This application for a K23 award contains two complementary components: a career development plan and a research plan. The career development plan will support critical additional training for the candidate, Dr. Steven DuBois, a pediatric oncologist at the University of California, San Francisco (UCSF). Dr. DuBois has used his previous training to develop a burgeoning developmental therapeutics research program focused on pediatric solid tumors. Given the increasing role of biomarkers in early phase clinical studies, Dr. DuBois now requires specific training in biomarker development and validation. He will use his flow cytometry-based marker of bone marrow micrometastatic disease in patients with Ewing sarcoma as a platform on which to obtain additional didactic and hands-on training in flow cytometry and phospho-flow cytometry. He will also complete dedicated training focused on other techniques for detecting micrometastatic disease, molecular markers in oncology, and pharmacogenomics. Dr. DuBois has assembled an outstanding team of multidisciplinary mentors to facilitate his training and research. Dr. Katherine Matthay, an international expert in clinical and translational studies in pediatric solid tumors, will serve as primary mentor. She will oversee the overall training and research plans, providing her wealth of experience in this field. Dr. Mignon Loh will provide her expertise on the use of phospho-flow cytometry to study intracellular signaling in cancer cells. Dr. Elizabeth Sinclair will provide her expertise in the use of flow cytometry to detect rare populations of cells. The research plan focuses on a flow cytometry-based technique for detecting occult tumor cells in the bone marrow of patients with Ewing sarcoma. Dr. DuBois developed this technique and his preliminary studies demonstrate that bone marrow micrometastatic disease is nearly universal in patients with Ewing sarcoma, though the number of tumor cells varies widely between patients.
In Aim 1 of this application, he proposes to assess the magnitude of the association between progression-free survival and baseline bone marrow tumor cells in untreated patients with Ewing sarcoma.
In Aim 2, he will determine the clearance rate of bone marrow tumor cells detected by flow cytometry in patients with Ewing sarcoma.
In Aim 3, he will evaluate the ability of flow cytometry to interrogate insulin-like growth factor-1 receptor (IGF-1R) signaling pathways in occult bone marrow Ewing sarcoma cells. Incorporation of this assay into his current flow cytometry assay will allow a clinically-relevant signaling pathway to be studied in bone marrow tumor cells. The proposed studies will provide additional data needed to support an R01 application to study bone marrow micrometastatic disease as a tool for risk-stratification in a national phase III clinical trial for Ewing sarcoma.

Public Health Relevance

Ewing sarcoma is a type of bone cancer that affects children and young adults. The research team will use a new technique to measure tumor cells that have spread from the main tumor to the bone marrow. The research team will then evaluate whether the number of tumor cells in the bone marrow predicts prognosis and response to therapy in these patients. The research has the potential to improve the outcomes for patients with this disease and may inform studies of other pediatric solid cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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Vo, Kieuhoa T; Edwards, Jeremy V; Epling, C Lorrie et al. (2016) Impact of Two Measures of Micrometastatic Disease on Clinical Outcomes in Patients with Newly Diagnosed Ewing Sarcoma: A Report from the Children's Oncology Group. Clin Cancer Res 22:3643-50
Daw, Najat C; Laack, Nadia N; McIlvaine, Elizabeth J et al. (2016) Local Control Modality and Outcome for Ewing Sarcoma of the Femur: A Report From the Children's Oncology Group. Ann Surg Oncol 23:3541-3547
Karski, Erin E; McIlvaine, Elizabeth; Segal, Mark R et al. (2016) Identification of Discrete Prognostic Groups in Ewing Sarcoma. Pediatr Blood Cancer 63:47-53
Tilan, Jason U; Krailo, Mark; Barkauskas, Donald A et al. (2015) Systemic levels of neuropeptide Y and dipeptidyl peptidase activity in patients with Ewing sarcoma--associations with tumor phenotype and survival. Cancer 121:697-707
DuBois, Steven G; Krailo, Mark D; Gebhardt, Mark C et al. (2015) Comparative evaluation of local control strategies in localized Ewing sarcoma of bone: a report from the Children's Oncology Group. Cancer 121:467-75
Sharib, Jeremy; Horvai, Andrew; Gray Hazard, Florette K et al. (2014) Comparison of Latino and non-Latino patients with Ewing sarcoma. Pediatr Blood Cancer 61:233-7
Applebaum, Mark A; Thomas, Dafydd G; Hembrough, Todd et al. (2014) Comparative evaluation of strategies for quantifying signaling pathway proteins in Ewing sarcoma. Appl Immunohistochem Mol Morphol 22:593-9
Karski, Erin E; Matthay, Katherine K; Neuhaus, John M et al. (2013) Characteristics and outcomes of patients with Ewing sarcoma over 40 years of age at diagnosis. Cancer Epidemiol 37:29-33
Applebaum, Mark A; Goldsby, Robert; Neuhaus, John et al. (2012) Clinical features and outcomes in patients with secondary Ewing sarcoma. Pediatr Blood Cancer :