ESTIBALIZ LOPEZ RODRIGO, MD

Memorial Sloan Kettering Cancer Center

CureSearch Young Investigator Award: 2022-2025

Focus: Metastatic Osteosarcoma

Project title: Targeting macrophages in lung osteosarcomagenesis

Osteosarcoma is the most common primary bone tumor affecting children and young adults, yet, despite multiple efforts, treatment and outcomes have not changed over the past 40 years, and the presence of metastatic disease remains the main cause of death of osteosarcoma patients. Osteosarcoma recurs in approximately 30–40% of patients initially diagnosed with non-metastatic disease. The most common site of relapse is the lung, and 50–75% of patients with recurrent OS initially have lung involvement only. The presence of lung metastasis at diagnosis or relapse confers poor outcomes and long-term survival rates of only 20%.

Estibaliz Lopez Rodrigo, MD, is a CureSearch Young Investigator conducting research at the Memorial Sloan Kettering Cancer Center to develop a therapy that will disrupt osteosarcoma metastasis to the lung. Dr. Rodrigo Lopez’s project targets tumor-associated macrophages which are immune cells that can alter the immune response to cancer, reducing the ability for other immune cells to identify and destroy tumor cells. Combination of therapies targeting macrophages and chemotherapy is known to improve overall survival of osteosarcoma patients, yet the mechanism that underlies this synergy has not been fully elucidated. The development of more efficient treatment strategies requires the understanding of which and how macrophages interfere with osteosarcoma growth, both in primary and metastatic sites. Dr. Lopez Rodrigo hypothesizes that a specific set of macrophages are pro-tumorigenic, meaning that they promote osteosarcoma growth and metastasis (movement out of the bone and into the lung). She aims to determine how removal of pro-tumorigenic macrophages in the lung will prevent osteosarcoma metastasis to the lung. Upon identifying the mechanism by which macrophages promote osteosarcoma metastasis, she will ascertain therapies that disrupt the pro-tumorigenic functions of macrophages and assess their effectiveness in mouse models of metastatic osteosarcoma.

Dr. Rodrigo's Bio

My training as a physician scientist in pediatric oncology focused on the crosstalk between developmental biology and pediatric oncology. During my fellowship at MSKCC, I trained to create and characterize genetically engineered mouse models (GEMMs) for the generation of primary pediatric tumor models. This skillset combined with my clinical insight led me to develop a model of neurodegenerative disease in histiocytosis for which I started working with Dr. Geissmann. For the past 3 years in Dr Geissmann’s lab, driven by his mentorship and the labs expertise, I have narrowed my focus on the study of the role of the microenvironment, and in particular tissue resident macrophages, in developmental tumors, generating models that allow functional characterization studies in mice. My initial work focused on microglia (brain resident macrophage), and its role in histiocytosis neurodegeneration and glioma malignant transformation in mice. Yet, as a pediatric oncologist, the question on the therapeutic role of macrophages is invariably linked to osteosarcoma, where their contribution remains unanswered and relevant, especially because aside from L-MTP-PE no other drug has changed the prognosis of these patients in over 40 years. Hence, over the past 2 years, with the institutional and lab’s support and expertise, I have developed a project that will allow a better characterization of the role of the different macrophage subsets in OS, with an initial focus on lung metastatic disease. Our preliminary data is encouraging, as it shows that manipulation of macrophages can have a major impact in lung osteosarcomagenesis. The purpose of this grant is to further characterize the mechanism/s involved and to test in other validated models of OS. We would ultimately want to correlate our macrophage phenotypes with those found in human lung OS tumors. Our findings may not only help better characterize macrophages in OS, but also more precisely uncover new therapeutic strategies targeting macrophages that aim to improve prognosis of OS patients.

"The prognosis of patients affected with osteosarcoma has not changed in over 40 years, and treatment of metastatic patients remains the biggest challenge. We have uncovered new approaches manipulating macrophages that impair the development of metastatic disease in novel mouse models of osteosarcoma. Through this award from CureSearch, we want to translate our findings into therapeutic strategies and facilitate the design of more efficient immunotherapeutic approaches targeting macrophages that could be readily translated into new treatments for osteosarcoma patients."

-Estibaliz Lopez Rodrigo

ESTIBALIZ LOPEZ RODRIGO, MD – YOUNG INVESTIGATOR – METASTATIC OSTEOSARCOMA