Sildenafil to Prevent and Reduce Cancer Related Cognitive Impairment

Cancer related cognitive impairment (CRCI) severely impacts neurocognitive function and is characterized by deficits in memory, learning, processing speed, and executive function. This cognitive impairment commonly referred to as "brain fog" or "chemo-brain," often co-occurs with central and peripheral fatigue. Symptoms typically begin acutely with the initiation of therapy, and persist chronically throughout prolonged treatment. Despite advancements in cytotoxic chemotherapies, CRCI plagues 75% of breast cancer patients during treatment, and development of new therapeutic options have been hampered by an incomplete understanding of the underlying mechanisms that cause CRCI. Although the etiology is not clear, CRCI is known to be associated with oxidative stress, increased inflammation, and disruption to the blood-brain barrier (BBB). Importantly, the endothelial cells of the BBB protect the central nervous system (CNS) from harmful and inflammatory bloodborne factors. Similarly, endothelial and epithelial barriers in the gut prevent microbial invasion and resulting regional and systemic inflammatory signaling. Thus, gut and brain barriers regulate exposure of the CNS to inflammatory factors and represent an important source of communication in the gut-brain axis. Research suggests that cytotoxic chemotherapeutic agents compromise both brain and gut endothelial and epithelial barrier integrity, leading to extravasation of toxins and immune cells into the CNS, causing neuroinflammation and CRCI. This study proposes that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, will preserve barrier integrity during chemotherapy by downregulating oxidative and nitrosative stress that leads to endothelial dysfunction via multiple pathways. Thus, the goal of this project is to interrogate how chemotherapy-induced brain and gut barrier dysfunction mediate CRCI, neurotoxicity, and neuro- and systemic inflammation. Outcomes will be measured at baseline and throughout standard of care treatment, specifically after neoadjuvant chemotherapy, surgery, radiation treatment, chemotherapy treatment and after 24 weeks of endocrine treatment.

• Quantify absolute abundance of gut microbiome using using metagenomic analysis at baseline [Time frame: baseline]
• Quantify absolute abundance of gut microbiome using metagenomic analysis after neoadjuvant chemotherapy treatment [Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline]
• Quantify absolute abundance of gut microbiome using metagenomic analysis after surgery [Time frame: through completion of surgery, average of 24 weeks from baseline]
• Quantify absolute abundance of gut microbiome using metagenomic analysis after radiation treatment [Time frame: through radiation treatment completion, average of 30 weeks from baseline]
• Quantify absolute abundance of gut microbiome using metagenomic analysis after chemotherapy treatment [Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline]
• Quantify absolute abundance of gut microbiome using metagenomic analysis after 24 weeks of endocrine treatment [Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline]
• Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after neoadjuvant chemotherapy treatment [Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline]
• Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after surgery [Time frame: through completion of surgery, average of 24 weeks from baseline]
• Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after radiation treatment [Time frame: through radiation treatment completion, average of 30 weeks from baseline]
• Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after chemotherapy treatment [Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline]
• Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after 24 weeks of endocrine treatment [Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline]