Tumor Extravasation in Zebrafish as a Prognostic Marker and a Therapeutic Target for Metastasis of Kidney Cancer
Abstract
Objective and Rationale: In the U.S., kidney cancer is the 7th most common cancer in men, and the 9th most common in women, with renal cell carcinoma (RCC) accounting for over 90% of cases. Recurrence after surgical removal of RCC is very high (~40%) and survival in the presence of metastasis is poor (approximately 10% in 5 years). Thus predicting and treating metastasis are crucial aspects for patients with RCC. Our proposal addresses these problems and offers novel solutions. It is widely assumed that cancer cells are released into circulation even in patients with no detectable metastasis. While metastasis involves several phases, it stands to reason that the juncture at which tumor cells exit from blood is a crucial determinant of metastatic risk. To determine whether this component can be used to predict metastasis, we will use zebrafish larvae (in which human tumor cells are allowed to survive) as a vehicle for measuring tumor-cell traffic in and out of circulation (TExZ score). An existing platform for RCC at our institution will allow us to correlate this measure with metastatic risk based on the clinical profile (including treatment outcomes). Having discovered DC-HIL and its ligand rHS (unique carbohydrates) as novel immune checkpoint molecules that inhibit T-cell defense against cancer, promote tumor angiogenesis, and regulate T-cell extravasation, we will use our monoclonal antibody (mAb) against rHS in zebrafish and mouse models to develop prognostic markers and treatments for metastatic RCC. FY22 KCRP Focus Area(s): Develop new strategies for accurate prognosis prediction and for novel therapeutic modalities of kidney cancers. What types of patients will it help, and how will it help them? We focus on patients with RCC to validate markers for predicting and treating metastasis. Our results can be applied to managing other solid cancers. What are the potential clinical applications, benefits, and risks? Zebrafish is a relatively low-cost (vs. mice and humans) and rapid mode of predicting metastasis. Targeting rHS as treatment (for which we have already created the mAb) is a new modality for RCC and potentially other cancers. What is the projected time it may take to achieve a clinically relevant outcome? 3-4 years of research. What are the likely contributions of this study to advancing the field of kidney cancer research? Our studies will expand the utility of the existing Kidney Cancer Program at UT Southwestern. It will be a game changer in predicting risk for metastasis and in preventing metastasis. Finally we should get useful information regarding how RCC behaves and how cancer cells leave blood circulation to reach secondary organs. The impact that the proposed research project results might have on the field of kidney cancer research and/or patient care in the short term and/or long term for Service Members, their Families, Veterans, and the American public. RCC is a growing cause of death and sickness among Americans, Veterans, and Military Service members and Families. Reliable predictive markers are lacking and the cancer is very unresponsiveness to currently available treatments. The innovative aspects of the proposed research project. (1) Discoveries of DC-HIL and its ligand (rHS) as regulators of immune defense vs. cancer progression. (2) Exiting of cancer cells from blood circulation is a key process of metastasis, so measuring is important. (3) Kidney Cancer Program at UT Southwestern provides a reservoir and registry of renal cell cancers. (4) Zebrafish model is a relatively economical and rapid way of studying metastasis. (5) Develop our monoclonal antibody against rHS to treat and prevent metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310596
Entities
People
- Kiyoshi Ariizumi
Organizations
- United States Army
- University of Texas Southwestern Medical Center