Hospital/Michigan State University, Dr. Gedminas received additional training as a pediatric solid tumor fellow at the Children’s Hospital of Philadelphia, where she now continues as an instructor in the Division of Oncology. She conducts sarcoma research in the laboratory of Dr. Patrick Grohar.
Acknowledgement of Support
The AACR-QuadW Foundation Fellowship for Clinical/Translational Sarcoma Research provides me with essential support to continue my work developing novel therapeutic approaches for desmoplastic small round cell tumor while I continue the path toward becoming an independent investigator in the field of pediatric sarcoma.
Cancer associated mutations in chromatin pathways affect proteins that regulate chromatin, as well as their substrates, histone proteins. Histone mutations occur in sarcomas such as giant cell tumor of bone, chondroblastoma, chondrosarcoma, undifferentiated pleomorphic sarcoma (USP), and osteosarcoma. A sarcoma-associated mutation in histone H3 at lysine 36 (H3K36M) is sufficient to induce a UPS-like tumor in a murine model and blocks differentiation of mesenchymal progenitor cells. Given the role of chromatin in controlling cell fate, a process which is often dysregulated in cancer, the awarded research program is designed to target H3K36M-driven differentiation blockade. Based on a preliminary screen, Dr. Nacev will explore the activity of small molecules in rescuing differentiation blockade along multiple lineages and in inhibiting growth of a H3K36M-tumor model. The effects of active compounds on H3K36M-induced chromatin changes and on transcription will be explored. This work could establish a novel approach to targeting epigenetically-driven sarcomas.
Dr. Nacev earned his MD and PhD degrees from the Johns Hopkins University School of Medicine, where his work focused on the mechanisms of small molecule inhibitors of angiogenesis. Following his doctoral training, Dr. Nacev completed internal medicine residency in the Osler Medical Training Program at the Johns Hopkins Hospital before being recruited to the Memorial Sloan Kettering Cancer Center, where he is currently a medical oncology fellow under Dr. William Tap of the sarcoma service. Dr. Nacev conducts postdoctoral research under the mentorship of Dr. C. David Allis at the Rockefeller University.
Acknowledgement of Support
The QuadW Foundation-AACR Fellowship for Clinical/Translational Sarcoma Research provides essential support during the critical final stage of my training as I prepare to embark on an independent career as a sarcoma medical oncologist and scientist studying novel therapies for epigenetically-driven sarcomas.