Construction and Validation of the Replicative Retroviral Vector RRV-p14ARF in Solid Tumor Models

• Grant number: 25/08334-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2025
• End date: August 31, 2027
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Mariana Barbosa de Souza
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Cancer is considered one of the main causes of death worldwide, with a worsening epidemiological outlook given that 32.6 million new cases and 16.9 million cancer-related deaths are expected by the year 2045. The most widely used therapeutic approaches, such as surgery, chemotherapy and radiotherapy, still have considerable limitations in their effectiveness, such as the risk of resistance to treatment, tumor recurrence and toxicity to the patient. Because of these problems, immunotherapy stands out as an excellent therapeutic proposal for cancer treatment, since it offers precise targeting of cancer cells and simultaneously strengthens the immune system's responses in all their complexity. Among the methodological aspects of immunotherapy, the induction of oncolysis mediated by gene transfer brings great therapeutic value to translational oncology. Gene delivery vectors modified from the MLV retrovirus to transfer suicide genes have been widely explored as oncolytic effectors. As an example of such a therapeutic tool, the replicative retroviral vector (RRV) Toca511 - vocimagene amiretrorepvec (AC3yCD2) promotes the integration of the cytosine desaminase transgene, responsible for converting the prodrug 5-FC into the chemotherapeutic 5-FU, into the genome of tumor cells, inducing cell death. With Toca511, the RRV system proved to be an excellent proposal for the treatment of solid tumors, presenting a safe therapeutic profile. However, the phase III clinical trials were inconclusive as to its effectiveness, thus making further efforts necessary to improve and develop the RRV system as an immunotherapeutic tool. Therefore, based on the oncolytic effects of gene transfer of p14ARF (CDKN2a, alternate reading frame - ARF) using adenoviral vectors observed in previous work, we now propose the construction and validation of replicative retroviral vectors (RRV) as platforms for the delivery of cDNA encoding p14ARF as an oncolytic effector in solid tumor models. (AU)