Abordagens genômicas amplas e análise de DNA tumoral circulante para detecção de biomarcadores preditivos de resposta ao tratamento oncológico com inibidores de checkpoint imunológico

Abstract

The development of ICIs was due to better knowledge of the mechanisms of interaction between the tumor and cells of the immune system, representing a radical change and bringing substantial advances in the field of immuno-oncology. ICIs, such as anti-CTLA4 and anti-PD1, which enhance antitumor immune responses, have significantly altered the natural trajectory of several cancer types in a group of patients. However, about 60% of patients treated with ICIs are resistant to the therapy, depending on the type of cancer and the stage of the disease (Sharma et al., 2020). The search for predictive biomarkers for immunotherapy has been widely explored, with most of the evaluated candidates belonging to tumor-intrinsic biomarkers (PD-1/PD-L1 expression, tumor mutational burden (TMB)) (Liu et al., 2021) , biomarkers of the tumor microenvironment (tumor-infiltrating lymphocytes (TILs)) and systemic biomarkers (e.g., circulating factors and microbiota) (Waldman et al., 2020). However, to date, none of them have adequate sensitivity and specificity to efficiently predict patients' response to immunotherapy, which is essential to personalize and improve cancer treatment with these drugs.In this context, motivated to contribute to the countless unmet needs in cancer treatment with immunotherapy, the Center for Research in Immuno-Oncology (CRIO) was created, to which the present postdoctoral scholarship proposal is linked (Process: 2021/ 00408-6, responsible researcher: Dr. Kenneth Golob, and I participate as Principal Investigator (PI)).In a simplified way, the objectives of CRIO are to study suppression mechanisms associated with the tumor microenvironment to detect potential targets and therapeutic strategies to combat cancer; and characterize molecular and genomic changes in tumors with the potential to be predictive biomarkers of response to immunotherapy. To this end, a scientific research platform was developed containing three work plans: 1) identification of potential targets through studies in animal and cellular models; 2) use of multi-omics approaches to support the discovery of new immunomodulatory targets and potential predictive biomarkers of treatment response in tumor samples from prospective and retrospective series, and 3) validate the potential targets and biomarkers selected in work plans 1 and 2 in cellular/animal models or series of patient samples. Three types of cancer are being prioritized: colorectal cancer, non-small cell lung cancer (NSCLC) and oral cavity tumors. These neoplasms were chosen due to their relevant incidence in the global population and great impact on health (Ferlay et al., 2024). Colorectal and lung tumors stand out for being among the ten most frequent malignant neoplasms treated at A.C.Camargo from 2000 to 2020 (Mendonça et al., 2023). There is currently approval for the use of immunotherapy for the 3 neoplasms, but there is still a lack of effective therapeutic options for a significant group of patients diagnosed with these types of tumors.This proposal for a Junior Postdoctoral Fellowship (PDJ) is included in work plan 2 for the use of genomic approaches to discover potential response-predictive biomarkers.Our hypothesis is that a comprehensive genomic characterization carried out in tumor tissue will be able to provide a broad and complete view of active and inactive gene pathways and, in combination with monitoring by circulating tumor DNA (ctDNA), favor the discovery of predictive biomarkers of response to oncological treatment that includes ICI therapies. Additionally, together with the results of CRIO's multidisciplinary and complex approaches, such strategies will provide clues to the mechanisms underlying resistance to oncological treatment with ICIs and, consequently, opening new opportunities in this area. (AU)