Multiscale Models of VEGF-mediated Molecular Signaling Pathways in Intratumoral Angiogenesis.

Tumor-induced angiogenesis is a highly complex process involving several cellular and subcellular events, and is critically dependent upon the activities of endothelial cells and the chemokines that stimulate them. Therefore a better understanding of it's mechanisms is essential for the development of anti cancer therapies. The goals of this dissertation are threefold: (1) detailed modelling of growth factor- receptor interactions, at a molecular level, (2) application of this information to aid the development of a multiscale delay differential equation (DDE) model of tumor angiogenesis, relating processes occurring at a cellular and intracellular level with global population behavior dynamics, (3) development of a hybrid model of tumor vascularization based on the theory of reinforced random walks, incorporating cellular chemotactic response to activated cell-surface receptors, governed by a novel chemotactic function. Using the DDE model, the potential of anti-angiogenic therapy targeting either the potent chemotactic and mitogenic cytokine CXCL8 or the pro-survival protein Bcl-2 for endothelial cells is evaluated. Bcl-2 is found to be the more effective target. Consequently, the model is expanded to allow for the testing of the therapeutic potential of a small molecule inhibitor of Bcl-2. A sensitivity analysis is carried out on various design parameters to aid in drug development. These results provide insight into the functioning of molecular signaling pathways that govern tumor growth and vascular development. Finally, a hybrid model of tumor angiogenesis is proposed which is, to the best of our knowledge, the first of its kind to account for experimentally observed phenomena such as endothelial cell polarization and response to activated cell-surface receptors. This lays the perfect groundwork for the incorporation of further details at a molecular level, of subcellular signaling cascades in models of tumor vascularization, that are able to account for spatial inhomogeneity in intra-tumoral vascular networks. Continued quantitative modelling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines.Ph.D.MathematicsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61597/1/hjain_1.pd

Combining Androgen Deprivation and Immunotherapy in Prostate Cancer Treatment: A Mechanistic Approach

Due to its initial dependence on testosterone, prostate cancer patients are initially treated with androgen deprivation therapy, a form of chemical castration. However, in many cases, the cancer develops resistance to this treatment. Sipuleucel-T (Provenge), is the first live cell vaccine approved for treating patients with advanced, hormonally refractive prostate cancer. However, it has shown limited survival benefit. Recently, it has been proposed that combining Provenge with androgen deprivation may result in a better treatment outcome. Here, we develop a nonlinear dynamical systems model with a view to predicting the therapeutic potential of such a combination. Our model accounts for the mechanism of action of Provenge and the immune system response elicited by androgen deprivation. We use data from mouse xenograft experiments to calibrate and validate our model. The validated model is then used to explain the limited clinical success of Provenge, and predict optimal scheduling that maximizes the anti-tumor potential of Provenge combined with androgen deprivation. In particular, we demonstrate that the two treatments should be given concurrently, rather than sequentially, as is current practice

Combining Androgen Deprivation and Immunotherapy in Prostate Cancer Treatment: A Mechanistic Approach

Due to its initial dependence on testosterone, prostate cancer patients are initially treated with androgen deprivation therapy, a form of chemical castration. However, in many cases, the cancer develops resistance to this treatment. Sipuleucel-T (Provenge), is the first live cell vaccine approved for treating patients with advanced, hormonally refractive prostate cancer. However, it has shown limited survival benefit. Recently, it has been proposed that combining Provenge with androgen deprivation may result in a better treatment outcome. Here, we develop a nonlinear dynamical systems model with a view to predicting the therapeutic potential of such a combination. Our model accounts for the mechanism of action of Provenge and the immune system response elicited by androgen deprivation. We use data from mouse xenograft experiments to calibrate and validate our model. The validated model is then used to explain the limited clinical success of Provenge, and predict optimal scheduling that maximizes the anti-tumor potential of Provenge combined with androgen deprivation. In particular, we demonstrate that the two treatments should be given concurrently, rather than sequentially, as is current practice

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas.

Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against in vivo experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics

Exploiting the Synergy between Carboplatin and ABT-737 in the Treatment of Ovarian Carcinomas

<div><p>Platinum drug-resistance in ovarian cancers mediated by anti-apoptotic proteins such as Bcl-xL is a major factor contributing to the chemotherapeutic resistance of recurrent disease. Consequently, concurrent inhibition of Bcl-xL in combination with chemotherapy may improve treatment outcomes for patients. Here, we develop a mathematical model to investigate the potential of combination therapy with ABT-737, a small molecule inhibitor of Bcl-xL, and carboplatin, a platinum-based drug, on a simulated tumor xenograft. The model is calibrated against <i>in vivo</i> experimental data, wherein xenografts established in mice were treated with ABT-737 and/or carboplatin on a fixed periodic schedule. The validated model is used to predict the minimum drug load that will achieve a predetermined level of tumor growth inhibition, thereby maximizing the synergy between the two drugs. Our simulations suggest that the infusion-duration of each carboplatin dose is a critical parameter, with an 8-hour infusion of carboplatin given weekly combined with a daily bolus dose of ABT-737 predicted to minimize residual disease. The potential of combination therapy to prevent or delay the onset of carboplatin-resistance is also investigated. When resistance is acquired as a result of aberrant DNA-damage repair in cells treated with carboplatin, drug delivery schedules that induce tumor remission with even low doses of combination therapy can be identified. Intrinsic resistance due to pre-existing cohorts of resistant cells precludes tumor regression, but dosing strategies that extend disease-free survival periods can still be identified. These results highlight the potential of our model to accelerate the development of novel therapeutics such as BH3 mimetics.</p></div