Mentor Search Summer 2022 Projects

Nemours

Sonali S. Barwe — Pediatric Leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric leukemia. Majority of patients are cured, but about 10% of patient’s experience disease relapse due to drug resistant leukemic cells. The bone marrow microenvironment comprising stromal cells, osteoblasts, endothelial cells, along with secreted extracellular matrix components and soluble factors provides a sanctuary for leukemic cells. Adhesion and retention of leukemic cells within the bone marrow is a major contributor to drug resistance and relapse. We and others have shown that chemotherapy drugs are unable to kill leukemic cells co-cultured with stromal cells (to mimic the bone marrow microenvironment) as efficiency as in monoculture. Signaling induced by cell surface proteins such as CD81 plays an important role in this process. CD81 knockout cells had reduced bone marrow microenvironment induced chemoprotection and altered expression of cell surface proteins. Identification of cell surface proteins regulated by CD81 is crucial to develop novel therapeutic options to overcome the adhesion-induced cyto-protective effect and prevent relapse.
Cell culture and flow cytometry will be utilized to determine leukemia cell binding to stromal cells and to evaluate cell viability following exposure to chemotherapy drugs.

Email: sbarwe@nemours.org

Sigrid A. Langhans — A Translational Approach to Evaluation of Hippo/YAP Signaling in Pediatric Brain Tumors

The prognosis of many pediatric brain cancers remains poor. However, with advances in our understanding of how cancer cells interact with their immediate environment, pathways that relate information from the tumor microenvironment have moved to the forefront in cancer drug discovery. Hippo/YAP signaling is part of a network of major signaling pathways involved in organ development and function. It also serves as a regulatory hub integrating information from a cell’s microenvironment with its phenotypic behavior. In cancer, including in pediatric brain cancers, aberrant YAP activation has been implicated in cancer cell dedifferentiation and proliferation, in promoting genomic instability, and in therapeutic resistance. Despite this, little is known about YAP activation in specific tumor subgroups. This project is a bed to bench (clinical to lab) model of investigation: by reviewing clinical information and tissue samples of children with brain cancer, we will first describe clinical, genetic, and neuroradiologic findings, classify the patients into subcategories, then explore the specific regulators and pathways for mutation through laboratory analyses.
Aim 1. Develop a database of Nemours patients diagnosed with benign and malignant brain cancers who have genetic testing results and group by type. Aim 2. Determine subgroup-specific YAP activation levels in pediatric brain tumors.

Email: sigrid.langhans@nemours.org

Zhengyu Ma — Tumor Activated Alloreactive T Cells for Cancer Immunotherapy

One of the major breakthroughs in cancer therapy in recent years is the development of engineered T lymphocytes (T cells) that can recognize and kill cancer cells. T cells using chimeric antigen receptors (CARs) recognizing CD19, a pan-B cell marker expressed on all cancerous B cells, have been approved by the FDA for B cell malignancies based on striking results in clinical trials. Using CAR T cells to treat solid tumors, however, has not been as successful. Unlike CD19, biomarkers for solid tumors, i.e., tumor antigens (TAs), tend to be expressed in a heterogeneous fashion in tumors, with only a fraction of tumor cells expressing a particular type of TA. As a result, therapeutic T cells that are capable of targeting and killing tumor cells expressing a particular type of TA are often incapable of halting tumor growth due to the expansion of TA-negative tumor cells. To overcome these challenges, a T cell therapy strategy that targets a wide range of tumor cells is urgently needed. We propose to develop Tumor Activated Alloreactive T cells (TAATs) that target all tumor cells expressing HLA class I (HLA-I), which are present on almost all nucleated cells in the body, including many types of tumor cells. This approach exploits T cell alloreactivity, i.e., the ability of T cells from one individual to recognize and kill cells from another individual. To prevent toxicities associated with targeting normal tissues that also express HLA-I, a control mechanism is incorporated in TAATs to restrict their alloreactivity to tumors and to avoid normal tissues. We hypothesize that TAATs are capable of killing both TA+HLA+ and TA-HLA+ cells in tumors without causing significant normal tissue damages or graft vs host diseases. To test our hypothesis, we will 1) establish the process of generating TAATs; 2) test the ability of TAATs to kill TA+HLA+ and TA-HLA+ tumor cells in cell cultures and in animal models.

Email: zma@nemours.org

Suken Shah — Predictive Modeling of Social Determinants of of Health and Influence on Treatment Progression of Patients who have Adolescent Idiopathic Scoliosis

To date, social determinants of health (SDOH) have not been adequately studied to determine how a clinician can engage in shared decision making with patients and parents who have Adolescents Idiopathic Scoliosis to provide optimal outcomes. With the collection and analysis of this data, we hope in the future to provide the treatment team with an understanding of clinical, patient reported outcomes (SRS-22r) and SDOH data in developing an appropriate treatment plan. This will also help to lessen the burden on the patient and family from a financial, functional and emotional perspective
The summer scholar will be involved in the understanding of the protocol, how to collect the data from the electronic medical record (EMR), utilization of REDCap, preparation of data for statistical analysis and manuscript submission. Person will interact with investigative and clinical staff during visits of patients with AIS to understand the treatment of AIS and subsequently understand the data that is captured in the EMR. Finally, person will have a schedule to meet with clinical and investigative team to discuss project progression and have full integration within the department.

Email: suken.shah@nemours.org