The Cancer and Microbes Working Group will be holding regular meetings during the spring semester to showcase the collaborative projects initiated and supported by Cancer and Microbes connections.
Attendance is open to all. Presentations by students, postdocs, or others directly involved in the experimental workflow are encouraged.
Talk 1 - Expanding the therapeutic capacity of engineered antibody fragments
Presenter: Vince Kelly, graduate student, Bioengineering
Brief description: One of the great challenges in the development of biotherapeutics to treat cancer is the high cost associated with these drugs, both in terms of manufacturing cost and the patient’s cost for treatment. Dosing regimens requiring repeated administration, trips to a healthcare provider, and large amounts of formulated therapeutic, are a significant driver of these costs. The goal of our research is to leverage the inherent capabilities of the diverse microbial community of the human gut to reduce these costs by acting as therapeutic factories in situ. Recent developments in microbial genetics, synthetic biology, and the study of niche-optimized, non-pathogenic members of the human gut microbiota have paved the way for the engineering of commensal bacteria to carry out novel functions. Using species-specific genetic components, therapeutic production can be achieved in both transiently and persistently colonizing members of the gut microbiota. While these engineered strains can be used to treat conditions localized to the gastrointestinal tract, we are currently utilizing a protein engineering approach to expand the potential applications of engineered microbes to systemic conditions. We have fused small (15 amino acid) peptides that mimic the neonatal Fc receptor (FcRn)-binding epitopes of IgG and albumin to single-chain Fv (scFv) antibody fragments. These modifications enable pH-dependent FcRn engagement and FcRn-mediated salvage or transport across polarized epithelial cell barriers, functionally mimicking the native FcRn-mediated half-life extension and transport of IgG and albumin. This work demonstrates the potential utility of peptide-modified scFvs either as purified therapeutics or as part of an in situ delivery system. Additionally, we are now engineering similar peptide-scFv fusions to engage immune-activating receptors CD16 and CD64 to improve the anti-cancer efficacy of engineered scFvs and are simultaneously exploring microbial and non-microbial non-traditional delivery for persistent, in situ production of these therapeutics.
Talk 2
Presenter: Lindsey Ly, graduate student, Nutritional Sciences
Brief description: The gut microbiome generates steroid metabolites that act as hormones, affecting not only local physiology, but also having systemic consequences if absorbed into circulation. One microbial pathway of emerging interest is the steroid-17,20-desmolase (DesAB) pathway that converts cortisol, a C21 glucocorticoid (GC), to 11b-hydroxyandrostenedione (11b-OHAD), a C19 pro-androgen. This is of clinical significance because 11b-OHAD is a precursor to 11-oxy-androgens, a class of androgens with potent androgenic activity, which can be generated by both host and resident microbes. In this work, the number of substrates for DesAB were expanded to also include pharmaceutical analogs of cortisol using both purified recombinantly expressed DesAB (rDesAB) and whole cells from two microbes from gut and urinary tract, Clostridium scindens ATCC 35704 and Propionimicrobium lymphophilum ACS-093-V-SCH5, respectively. In vitro culturing of androgen-responsive prostate cancer cells (LNCaP) showed that 1,4-androstadiene-3,11,17-trione, the product of bacterial side-chain cleavage of prednisone, caused significant proliferation relative to vehicle at 24 and 72 hours. We hypothesize that urinary microbes inhabiting a minimal nutrient environment metabolize GCs for energy, generating androgens that diffuse into surrounding prostate tissue, which may lead to increased proliferation of androgen-dependent prostate cancer cells. To better understand the physiological function of DesAB, the in vitro cortisol-induced transcriptome of a desAB-encoding gut microbe, Butyricicoccus desmolans ATCC 43058, was analyzed using RNA-Seq. Understanding bacterial androgen production is particularly important when assessing risk and progression in diseases that are exacerbated by high androgen levels, such as prostate cancer or polycystic ovary syndrome. Basic understanding of why and how the microbes are responding to cortisol, will lead to rational modulation of the extracellular environment to shift metabolism away from side-chain cleavage of GCs, which may have translating applications for human dietary interventions if DesAB is indeed contributing to disease.
