Beyond a prognostic factor: uncovering the use of CTCs as a source of tumor RNA for cancer therapy

• Grant number: 24/22431-8
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 28, 2025
• End date: April 27, 2026
• Field of knowledge: Biological Sciences - Immunology - Applied Immunology
• Principal Investigator: Jose Alexandre Marzagão Barbuto
• Grantee: Giovanna Manga Guimarães
• Supervisor: Massimo Cristofanilli
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Weill Cornell Medical College, United States
• Associated to the scholarship: 22/06056-7 - Vaccines based on dendritic cells transfected with RNA from tumor biopsies or circulating tumor cells: a new immunotherapeutic strategy in the context of breast cancer?, BP.DR

Abstract

Despite the pivotal impact of target therapies and immunotherapy on cancer cure rates, tumor metastasis remains a major challenge to be overcome, being the leading cause of cancer-related death worldwide. In this sense, it is crucial not just to expand our understanding about the biology of tumor cell dissemination but also to translate the knowledge acquired so far into effective therapeutic strategies. Considering this scenario, liquid biopsies have emerged as a minimum-invasive way to evaluate patient's prognostic and response to treatment, comprising tumor's circulating DNA (ctDNA), extracellular vesicles and circulating tumor cells (CTCs). Of these, the use of CTCs stood out due to its prognostic impact in many cancers, with different isolation techniques being developed. In parallel, RNA vaccines were brought back into spotlight after SARS-CoV-2 pandemic, with new advances in mRNA optimization and delivery. The technique is now being also tested for cancer therapy, with promising results. Here, we propose a new way of integrating the use of CTCs and mRNA technology for cancer personalized therapy by (1) testing three different CTCs isolation techniques for subsequent RNA extraction and analysis; (2) applying the chosen technique to blood samples from breast cancer patients with HER2+ tumors; (3) testing if the RNA extracted from CTCs represents their antigenic profile at a protein level and (4) transfecting monocyte-derived dendritic cells (mo-DC) with the RNA in order to see if the transfection results in tumor antigen expression by the cells. Such strategy may provide novel insights into distinct ways of using CTCs, beyond its prognostic value, also contributing for the advancement of active cancer immunotherapy that could be designed taking into account the antigenic profile of metastatic tumor cells.