Novel Antimicrobial Approach to Treat Chemoradiation Resistant Cervical Cancer by Selectively Inhibiting Lactobacillus iners

Novel Antimicrobial Approach to Treat Chemoradiation Resistant Cervical Cancer by Selectively Inhibiting Lactobacillus iners We recently discovered a novel narrow-spectrum inhibitor of Lactobacillus iners, a commensal pathobiont of the vaginal microbiome that is implicated in decreased survival in patients undergoing treatment for cervical cancer. Current interventions cisplatin and radiation, become less effective when the tumor-specific pathotype of L. iners is present. The inhibitor, a class IIb two-peptide bacteriocin (GasK7B), kills L. iners at low nM concentrations but not beneficial Lactobacillus species, potentially providing a new, much needed treatment strategy for women with cervical cancer and dysplasia. What is the proposed project: Previous work identified and characterized bacteriocins purified from Lactobacillus paragasseri K7 cell-free supernatant. The proposed project is to synthesize the most potent bacteriocin, GasK7B, and to characterize its in vitro potency, selectivity, safety, and stability in an in vitro model. Finally, we will test in an in vitro model whether synthetic GasK7B reverses the resistance of cancer cells to chemoradiation treatment induced by cancer-associated L. iners induced resistance of cancer cells to chemo-radiation treatment. Our goal is to establish synthetic GasK7B as a drug candidate, thus paving the way for future for future IND-enabling studies. Why is the important? This inhibitor represents the first known narrow-spectrum antimicrobial agent that selectively kills L. iners without affecting most other beneficial lactobacilli of the female reproductive tract, including L. crispatus. A selective inhibitor is important because an oncogenic strain of L. iners has been strongly linked to cervical cancer and other species of vaginal lactobacilli such as L. crispatus are associated with reproductive health and decreased cervical cancer risk. Selective inhibition of the pathogenic L. iners could therefore open up new prevention and treatment strategies for cervical cancer. The L. iners inhibitor would nicely synergize with Osel’s live biotherapeutic product, LACTIN-V, that contains L. crispatus CTV- 05, that could help prevent recurrence of L. iners facilitated cervical dysplasia and cancer. LACTIN-V has completed a Phase 2b clinical trial showing a significant reduction in recurrent bacterial vaginosis (NCT02766023) and a replacement of L. iners with L. crispatus. GasK7would facilitate the removal of L. iners. We refer to this approach as microbiome deletion and replacement. How will the project be accomplished? Preliminary data established that the L. iners inhibitor is a selective bacteriocin, produced by an L. paragasseri strain K7. The inhibitor has been purified from culture supernatants and characterized. We have synthesized the inhibitor (small scale) and propose a larger scale synthesis to demonstrate that it inhibits cervical cancer-associated L. iners strains, while still not inhibiting beneficial lactobacilli such as L. crispatus. We will evaluate toxicity on vaginal epithelial cells, and organoid cultures in vitro. Finally, we will test whether synthetic GasK7B reverses the L. iners-induced resistance of cancer cells to chemo-radiation treatment using an in vitro model. These studies will enable future pre-clinical work and move this inhibitor towards an IND for clinical testing.