G-TACs: A novel platform for ALK inhibition in neuroblastoma
Neuroblastoma is a cancer that develops in young children and is one of the leading causes of pediatric cancer-related death. While many children can be cured, those with high-risk disease often relapse despite intensive therapy, including chemotherapy, radiation, surgery, and antibody treatments. For these patients, new and more effective treatment strategies are urgently needed.
One important driver of neuroblastoma growth is a protein called ALK, which sends signals that help cancer cells survive and multiply. Although drugs that block ALK are available, they often stop working over time because cancer cells develop resistance. This highlights the need for new approaches that can more effectively shut down ALK signaling.
Our research focuses on a new type of therapy that works differently from current drugs. Instead of simply blocking ALK, we aim to change how it is organized on the surface of cancer cells. We take advantage of GD2, a molecule found at high levels on neuroblastoma cells but much less on normal tissues. By designing specialized antibodies that bind both GD2 and ALK, we aim to physically reorganize ALK on the cell surface, preventing it from sending growth signals. This innovative strategy could provide a more effective and potentially safer way to treat neuroblastoma. In the future, this approach may also be applied to other cancers, offering a new way to target disease-driving proteins.
Project Goals
The goal of this project is to develop and test a new type of targeted therapy for neuroblastoma that can more effectively stop tumor growth. We aim to create specialized antibodies, called G-TACs, that simultaneously bind two key targets on cancer cells: GD2, which is highly expressed on neuroblastoma, and ALK, a protein that drives neuroblastoma cell growth. By linking these two targets, we seek to disrupt how ALK functions on the surface of tumor cells.
In the first part of the project, we will design and optimize these G-TAC molecules to ensure they bind effectively and alter the organization of ALK on the cancer cell surface. We will study how this changes ALK signaling and whether it prevents neuroblastoma cells from growing and surviving. In the second part, we will test the most promising G-TAC candidates in laboratory models and animal models of neuroblastoma to evaluate their ability to slow or stop tumor growth.
Our ultimate goal is to establish a new treatment strategy that works differently from existing therapies by physically reorganizing cancer-driving proteins rather than simply blocking them. If successful, this approach could lead to more effective and potentially less toxic treatments for children with neuroblastoma and may open new possibilities for targeting other cancers.
