Modular a Diversidade do Microbioma Vaginal para Melhorar a Resposta ao Tratamento no Cancro do Ovário

VAGOME aims to develop an innovative medical device for modeling and screening potential new therapies for OC, with the long-term general objective of unraveling the complex interplay between VD and OC. This goal directly addresses the important clinical challenge posed by animal models, which frequently exhibit a bacterial microbiome distinct from those of humans. For this, we have defined the following specific objectives (SO) and KPIs: SO1: Develop a VDOC-on-chip model to faithfully replicate the native environment, accommodating vaginal bacteria microbiota and OC cells. This model will provide the experimental tool for interrogating the impact of VD in the development, progression, and resistance to treatment in OC. KPI: Functional organ-on-chip to study VD-OC interaction enabling long-term co-culture (72h) and drug screening. SO2: Identify how VD contributes to OC development. We will characterize the specific mechanisms of the migration of pathological bacteria towards ovarian tissue triggering the production of inflammatory events that produce BRCA1/2 mutations. KPI: Quantification of non-optimal bacterial migration, identify inflammatory cytokine released, and identify the complex interactions between genetic mutations, bacteria, and OC across various physiological conditions. SO3: Explore the use of live biotherapeutics to restore vaginal bacteria homeostasis. This involves encapsulating Lactobacillus spp. within pH-responsive microcapsules for targeted delivery. These capsules will serve as vaginal suppositories to modify non-optimal bacteria in the lower and upper female genital tract, improving treatment response. KPI: Responsive, biodegradable capsules encapsulating living Lactobacillus working; improved response to conventional anti-cancer drugs. SO4: Validate VAGOME technology using primary cervicovaginal swaps collected from patients. The samples (see Ethics) will be first characterized for bacterial microbiota content (optimal, non-optimal) and expected response, encapsulated, and subsequently injected into the chip for validation. KPI: Number of samples collected, validation of platform efficacy, and detection of OC-microbiota response on-chip. SO5: Disseminate the potential of VAGOME technologies to increase market awareness and facilitate future exploitation. KPI: 2 papers/yr; 1 book chapter, special issue, and/or book edition/yr; remote meetings with clinicians/biotech companies (1/yr); 1 webinar for the science community; 2 scientific conferences/yr; 1 invited lecture/yr. ADVANCES BEYOND THE STATE-OF-THE-ART: NOVELTY & AMBITION Several studies using next-generation sequencing and bioinformatic techniques have suggested a potential link between the vaginal bacterial microbiome and OC development. However, this causal relationship remains to be definitively established, and few models –none based on organ-on-chip technology– have addressed this challenge due to the complexities in co-culturing bacteria and mammalian cells (see State-of-the-Art section). Therefore, the development of a VDOC-on-chip platform to investigate the interaction between VD and OC represents a novel and ambitious endeavor. Additionally, the exploration of innovative biotherapeutics using stimuli-responsive capsules as a novel therapeutic approach, akin to fecal transplantation, pushes the boundaries of current research in gynecological malignancies, particularly OC.