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      Quantitative translational modeling to facilitate preclinical to clinical efficacy & toxicity translation in oncology


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          Significant scientific advances in biomedical research have expanded our knowledge of the molecular basis of carcinogenesis, mechanisms of cancer growth, and the importance of the cancer immunity cycle. However, despite scientific advances in the understanding of cancer biology, the success rate of oncology drug development remains the lowest among all therapeutic areas. In this review, some of the key translational drug development objectives in oncology will be outlined. The literature evidence of how mathematical modeling could be used to build a unifying framework to answer these questions will be summarized with recommendations on the strategies for building such a mathematical framework to facilitate the prediction of clinical efficacy and toxicity of investigational antineoplastic agents. Together, the literature evidence suggests that a rigorous and unifying preclinical to clinical translational framework based on mathematical models is extremely valuable for making go/no-go decisions in preclinical development, and for planning early clinical studies.

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          Significant scientific advances in biomedical research have expanded our knowledge of the molecular basis of carcinogenesis, mechanisms of cancer growth and the importance of the cancer immunity cycle. However, despite that in many cases drug treatment can eradicate tumors in animals, treating human tumors remains very difficult. This article describes a mathematical modeling framework to facilitate the prediction of clinical efficacy and toxicity of investigational antineoplastic agents.

          Most cited references63

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          The Hallmarks of Cancer

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            Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age.

            In the human hematopoietic system, aging is associated with decreased bone marrow cellularity, decreased adaptive immune system function, and increased incidence of anemia and other hematological disorders and malignancies. Recent studies in mice suggest that changes within the hematopoietic stem cell (HSC) population during aging contribute significantly to the manifestation of these age-associated hematopoietic pathologies. Though the mouse HSC population has been shown to change both quantitatively and functionally with age, changes in the human HSC and progenitor cell populations during aging have been incompletely characterized. To elucidate the properties of an aged human hematopoietic system that may predispose to age-associated hematopoietic dysfunction, we evaluated immunophenotypic HSC and other hematopoietic progenitor populations from healthy, hematologically normal young and elderly human bone marrow samples. We found that aged immunophenotypic human HSC increase in frequency, are less quiescent, and exhibit myeloid-biased differentiation potential compared with young HSC. Gene expression profiling revealed that aged immunophenotypic human HSC transcriptionally up-regulate genes associated with cell cycle, myeloid lineage specification, and myeloid malignancies. These age-associated alterations in the frequency, developmental potential, and gene expression profile of human HSC are similar to those changes observed in mouse HSC, suggesting that hematopoietic aging is an evolutionarily conserved process.
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              Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt.

              We consider some of the problems involved in current discussions on stem cells in adult mammalian tissues. The present concepts involve a number of pitfalls, weaknesses and logical, semantic and classification problems. This indicates the necessity for new and well-defined concepts that are amenable to experimental analysis. One of the major difficulties in considering stem cells is that they are defined in terms of their functional capabilities which can only be assessed by testing the abilities of the cells, which itself may alter their characteristics during the assay procedure: a situation similar to the uncertainty principle in physics. The terms that describe stem cell functions are often not well defined and are used loosely, which can lead to confusion. If such context-dependent interactions exist between the manipulation and measurement process and the challenged stem cells, the question of, for example, the number of stem cells, in a tissue has to be posed in a new way. Rather than obtaining a single number one might end up with various different numbers under different circumstances, all being complementary. This might suggest that stemness is not a property but a spectrum of capabilities from which to choose. This concept might facilitate a reconciliation between the different and sometimes opposing experimental results. Given certain experimental evidence, we have attempted to provide a novel concept to describe structured cell populations in tissues involving stem cells, transit cells and mature cells. It is based on the primary assumption that the proliferation and differentiation/maturation processes are in principle independent entities in the sense that each may proceed without necessarily affecting the other. Stem cells may divide without maturation while cells approaching functional competence may mature but do not divide. In contrast, transit cells divide and mature showing intermediate properties between stem cells and mature functional cells. The need to describe this transition process and the variable coupling between proliferation and maturation leads us to formulate a spiral model of cell and tissue organisation. This concept is illustrated for the intestinal epithelium. It is concluded that the small intestinal crypts contain 4-16 actual stem cells in steady state but up to 30-40 potential stem cells (clonogenic cells) which may take over stem cell properties following perturbations. This implies that transit cells can under certain circumstances behave like actual stem cells while they undergo maturation under other conditions. There is also evidence that the proliferation and differentiation/maturation processes are subject to controls that ultimately lead to a change in the spiral trajectories.(ABSTRACT TRUNCATED AT 400 WORDS)

                Author and article information

                Future Sci OA
                Future Sci OA
                Future Science OA
                Future Science Ltd (London, UK )
                June 2018
                23 April 2018
                : 4
                : 5
                : FSO306
                [1 ]Department of Drug Metabolism & Pharmacokinetics, Takeda Pharmaceuticals International Co., 35 Lansdowne Street, Cambridge, MA 02139, USA
                Author notes
                *Author for correspondence: Tel.: +1 617 444 1550; andy.zhu@ 123456takeda.com
                © 2018 Andy Z. X. Zhu

                This work is licensed under a Creative Commons Attribution 4.0 License

                : 19 December 2017
                : 12 March 2018
                : 23 April 2018

                cancer growth modeling,drug combination,gri,myelosuppression,pharmacokinetics,pk/pd,qsp,toxicity,translational,xenograft


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