Characterizing determinants of response and therapeutic barriers to novel antibody-drug conjugates (ADCs) targeting the Anaplastic Lymphoma Kinase (ALK) oncoprotein in neuroblastoma
Neuroblastoma is a cancer of infants and children that arises from the developing nervous system. Patients with aggressive forms of the disease, termed high-risk neuroblastoma, continue to face poor long-term survival and substantial treatment-related side effects from an intensive treatment regimen of chemotherapy, surgery, radiation, and immunotherapy. There is an urgent unmet need for more effective precision therapies that target cancer cells while sparing healthy cells to improve survival outcomes and reduce treatment-related side effects. Antibody-drug conjugates (ADCs) function as targeted chemotherapy by linking potent chemotherapy drugs to an antibody that can precisely locate and bind to a specific protein found on the surface of cells. ADCs for pediatric cancers are currently limited to leukemia and lymphoma due to the scarcity of target proteins on the surface of cancer cells that are not present on healthy cells and due to the physical barriers surrounding neuroblastoma tumors, known as the tumor microenvironment (TME). We have shown that the Anaplastic Lymphoma Kinase (ALK) is a protein present on the surface of the majority of neuroblastoma tumor cells and not present on the surface of healthy tissue cells, underscoring ALK as an attractive ADC target. We have shown that ALK can be targeted with an ADC approach in neuroblastoma and have now produced optimized ALK targeting ADCs for rigorous investigation to identify an ADC candidate for future clinical trials.
Project Goals
My project will focus on demonstrating strong and targeted antitumor activity of our optimized ALK-targeting ADCs in neuroblastoma. Using neuroblastoma tumors removed from pediatric patients during treatment, I will demonstrate ADC antitumor activity in neuroblastoma cells and in neuroblastoma tumors implanted into mice and show that this activity is dependent on the ADCs binding to ALK on the tumor cell surface. I will define how much ALK protein is required on the surface of neuroblastoma tumor cells for strong ADC antitumor activity which will serve as a guide for future patient selection. Additionally, my project will focus on identifying factors in the area surrounding neuroblastoma tumors, known as the tumor microenvironment (TME), that lead to resistance to ADC therapy. I will use a specialized mouse model that bear neuroblastoma tumors with an intact immune system to realistically model the TME. I will characterize the specific proteins and the non-tumor immune cells in the TME before and after ADC treatment to identify specific factors in the TME that can be targeted to maximize ADC antitumor activity. The objective of this project is to identify a lead ADC candidate for future clinical trials, define the amount of ALK protein required for strong ADC activity, and identify barriers to ADC therapy in the TME to improve treatment outcomes and reduce treatment-related side effects in neuroblastoma while guiding future solid tumor ADC design and combination treatments.
