NIH grant: TGFβ Regulation of Immune Evasion and Metastasis in Ewing Sarcoma (1K08CA317035-01)

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NIH grant 1K08CA317035-01: TGFβ Regulation of Immune Evasion and Metastasis in Ewing Sarcoma
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Jessica Dietz Daley. Award: $214726.
Start: 2026-07-17T00:00:00.
The goal of this career development proposal is to build upon the applicant’s existing knowledge of mechanisms
of tumor immunosuppression to investigate the use of TGF inhibition during radiation therapy as a tool to
improve outcomes for patients with Ewing sarcoma (EwS). Patients with metastatic or relapsed Ewing sarcoma
continue to have very poor outcomes and novel treatment approaches are in high demand. CAR T cell therapies
targeting EwS surface antigens are an increasingly attractive approach, given advances in mapping the EwS
surfacesome. Roadblocks to the efficacy of CAR T cell therapy in EwS are the limited infiltration of immune cells
and cytokines that dampen immune cell function. TGF is an immunosuppressive cytokine that is activated
during radiation therapy, a treatment used as part of metastatic EwS local control. Little is known about the
impact of TGF and other immunomodulatory treatments on the Ewing sarcoma TIME due to the historic lack of
syngeneic or transgenic (i.e. immunocompetent) preclinical models of Ewing sarcoma and the paucity of tumor
samples from patients. The applicant played a key role in helping develop a novel, immunocompetent humanized
mouse model of Ewing sarcoma and utilized this model to conduct preliminary studies of the impact of TGF
inhibition on Ewing tumor immune cell infiltration and metastatic disease spread. For this career development
award, the applicant will build upon these preliminary studies while learning advanced skills in single-cell and
spatial RNAseq analysis, flow cytometry, and preclinical testing of CAR T cell therapies. A senior-career primary
mentor (a world-renowned cancer immunologist) and mid-career co-mentor (with expertise in the biology and
treatment of Ewing sarcoma) will guide the applicant on conduct of the proposed experiments and development
of new technical skills. They will also help the applicant develop skills in grant writing, laboratory management,
mentoring, etc. in order to launch a highly successful and productive independent research career. Additionally,
the applicant has a career mentoring committee and collaborators with expertise in TGF biology, advanced
bioinformatic and flow cytometry analyses, preclinical testing of cellular therapies, and statistics. This well
rounded and supportive team will help ensure the success of the applicant in the proposed studies and career
development goals. The applicant is currently an Assistant Professor of Pediatrics at the University of Pittsburgh
with 80% protected time for research. The University of Pittsburgh is an ideal environment for the conduct of
studies in cancer immunobiology and develop a thriving research career. With vast core facilities and access to
cutting-edge equipment, career development and leadership workshops, and graduate level courses in
immunology and computational biology, The University of Pittsburgh will provide a supportive environment as
the applicant grows her early research career. The proposed experiments, training, and didactic work will
position the applicant to successfully transition to an independent career as a physician-scientist with a focus on
the manipulating the microenvironment of pediatric sarcomas to increase the efficacy of cellular therapies.

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