The QSP Industry & Academia Symposium is a seminar series for presenting, learning, and discussing topics relevant to quantitative systems pharmacology (QSP).The goal of this event is to foster an active community of industry and academic participants interested in these topics, and create a forum for sharing of successes and challenges.
Register for the Symposium: www.appliedbiomath.com/QSPIAS
Date: Wednesday, February 7, 2018
Time: 5:00 PM - 8:30 PM
Venue: Cambridge Innovation Center | 1 Broadway, Cambridge, MA 02142 | Venture Cafe, 5th Floor
5:30 PM | Networking, food, and beverages (Venture Cafe)
6:00 PM | Opening remarks by John Burke, PhD, Applied BioMath (Havana Room)
6:15 PM | Presentation by Richard Allen, PhD, Pfizer: "Assessing Fructose as a Biomarker by Modeling the Metabolic Fate of Fructose in Essential Fructosuria Subjects" (Havana Room)
7:00 PM | Presentation by Carissa Young, PhD, Applied BioMath: "3D Metastatic Breast Cancer Model Recapitulates Dormancy and Emergence" (Havana Room)
7:30 PM | Networking, food, and beverages (Venture Cafe)
8:30 PM | Event concludes
Assessing Fructose as a Biomarker by Modeling the Metabolic Fate of Fructose in Essential Fructosuria Subjects
R.J. Allen*, C.J. Musante, Internal Medicine Research Unit, Pfizer Inc, 1 Portland Street, Cambridge, MA, USA
Fructose is a major component of Western diets and is implicated in the pathogenesis of obesity and type 2 diabetes. In response to an oral challenge, the majority of fructose is cleared during “first-pass” liver metabolism, primarily via phosphorylation by ketohexokinase (KHK). A rare benign genetic deficiency in KHK, called essential fructosuria (EF), leads to altered fructose metabolism. The only reported symptom of EF is the appearance of fructose in the urine following either oral or intravenous fructose administration. Here we develop and use a mathematical model to investigate the adaptations to altered fructose metabolism in people with EF. Firstly, the model is calibrated to fit available data in normal healthy subjects. Then, to mathematically represent EF subjects we systematically implement metabolic adaptations such that model simulations match available data for this phenotype. We hypothesize that these modifications represent the major metabolic adaptations present in these subjects. This modeling approach suggests that several other aspects of fructose metabolism, beyond hepatic KHK deficiency, are altered and contribute to the etiology of this benign condition. Specifically, we predict that fructose absorption into the portal vein is altered, peripheral metabolism is slowed, renal re-absorption of fructose is mostly ablated and that alternate pathways for hepatic metabolism of fructose are up-regulated. Moreover, these findings have implications for drug discovery and development, suggesting that the therapeutic targeting of fructose metabolism could lead to unexpected metabolic adaptations, potentially due to a physiological response to high fructose conditions.
3D Metastatic Breast Cancer Model Recapitulates Dormancy and Emergence
Approximately 90% of cancer-associated mortality is a consequence of distant metastasis, a multistep process whereby cells from the primary tumor migrate to and colonize secondary organs. These cancerous cells may either proliferate immediately or lay dormant (e.g., as premalignant micrometastasis) for years before forming clinically overt macrometastases. Clinically, undetected metastases have serious implications for cancer patients; exemplified by ~ 33% of women whom suffer a metastatic relapse within 5 years following removal of breast cancer.
In general, distant metastases remain incurable as current chemotherapies are ineffective against them underscoring the need to develop improved therapeutic approaches, rationally designed and effective across a broad range of patient populations. The liver represents an ideal system to evaluate metastasis and efficacy of cancer therapeutics as: (1) a common site of metastasis for many carcinomas, and (2) the major organ for drug metabolism to assess efficacy and limiting toxicities of cancer therapies.
The absence of accessible all-human ex vivo metastatic models has hindered the identification of mechanistic insights towards targeted therapeutic intervention, plausible biomarkers of disease progression, and human-specific crosstalk between the tumor and the metastatic microenvironment. A 3D metastatic model composed of human hepatocytes, non-parenchymal cells, and breast cancer cell lines enabled the evaluation of tumor growth, dormancy, and emergence amongst multiple donors, as a consequence of chemotherapies and inflammatory stimuli. Multivariate statistical analyses integrated metrics of clinical and high-content signaling assays, thereby providing biological insights of plausible signatures and communication networks in early metastatic disease. Quality-by-design (QbD) and tissue engineering strategies further refined platform technologies. Collectively, our results recapitulate human disease pathophysiology using an all-human ex vivo microphysiological system, which may ultimately improve therapeutic strategies that target breast cancer dormancy and emergence.