Department of Surgery

Chair

Extensive clinical and basic research programs exist within the Department of Surgery. Faculty members dedicate a significant portion of time to advancing our understanding of pediatric solid tumors and developing novel therapeutic strategies to treat pediatric maladies. 

Improvement of CAR T-cell therapy for solid tumors 

Advances in immunotherapies such as CAR T-cell therapy have been paradigm shifting for treating pediatric cancers, but the clinical efficacy of this therapeutic strategy is limited for many common pediatric tumors. Research in the Department of Surgery is focused on improving CAR T-cell therapy for a broader range of tumors including osteosarcomas. Recent work on this front has resulted in the creation of a spontaneously metastasizing osteosarcoma model that allows researchers to more accurately predict the safety and efficacy of current and next generation CAR T-cell therapies. In addition, researchers have identified chemokine ligands produced by pediatric osteosarcomas, which has been instrumental in developing a modified CAR T-cell line expressing two chemokine receptors, CXCR2 and CXCR6. This modification has enhanced CAR T-cell homing to tumor sites, increased the anti-tumor activity of these cells and shown the value of evaluating CXCR-modified CAR T cells in a clinical capacity. 

Advances in Wilms tumor biology

Wilms tumor is the most common kidney cancer in the pediatric age group, accounting for up to 7% of all pediatric cancers. Of those diagnosed with Wilms tumor, a few high-risk groups exist: patients who have a histologic finding called diffuse anaplasia, those with favorable histology whose cancer then relapses and those with bilateral kidney tumors. For these subgroups, better therapies are needed but a lack of model systems along with an incomplete understanding of Wilms tumor biology has stymied progress. 

Research in the Department of Surgery has led to the development of patient-derived xenograft model systems for these renal tumors and the creation of an extensive library of over 45 xenografts that captures the genetic and clinical heterogeneity of these tumors. Additionally, work in this department has also advanced the understanding of Wilms tumor biology, identifying several mechanisms of TERT activation that could be of therapeutic interest. Increased TERT expression, a telomerase enzyme, has been associated with disease relapse, and a better understanding of the molecular drivers of TERT expression provides valuable insights for the development of the next generation of targeted therapeutics. Along these lines, researchers also discovered that targeting the histone lysine demethylase, KDM4A, may be of therapeutic interest as it showed cytostatic activity against multiple renal cell lines. 

Gene therapy

The application of gene therapy to the treatment of childhood cancers and catastrophic diseases is an active area of research for the department. Researchers have developed and optimized adeno-associated virus (AAV) vectors to deliver therapeutic transgenes to select patients diagnosed with hemophilia B and A. Results have already demonstrated that expressing the human factor IX transgene in an AAV vector improved the bleeding phenotype associated with hemophilia B in patients, and optimizing this treatment to be given as a single-infusion will increase its impact in resource-limited countries. 

AAV-mediated therapeutic strategies are also being developed for neuroblastoma, hepatoblastoma and other pediatric solid tumors. Additionally, researchers are pursuing epigenetic mechanisms as potential targets of interest. 

Mechanistic insight into high-risk tumors

Many high-risk pediatric tumors are driven by oncogenic transcription factors, making the cancers difficult to treat. Work in the department is aimed at developing genetic models for preclinical studies and making translational impact for patients with high-risk cancers. Notably, researchers have found that epigenetic modifiers, such as histone lysine demethylases (KDMs), are often targets of oncogenic transcription factors, leading to dysregulated transcription and tumorigenesis. Results have shown that inhibition of certain KDMs suppresses tumorigenesis and induces interferon responses, highlighting the potential of therapeutically targeting these molecules. Scientists have also discovered the importance of splicing factors to cancers driven by oncogenic transcription factors. Research by the department has outlined the importance of pre-mRNA splicing to MYC-driven neuroblastoma, identified a targetable metabolic sensor and provided mechanistic rationale for using an aryl sulfonamide drug in the treatment of high-risk neuroblastoma. 

Focus on dentistry

Oral health plays an integral role in the overall prognosis of children undergoing treatment for cancer. The department engages in research aimed at optimizing dental materials and technology for pediatric patients; this includes prefabricated zirconia crowns, dental sealants and high-powered light emitting diode curing lights. In parallel with these technical advances, researchers are also interested in understanding effective ways to help children cope with dental procedures. This work has increased our understanding of how parents and patients respond to different treatment modalities and provided a framework for behavior guidance. 

Education and training efforts

In addition to providing specialized surgical care, members of the Department of Surgery also participate in education and training efforts. The department is a valuable resource for pediatric surgical oncologists locally, nationally and internationally. Additionally, the department offers a two-year fellowship program which provides fellows with a strong clinical foundation and customized surgical training in pediatric surgical oncology.