Project Term
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Columbia University Medical Center
New York, NY
United States
Project Summary
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive blood cancer with limited treatment options and poor prognosis. Our studies reveal that aberrant activation of S1PR1 drives tumor cell migration, dissemination, and survival, identifying it as an important element in malignant transformation. Because S1PR1 is a druggable target with FDA-approved inhibitors already in clinical use, this project aims to define its mechanistic role in AITL and evaluate its therapeutic potential.
Lay Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive blood cancer that develops from a type of immune cell called T follicular helper cells. For people diagnosed with AITL, the outcome is poor. Standard chemotherapy often does not work well, and many patients relapse. Cure rates remain below 30 percent, and treatment options have changed very little in the past two decades. This has created an urgent need for more effective and less toxic therapies.
Our research has uncovered a new way that AITL tumor cells grow and survive. Many patients with AITL have a genetic alteration called the RHOA G17V mutation. We found that this mutation disrupts the activity of a receptor called sphingosine one phosphate receptor one (S1PR1). In healthy immune cells, this receptor acts like a “traffic controller,” guiding cells to where they are needed and helping them survive in the right environment. In lymphoma cells, the mutation keeps this receptor constantly switched on, sending powerful signals that allow the cancer cells to thrive and resist treatment.
We have shown that AITL tumor cells use this receptor for survival and that its levels are higher in tumors than in normal cells. Importantly, we have found that drugs already approved by the Food and Drug Administration to treat other conditions can block this receptor. In our laboratory models, these drugs reduced tumor growth in cells in culture and in animal models. This offers a unique opportunity to repurpose existing medicines for a new use in lymphoma treatment, which could speed up the path to clinical trials and patient benefit.
In this project, we will: (i) understand how the RHOA mutation disrupts the normal control of S1PR1; (ii) study how abnormal S1PR1 activity drives cancer cell growth and survival; and (iii) test whether blocking S1PR1 with approved drugs can stop tumor growth in animal and patient-derived models.
Our ultimate goal is to bring new treatment options to patients more quickly by building on what already exists. By repurposing available drugs, we can potentially reduce the time and cost required to translate discoveries into clinical care. This project gives real hope for more effective and less toxic therapies for patients with AITL offering the possibility of better outcomes, longer survival, and improved quality of life.
Program