Research projects

This proposal focusses on high-grade non-muscle invasive bladder cancer (hg-NMIBC), an aggressive but neglected subgroup of a highly costly human neoplasm. We aim to thoroughly characterize the microbiome profile of treatment-naïve human hg-NMIBC and investigate its association with immune infiltrates and response to BCG, the standard immune-based therapy of this type of cancer (Aim 1). We will perform dynamic profiling of the changes in microbial and immune composition of tumors in the context of a prospective study of hg-NMIBC patients receiving BCG (Aim 2). Lastly, we will study the molecular mechanisms involved using syngeneic chemical carcinogenesis mouse models of hg-NMIBC i) to test the effect of bacterial species identified in Aims 1 and 2 on the local and systemic immune landscape and response to intravesival BCG, and ii) to assess whether the findings from (i) are recapitulated in human tumors from patients treated with intravesical BCG (Aim 3) . We have identified the groups of patients to be included in objective 1 and we have recovered the tumor tissue samples paired with urine samples from these patients (N=125). We have carried out pilot studies in coordination with the WIS to identify the best performing DNA extraction procedures from urine samples. The protocols have been established and the extraction of DNA and RNA from both types of samples is being completed. We have designed and translated the questionnaires into English, implemented the databases in RedCAP, and fine-tuned the sample collection protocols (blood, urine, feces, and tissue) to begin the prospective study (objective 2). Permits are currently being completed to carry out this study in five Spanish hospitals and two in Israel.