The Regents of the University of California, Los Angeles Archives

2019

Scholar Grant

Steven Jonas

Los Angeles, CA

Title: Nanotechnologies for establishing tumor-on-a-chip models of pediatric sarcomas from circulating tumor cells

Executive Summary:
Ewing Sarcoma is a highly aggressive form of bone and soft tissue cancer that primarily affects pediatric patients, particularly adolescents and young adults. Tumor cells shed from primary and metastatic sites (i.e., circulating tumor cells, CTCs) can provide important diagnostic information on patient response to treatment and prognosis. However, the isolation of viable CTCs is challenging since they are mixed with other blood components and are present only at low concentrations. We propose a microfluidic platform integrated with precision engineered nanostructures that enables the selective capture and release of Ewing sarcoma circulating tumor cells. With our platform, we will design and utilize selective surface chemistries to isolate the desired CTCs and leverage click chemistry-based strategies to release the captured cells selectively for further analyses. We will apply this new capability to introduce Ewing Sarcoma-derived CTCs into organ-on-a-chip devices where they can be cultured and used for drug screening, paving the way for patient-tailored therapeutic strategies driven by precision medicine methods. The proposed nanotechnologies offer unique capabilities that can drive innovation within pediatric oncology, leading to a set of highly scalable diagnostic technologies that can be adapted easily for the capture and analysis of CTCs from a variety of malignancies. Successful implementation of this research clinically will revolutionize disease monitoring and treatment, enabling earlier and more refined responses to metastatic and/or recurrent disease, and potentially helping to minimize late effects.

Key Features of the proposed project include:
– Design and testing microfluidic technologies that integrate precision-manufactured nanostructures that enable new diagnostic methods for monitoring a patient’s cancer via “liquid biopsies” from a patient’s blood
– Optimize and apply these technologies to isolate and to detect CTCs from Ewing sarcoma as an initial target
– Design and testing of click-chemistry-based approaches to release captured CTCs safely for downstream analysis
– Utilize captured Ewing sarcoma CTCs to seed bone-on-a-chip devices to establish sarcoma-on-a-chip disease models
– Application of these patient-specific models of Ewing Sarcoma to enable molecular profiling and characterization of disease response to chemotherapeutic and targeted agents

2019

Young Investigator

Theodore Nowicki

Los Angeles, CA

Executive Summary:
New immunotherapies, in which the body’s own immune system is used as a weapon against cancer, are revolutionizing the treatment of a variety of cancers. One such immunotherapy, which uses genetically engineered immune cells (known as T cells), is revolutionizing the treatment of leukemia and lymphoma, but there remain significant incidences of treatment failure or relapsed disease after an initial clinical response. I propose that the DNA structure of these engineered T cells changes over time, and can ultimately impair the expression of receptors responsible for tracking the engineered immune cells to the cancer cells. Such changes in DNA structure and receptor loss can lead to cases of treatment failure. This research plan will examine samples of genetically engineered T cells from patients receiving them for cancer treatment. The goals of these analyses will be:

– Analyze how the cells’ DNA structure changes over time, and how this impacts the expression of the cancer-tracking receptors in these cells.
– Determine the impact this phenomenon has on clinical outcomes to these cellular therapies.

I anticipate that these studies will result in a robust classification of the changes in DNA structure that occurs in these engineered cellular therapies that impact expression of their cancer-tracking receptors, and ultimately impair their functionality. While genetically engineered T cell therapeutics have revolutionized the treatment of pediatric cancers, the need to improve response rates is of critical importance. Information learned from these studies can generate “blueprints” of potential weaknesses in DNA structure that can develop over time in these cellular therapeutics and impair their long-term functionality. Eventually, such DNA features can potentially serve as targets for genetic engineering in newer generations of cell therapies. This information can also lead to better clinical monitoring programs for pediatric patients receiving these therapies, which can guide clinical decision-making.