Children's Hospital of Los Angeles Archives - Page 2 of 3

2019

Scholar Grant

Jesse Berry

Los Angeles, CA

Title: The Aqueous Humor Liquid Biopsy for Retinoblastoma: Evaluating Tumor Heterogeneity

Executive Summary:
Our research has shown significant potential to use the aqueous humor (AH), the clear fluid in front of the eye, as a liquid biopsy for retinoblastoma (RB), a pediatric eye cancer. We demonstrated that tumor DNA is present in the AH, which is safe to extract, and we defined gain of a region of chromosome 6p as a potential prognostic tumor biomarker for aggressive disease. However, RB forms multiple tumor clones and seeds which may be heterogeneous in their genomic states. Thus, we aim to refine the AH as a liquid biopsy by evaluating differences in genomic profiles in the AH compared to separate tumor clones, seeds, and in children with both eyes affected (1/3 of cases). We expect to determine the level of tumor heterogeneity in the AH which will be critically informative to the biology of tumorigenesis. We further expect to refine the role of 6p gain as a prognostic biomarker in a larger cohort of eyes. While RB is a rare cancer, its consequences are devastating – including loss of vision, eyes, and life. Unlike most solid tumors, RB cannot be biopsied due to the risk of tumor spread outside the eye. To overcome this problem, we aim to establish the aqueous humor as a liquid biopsy. This technique safely overcomes the contraindication to biopsy and allows us to correlate tumor markers with clinical outcomes. This is critically needed for children with RB.
• RB is a rare tumor that forms in the eyes of young children: it can affect one or both eyes, be blinding and deadly to the child. Unlike most other solid tumors, biopsy in contraindicated for RB due to the risk of tumor spread outside the eye.
• Our novel research demonstrated that the aqueous humor, the clear fluid in the front of the eye, can be safely used as a liquid biopsy for RB. A liquid biopsy uses fluid (often blood, or urine), instead of tumor tissue, to evaluate for floating tumor cells or snippets of cell-free DNA –this overcomes the need for invasive tissue biopsy.
• RB tumors shed cell-free DNA into the aqueous humor and there are biomarkers which may be used to predict treatment response and the likelihood that an eye may need to be surgically removed due to aggressive disease.
• This proposal aims to refine the aqueous humor as a liquid biopsy for RB by evaluating differences in genomic tumor profiles in the aqueous humor in eyes with multiple tumors, with small pieces of tumor floating in the eye called seeds (a bad finding) and in children with cancer in both eyes.
• The goal is to determine the level of tumor heterogeneity in the aqueous humor which is critical to our understanding of the biology of tumor growth
• We expect this research will establish diagnostic and prognostic biomarkers in the aqueous humor for children with eye cancer.
• This liquid biopsy technique has tremendous potential to change our understanding of tumor growth in RB, but more so, to change paradigms of diagnosis, prognosis and treatment protocols for this pediatric cancer.

2018

Scholar Grant

Eugene Kim

Los Angeles, CA

Altering the Premetastatic Niche by Targeting CCL2 and CCL7 in Metastatic Neuroblastoma

Nearly 80% of patients with high-risk neuroblastoma will achieve a cancer-free state after initial chemotherapy and surgery, however, the majority of these children eventually die from recurrent metastatic disease–tumor spread throughout the body–and unfortunately there are no effective treatment options. To better study metastatic disease, we have developed a ground-breaking surgical mouse model, which faithfully simulates the human disease. This model requires two technically challenging surgical operations to implant and remove a neuroblastoma tumor in mice, leaving behind metastatic disease. From this model, we have isolated and studied these metastatic cells and found that they over-produce the genes CCL2 and CCL7 compared to regular tumor cells. CCL2 and CCL7 are molecules which have not been studied in neuroblastoma and represent exciting new targets. While immune cells in our bodies are known to fight infection, some immune cells can be dangerous and lead to tumor growth. CCL2 and CCL7 are known to promote the influx of such dangerous immune cells, which have been found to increase tumor growth and spread in other cancers. Therefore, we hypothesize that CCL2 and CCL7 are highly expressed in metastatic neuroblastoma and that suppressing them with a drug that inhibits CCL2/CCL7, will decrease metastasis and prolong survival in our mouse model of neuroblastoma. In addition, we will study actual human tumor specimens to better understand the role of these immune cells and CCL2/CCL7 in neuroblastoma. By targeting metastatic disease, this pioneering research will specifically target the primary cause of death for children with high-risk neuroblastoma.

2018

Young Investigator

Babak Moghimi

Los Angeles, CA

Impact of neuroblastoma tumor microenvironment on chimeric antigen T cell receptor therapy

In recent years, a very successful immunotherapy strategy to modify patient’s own immune cells (called T-cells) to attack cancer has been developed for children with leukemia (cancer of blood cells). These modified immune cells are called Chimeric Antigen receptor T cells (CAR-T cells). These CAR-T cells are very potent and do a better job killing cancer than any chemotherapy. However, their impressive response has been limited to cancers of blood and results have been disappointing in many solid tumors including neuroblastoma, a deadly childhood cancer of the nervous system. The reason why these CAR-T cells are not effective in neuroblastoma is not well understood. The goals of this proposal are to identify mechanisms which neuroblastoma tumor prevents the CAR-T from working. Recent discoveries have pointed out that normal cells (sometimes immune cells) within the tumor may have been co-opted by tumor cells to help them grow and evade other immune cells. We believe the reason CAR-T cells are not effective is due to the presence of these tumor-supporting normal cells (called macrophages) within the tumor environment. Our aims are 1) to identify changes that occur in the tumor environment when CAR-T cells are infused using animal models and identify mechanisms used by tumors to resist CAR-T therapy and 2) test certain drugs that we have identified that block the communication between pro-tumor normal cells and neuroblastoma tumor cells and see their effect on CAR-T cells effectiveness. In this proposal, we will utilize latest sophisticated technology to analyze immune cells in the tumors of mice treated with CAR-T cells. Successful completion of aim 2 in our mouse clinical trials using two FDA approved drugs should provide the rationale for combining these agents with CAR-T cells. Our results would provide pre-clinical evidence to quickly establish clinical trials in children with relapsed neuroblastoma through the 14-hospital new approaches to neuroblastoma therapy (NANT) consortium headquartered at our hospital.