In Vivo Xenografts, Pharmacokinetics & Pharmacodynamics
Below are additional details on each division and their role in helping to advance the Penrose scientific platform.
The Biology Division consists of two key areas, Cell Biology and Molecular Biology/Biochemistry. Our Cell Biology Division focuses on determining how cells function in response to our drugs and the significance of those functions in translation to drug discovery. Our scientists study the mechanisms that control the essential aspects of cell behavior, from the single cell level to the multicellular level, using bioassays to determine the potency of our drugs on a variety of cell lines. We then compare the biological response related to its mode of action with that of a control preparation. We use flow cytometry to detect and measure changes in cellular processes including mitochondrial dynamics, cell proliferation, and cell death upon treatment of our anti-cancer agents. Using enzyme activity and kinetics assays, we assess functional inhibition of critical metabolic enzymes by our anti-cancer agents, in both cell-based and purified enzyme systems. In addition, we use chemical crosslinking followed by pulldown and mass spectrometry to identify protein targets of our anti-cancer agents.
The Molecular Biology/Biochemistry Division studies the metabolism and mechanism of the diseased state cells for the development of drugs and use molecular and biochemical approaches to address questions in cancer biology. We use polymerase chain reaction (PCR) techniques and use quantitative polymerase chain reaction (qPCR) analysis to precisely measure changes in mRNA levels. To study the global changes in protein expression in cell and tissue extracts we use a variety of methods, from more traditional methods for detection and characterization of protein expression to fully automated systems. As we are exploring the genes, proteins, and metabolites involved in the drug metabolism process, we are combining them with bioinformatics tools to better address our questions with the –omics approach: genomics, proteomics and metabolomics. This comprehensive perspective addresses target identification and metabolic network understanding, which is essential in generating future discoveries.
Our Cellular Imaging Division focuses on providing visual clarity to the bio-chemical and bio-physical mechanisms undergone on the cell and tissue level in response to our drug administration and is divided between Clinical Imaging, Fluorescence Imaging and Live-cell Imaging. The Clinical Imaging clinical sector looks at Hematoxylin and Eosin stains along with other histological staining. Our scientists for their wide range of studies use the facility for imaging subcellular structures in live and fixed cells. Immunohistochemistry to image discrete components in tissue samples are performed for extensive protein diagnosis studies.
Our Fluorescence Imaging sector has advanced our knowledge of cellular biology and diseases at the molecular level. This group is using the powerful tool of fluorescence imaging to explore a broad range of experimental observations, including studies involving location and dynamics of molecules, helping to show how our drugs localize and interact with cellular structures. With the help of fluorescent dyes and proteins as labels for molecular structures and processes, we access protein expression and gene expression in cells and tissues. Our imaging experiments involves organelle staining, immunocytochemistry, reporter gene assays etc., to support the basic science research in our organization. We are also building an imaging core with epifluorescence and confocal microscopes, with enhanced optical resolution, to understand the science through visual depiction of the biological processes involved in our mechanism.
Lastly, our Live-cell Imaging team uses live-cell imaging and analysis for observing cell structures and processes in real-time and over a period of time. We also monitor cellular integrity, protein trafficking, signal transduction and enzyme activity. We study the dynamic changes in the cell environment in response to the administration of drugs, including how molecules translocate and interact within the cell after the external stimuli. Ranging from proliferation, cytotoxicity, and spheroid assays, we conduct a number of live-cell assays for comprehension of the mechanism behind our therapy.
The Pharmacology Division is comprised of In Vivo Xenografts and Pharmacokinetics/Pharmacodynamics and uses cancer cell lines originally derived from patient tumors and grown as xenografts in immunocompromised mice models. We evaluate the ability of anticancer agents to reduce tumor growth in preclinical xenograft models to provide the basis for compound optimization. Pre-clinical in vivo xenograft models have been shown to be reasonably well-correlated with human clinical outcomes. At present we are in the process of testing various tumor models with different dose regimens and dosing schedules, helping us provide maximum efficacy and minimum toxicity. We are also utilizing Patient-Derived Tumor Xenografts (PDX) models because they have the advantage of maintaining the molecular and histological heterogeneity of the original tumor. Using both cell line-based and patient-derived xenografts models for investigating cancer initiation, progression, and treatment response is critical as we optimize our treatment.
Pharmacokinetics/Pharmacodynamics provide a basis for predicting drug effects in humans through pre-clinical in vivo experimental data and help to identify the key properties of our drugs, allowing us to characterize and predict the time-course effects of drugs under physiological and pathological conditions.
Our core R&D facility, based in Plymouth, MI, is comprised of some of the best scientific minds in academia and research across five major divisions that include chemistry, biology, cellular imaging, pharmacology, and high throughput screening.