State: New York

Funded by the Dick Vitale Pediatric Cancer Research Fund

Primary brain tumors are the most common solid tumors in children. They are also the most frequent cause of cancer-related death in children and teens. Genetic profiling is an important tool in the treatment of these tumors. DNA sequencing provides information for proper diagnosis. It can also be used to understand how tumors change over time and to monitor response to treatment. However, performing biopsies is very challenging for brain tumors.  Many tumors are in important areas of the brain and can’t be fully removed or repeatedly sampled.

“Liquid biopsy” is a new tool that can be used to diagnose cancer and track response for some systemic tumors. It works by detecting small pieces of DNA that break off from tumors. These can be found in the cerebrospinal fluid (CSF) and in blood (circulating tumor DNA, ctDNA). Accessing these “liquids” is usually easier and has fewer complications than surgery.

We previously showed that CSF ctDNA can be used to diagnose brain tumors and that ctDNA is associated with active disease. But there are instances where CSF ctDNA is not informative due to technical limitations. We propose to improve how these samples are analyzed so CSF liquid biopsies can help more patients. Our prior work was retrospective. For this project, CSF ctDNA monitoring will be added to a clinical trial. We will investigate whether there is a relationship between CSF ctDNA and disease burden. Validating CSF liquid biopsy could greatly improve how pediatric primary brain tumors are diagnosed and treated.

In the past decade, the incidence of pediatric IBD has doubled, and that of early-onset CRC has quadrupled in the United States. The aggressive clinical course of IBD and reduced overall survival of associated young-onset CRC represent an unmet clinical need. Notably, although the reasons for the upward trend of childhood IBD and early-onset CRC are poorly understood, food and nutrition that raises blood sugar have been identified as the major risk factor. Our research takes the nutrigenomic approach to investigate food-gene regulatory networks that can be exploited for harnessing tumor-initiating cells and pro-tumor inflammation. We anticipate that new mechanistic links and therapeutic targets identified in this study will inspire novel preventive and curative strategies to combat inflammatory diseases and cancer.

The role of the immune system is to survey the body in search of dangerous “non-self” elements and to eliminate them without damaging the host. Cancer is a disease which develops when host cells genetically change and begin growing in an uncontained fashion. It was therefore thought for many years that the immune system was incapable of recognizing or eliminating cancer cells due to their emergence from, and similarity to, “self” elements. The remarkable discovery that blocking signals (“immune checkpoints”) that restrain the ability of immune cells to recognize and destroy foreign elements can enable the immune system to treat cancer has fundamentally changed our approach to the treatment of these patients. Even in the setting of immune checkpoint inhibitors, however, immune cells lose functionality within tumors as part of a stepwise process known collectively as T-cell “exhaustion.” Reversing T-cell exhaustion is essential to make immunotherapy a viable treatment for all patients.

Our laboratory recently discovered that the metabolism of T-cells – the way that cells take up, break down, and utilize nutrients – becomes dysfunctional within tumors and, and moreover that this metabolic switch is required for T-cells to become fully exhausted. In work supported by the V foundation, we will understand how tumors exploit this metabolic dysfunction by creating metabolically inhospitable environments in which T-cells lose their capacity to control tumor growth. By identifying and reversing these environmental barriers, we hope to reverse or prevent T-cell exhaustion and make immunotherapy a viable strategy for every patient.

Funded by the Dick Vitale Pediatric Cancer Research Fund

Within days of birth, trillions of harmless, and even beneficial, bacteria colonize an infant’s skin and gut. The developing immune system must learn to tolerate these “commensal” bacteria to avoid the onset of destructive inflammatory diseases such as eczema and inflammatory bowel disease. Remarkably little is known about the cell types that instruct immune cells to accept commensal bacteria in early life. Our research will address the cross-talk between microbes and the developing immune system to elucidate the mechanisms by which the host and bacteria learn to develop a harmonious, symbiotic relationship. In this effort, we seek to reveal the role of a newly identified, early-life immune cell in establishing acceptance of commensal skin microbes. Overall, the project is expected to provide insights into basic mechanisms of immune-regulation, clues to pediatric inflammatory diseases, and a path to the development of new therapies.

Funded by the Constellation Gold Network Distributors

Genetic information is carried in DNA, which is present in every cell of our bodies. Most cells have 46 chromosomes, which carry DNA within the cell. However, more than 90% of tumors have cells without the correct number of chromosomes. These cells are called “aneuploid”. Some whole chromosomes or large chromosome fragments may be duplicated or lost. Aneuploidy is a contributing factor in cancer formation. However, its exact role in this process is an unanswered question in cancer biology. The goal of this research is to understand the effects of different changes in chromosome number.  

For our studies, we make use of a new technology that allows us to cut chromosomes at specific locations. With these experiments, we can study the effects of changes in large chromosome segments. Our current focus is a type of cancer called squamous cell carcinoma (SCC). In this cancer type, large pieces of chromosome 3 are affected. Here, we will uncover the interaction between chromosome 3 changes and DNA mutations. We will also create a human cell model of SCC. These studies address a gap in our understanding of aneuploidy in cancer by studying the effects of specific sets of chromosomal changes. With knowledge of how these chromosomal changes contribute to cancer formation, we will uncover new ways that cells can become cancerous. A better understanding of paths to disease formation will be crucial for designing new cancer treatments.