bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A33: An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma
Authors: Shirinifard Abbas , Thiagarajan Suresh , Patel Yogesh T. , Davis Abigail D. , Jacus Megan O. , Roberts Jessica , Stewart Clinton F. , Sablauer András 
Published: March 2017

Abstract
Resistance to chemotherapeutics and targeted therapies in pediatric solid tumors including neuroblastoma is a common cause of poor clinical outcome. These failures in part stem from shortcomings in understanding inter- and intra-tumor heterogeneities of drug penetration due to heterogeneities in blood perfusion. Herein we present an individualized predictive three-dimensional (3D) model of tumor response to topotecan (TPT) for a patient-derived orthotopic xenograft model of pediatric NB5 neuroblastoma. This model is integrated with an individualized physiologically-based pharmacokinetic (PBPK) model of TPT and accounts for the effects of inter- and intra-tumor heterogeneities in blood perfusion on tumor response. This model uses a set of 3D reaction-diffusion equations to simulate transport of TPT from blood vessels into the tumor tissue and its flux in and out of intracellular space. The transport model takes inputs from three spatial scales (systemic, tissue and cells) to predict TPT exposure maps defined over the volume of an individual tumor: a) plasma concentration-time profiles from an individualized physiologically-based pharmacokinetic (PBPK) model of TPT, b) 3D blood perfusion map of the individual tumor from contrast enhanced ultrasound (CEUS) using VEVO 2100 imaging system, and c) in vitro TPT cellular uptake and efflux kinetics from two-photon imaging. The transport model also gives feedback to the PBPK model. We use in vitro pharmacodynamics (PD) experiments with NB5 cells exposed to TPT to derive probabilistic PD-rules for drug effects (γ-H2AX response). Based on these rules and exposure maps predicted by the transport model, we then compute probabilities of effects for the entire tumor volume. We validate the predicted drug effect maps by comparing them to observed effect data (from three dosage levels) measured by immunohistochemistry marker for γ-H2AX from the same tumor (location matched serial sections) using spatial correlation techniques.
Citation Format: Abbas Shirinifard, Suresh Thiagarajan, Yogesh T. Patel, Abigail D. Davis, Megan O. Jacus, Jessica Roberts, Clinton F. Stewart, András Sablauer. An individualized predictive 3D model of tumor response to topotecan for a patient-derived orthotopic xenograft model of pediatric neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A33.
Abstract A36: Study of stromal mechanoregulation of tumor metabolism and growth dynamics
Authors: Anderson Michael , Celli Jonathan , El-Hamidi Hamid 
Published: March 2017

Abstract
As tumors develop and mature they are subjugated to compressive forces and a rigid stroma. This is particularly true in pancreatic cancer where its defining feature is a particularly rigid and fibrous stroma. The mechanical properties of the stroma can have a large influence on the growth behavior and invasiveness of tumors. An intriguing recent example of this is that the PI3K pathway is activated via integrin engagement on a rigid stroma and can affect some metabolic pathways. What makes this exciting is that both the stromal stiffness and reprogrammed metabolism have long been known to be features of cancer and this showed that these features may be intertwined in a feedback loop. From another angle, tumors are subjugated to high compressive forces and many have shown that this force can alter spheroid growth dynamics and shift cells to a more invasive phenotype. While compressive stress on spheroid growth certainly influences its growth dynamics, it is unclear whether it is due to stress or strain on the spheroid. Additionally, it implicates compressive force in altering the cellular metabolism as well. Going a step further, extracellular acidity is a well-known phenotype of solid tumors and is intrinsically linked to an altered metabolism. To study this feedback loop between stromal mechanical properties and metabolism/acidity we will utilize two different models alongside the pH dependent fluorophore, SNARF. The first is a hybrid gel model that is constructed of a base polyacrylamide (PA) layer that is covalently bound to select ECM proteins such as matrix gel and collagen. The second is a spheroid embedded in agarose model in which a base coat of agarose is applied to the bottom of each well in a multiwall plate and after setting, an ungelled mixture of spheroids, agarose and fluorescently labelled latex beads are poured over the base coat and allowed to set. The agarose is bio inert and cannot be broken down by cells. Thus it effectively acts like a compressible, non-integrin activating, isotropic media that completely surrounds the embedded spheroid. To study the cell packing density we will explore a model that predicts strain on an embedded spheroid due to compressive stress drives the cell density in spheroids. To experimentally explore this model, we will use the spheroid embedded in agarose model and vary starting implanted spheroid sizes, but remove them from the agarose at identical stress levels. All of this together will lead us to a better understanding of how the cell metabolism/pHe and tumor cell packing are mechanoregulated by the stroma.
Citation Format: Michael Anderson, Jonathan Celli, Hamid El-Hamidi. Study of stromal mechanoregulation of tumor metabolism and growth dynamics. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A36.
Abstract A48: Computational modeling of vessel growth and blood flow in the tumor microvasculature
Authors: Lee Tae-Rin , Yoo Sung Sic , Jo Junhong , Go Anna , Seo Hyung-Kwon 
Published: March 2017

Abstract
Tumor-induced angiogenesis is important to understand the mechanism of tumor growth. However, due to its heterogeneous microenvironment, it is challenging to elucidate the correlation between tumor growth and angiogenesis. In this talk, we develop a computational model of tumor-induced angiogenesis with blood flow. The complex steps of angiogenesis are expressed by mathematical models from diffusion of growth factor, sprouting from existing vessels, vessel growth and anastomosis. Furthermore, the blood flow in the new vessels is simulated by using one dimensional flow model with hematocrit redistribution. First of all, the computational model will be validated by comparing with experimental data. In addition, the developed model will be tested in predicting tumor-induced angiogenesis with different model parameters. Finally, the future perspectives of computational modeling in tumor-induced angiogenesis will be fully discussed.
Note: This abstract was not presented at the conference.
Citation Format: Tae-Rin Lee, Sung Sic Yoo, Junhong Jo, Anna Go, Hyung-Kwon Seo. Computational modeling of vessel growth and blood flow in the tumor microvasculature. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A48.
Abstract A62: Unjamming and spreading of a cellular aggregate as a model of breast cancer migration
Authors: Wang Karin , Fredberg Jeffrey J. 
Published: March 2017

Abstract
Traditional understanding holds that metastasis begins as tumor cells undergo epithelial-to-mesenchymal transition (EMT) to migrate and escape. Recent studies suggest that EMT is not necessary for metastasis, however. Tumor cells may retain their epithelial phenotype to migrate collectively during metastasis. But if EMT is not the crucial permissive step, what is?
Our group recently discovered cellular jamming; a process by which an epithelial layer is dormant, non-migratory, and solid-like, corresponding to the jammed state, but in other circumstances becomes active, migratory, and fluid-like, corresponding to the unjammed state. Therefore, based on this phenomenon, do breast cancer cells unjam before they can collectively migrate and metastasize? Spheroidal aggregates of MCF10A and MDA-MB-231 cells spreading on collagen-coated polyacrylamide gels, modeling normal and malignant breast epithelium, respectively, were used to investigate cell jamming, cell-matrix adhesion, and associated traction forces.
Compared with MCF10A spheroids, MDA-MB-231 spheroids permeated more rapidly onto gels, generated largely localized traction forces, and dissociated to spread more rapidly outwards. These results suggest MDA-MB-231 cells are more susceptible to unjamming and collective migration. This work will provide a new framework by which to explain collective cellular behavior of normal and malignant breast epithelium.
Citation Format: Karin Wang, Jeffrey J. Fredberg. Unjamming and spreading of a cellular aggregate as a model of breast cancer migration. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr A62.
Abstract B13: High-content imaging to quantitate colorectal cancer associated fibroblast heterogeneity
Authors: Garvey Colleen M. , Chen Oscar , Lau Roy , Mumenthaler Shannon M. 
Published: March 2017

Abstract
Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment known to influence various aspects of tumor progression, including response to therapy. However, this stromal cell subtype is extremely heterogeneous, both between and within individual tumors. Targeting of the CAF population has not been successful in the clinical setting, which could be due in part to the myriad of functions of different CAF subpopulations. In order to elucidate the overall implications of CAF heterogeneity, we gathered quantitative phenotypic data using a novel high-content imaging platform. Specifically, we calculated several morphological parameter values and estimated birth and death rates of individual populations of CAFs isolated from colorectal cancer patients. We also performed co-culture experiments with tumor cells and characterized the influence of different CAF populations on tumor evolutionary dynamics (i.e. birth and death rates) in response to drug treatment. Further, these features were correlated to molecular analyses (i.e. -smooth muscle actin and fibroblasts activated protein expression) and patient outcome (i.e. sites of metastasis). We observed high levels of heterogeneity in cell area and cell roundness as well as altered rates of growth in response to perturbations in oxygen levels. This quantitative method for investigating multiple cellular phenotypes provides novel insight into patient-level heterogeneity and its possible implications on response to drug.
Citation Format: Colleen M. Garvey, Oscar Chen, Roy Lau, Shannon M. Mumenthaler. High-content imaging to quantitate colorectal cancer associated fibroblast heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B13.
Abstract B14: The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles
Authors: Gaustad Jon-Vidar , Simonsen Trude G. , Andersen Lise Mari K. , Rofstad Einar K. 
Published: March 2017

Abstract
The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. Treatments with these agents have induced substantial reductions in vessel density in some tumor models, and minor or no reductions in vessel density in others. Additionally, the treatments have improved vascular function and oxygenation in some tumor models, and induced hypoxia in others. The purpose of this study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature in melanoma xenografts with different angiogenic profiles.
A-07, U-25, D-12, and R-18 melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Tumor-bearing mice were treated with sunitinib (40 mg/kg/day) or vehicle. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply times were assessed from first-pass imaging movies recorded after a bolus of 155 kD tetramethylrhodamine isothiocyanate-labeled dextran was injected intravenously. Tumor hypoxia was assessed in immunohistochemical preparations by using pimonidazole as hypoxia marker, and the gene expression and the protein secretion rate of angiogenic factors were assessed by quantitative PCR and ELISA, respectively.
The melanoma lines differed substantially in the expression of VEGF-A, VEGF-C, and platelet-derived growth factor A. Sunitinib treatment reduced vessel densities and induced hypoxia in all melanoma lines, and the magnitude of the effect was associated with the gene expression and protein secretion rate of VEGF-A. Sunitinib treatment also increased vessel segment lengths, reduced the number of small-diameter vessels, and inhibited growth-induced increases in the diameter of surviving vessels, but did not affect blood supply times.
In conclusion, sunitinib treatment did not improve vascular function but reduced vessel density and induced hypoxia in human melanoma xenografts. The magnitude of the treatment-induced effect was associated with the angiogenic profiles of the melanoma lines.
Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad. The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B14.
Abstract B37: Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in extracellular space
Authors: Eldridge Brittany , Bernish Brian , Fahrenholtz Cale , Singh Ravi 
Published: March 2017

Abstract
Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor with a 5 year overall survival rate of approximately 5%. Currently, no therapy is curative and all have significant side effects. Focal thermal ablative therapies that heat malignant tissue to ablative temperatures (&gt;55°C) to induce tumor cell death are being investigated as a novel treatment modality. Such thermal ablative therapies can be enhanced by using nanotechnology, with the addition of nanoparticles. Carbon nanotube mediated thermal therapy (CNMTT) uses lasers that emit near infrared radiation to excite carbon nanotubes (CNTs) localized to the tumor volume to generate localized heat needed for thermal ablation. Clinical translation of CNMTT for GBM will require development of effective strategies to deliver CNTs to tumors, clear structure-activity and structure-toxicity evaluation, and an understanding of the effects of inherent and acquired thermotolerance on the efficacy of treatment. In our studies, we look at the effects of different coatings on multiwalled CNT (MWCNTs) diffusion and show that a dense coating of phospholipid-poly(ethylene glycol) on MWCNTs allows for better diffusion through brain ECM-mimicking hydrogels, while maintaining the ability to achieve ablative temperatures after laser exposure. We investigate the effects of phospholipid-poly(ethylene glycol) coated MWCNTs on the heat shock response in GBM and show that they do not induce a HSR in GBM cell lines. Activation of the HSR in GBM cells via exposure to sub-ablative temperatures or short term treatment with an inhibitor of heat shock protein 90 (17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG)), induces a protective heat shock response that results in thermotolerance and protects against CNMTT. Finally, we evaluate the potential for CNMTT to selectively heat GBM multicellular spheroids comparing different methods of heat generation in a three dimensional spheroid model. These data provide pre-clinical insight into key parameters needed for translation of CNMTT including nanoparticle delivery through a three-dimensional volume, cytotoxicity, and efficacy for treatment of thermotolerant GBM.
Citation Format: Brittany Eldridge, Brian Bernish, Cale Fahrenholtz, Ravi Singh. Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in extracellular space. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B37.
Abstract B57: RNAi Nanotechnology for Cancer Target Validation and Therapy
Authors: Shi Jinjun 
Published: March 2017

Abstract
RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets, and for treatment of a myriad of important human diseases including cancer. The ubiquitous application of RNAi in cancer research and therapy is nevertheless hindered by the challenge of effective systemic in vivo delivery of RNAi agents (e.g., siRNA) to solid tumors, which requires overcoming of multiple physiological barriers, such as enzymatic degradation, rapid elimination by renal excretion or by the mononuclear phagocyte system (MPS), poor tumor penetration, and insufficient cellular uptake and endosomal escape. Here we will describe the rational design and development of unique nanoparticle platforms to address these obstacles. These siRNA nanoparticles have been successfully applied to evaluate the therapeutic role of different targets (e.g., prohibitin1) in treating solid tumors, and have demonstrated significant potential for the clinical development of novel cancer therapies.
Note: This abstract was not presented at the conference.
Citation Format: Jinjun Shi. RNAi Nanotechnology for Cancer Target Validation and Therapy. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B57.
Abstract B61: Intratumoral oxygen gradients mediate sarcoma cell invasion
Authors: Lewis Daniel M. , Park Kyung Min , Eisinger-Mathason T.S. Karin , Simon Celeste , Gerecht Sharon 
Published: March 2017

Abstract
Hypoxia is a critical factor in the progression and metastasis of many cancers including soft tissue sarcomas. Frequently, oxygen (O2) gradients develop in tumors as they grow beyond their vascular supply leading to heterogeneous areas of O2 depletion. Here we report the impact of hypoxic O2 gradients on sarcoma cell invasion and migration. O2 gradient measurements showed that large sarcoms mouse tumors (&gt;300mm3) contain a severely hypoxic core (≤0.1% pO2) whereas smaller tumors possessed hypoxic gradients throughout the tumor mass (0.1%-6% pO2). To analyze tumor invasion, we utilized O2-controllable hydrogels to recreate the physio-pathological O2 levels in vitro. Small tumor grafts encapsulated in the hydrogels revealed increased invasion that was both faster and extended over a longer-distance in the hypoxic hydrogels compared to nonhypoxic hydrogels. To accurately model the effect of the O2 gradient, we examined individual sarcoma cells embedded in the O2-controllable hydrogel. We observed that hypoxic gradients guide sarcoma cell motility and matrix remodeling through HIF1α activation. We further found that in the hypoxic gradient, individual cells migrate more quickly, across longer distances, and in the direction of increasing O2 tension. Treatment with minoxidil, inhibitor of hypoxia-induced sarcoma metastasis, abrogated cell migration and matrix remodeling in the hypoxic gradient. Overall, we show that O2 acts as a 3D physico-tactic agent during sarcoma tumor invasion and propose the O2-controllable hydrogels as a predictive system to study early stages of the metastatic process and therapeutic targets.
Citation Format: Daniel M. Lewis, Kyung Min Park, T.S. Karin Eisinger-Mathason, Celeste Simon, Sharon Gerecht. Intratumoral oxygen gradients mediate sarcoma cell invasion. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B61.
Abstract B62: Role of the blood microenvironment in the upregulation of oncoproteins in circulating pancreatic cancer cells
Authors: Mitrugno Annachiara , Pelz Katherine , Sears Rosalie , McCarty Owen 
Published: March 2017

Abstract
Background: Platelets are promoters of cancer cell proliferation at the metastatic niche, however the exact mechanism(s) by which platelets drive cancer cell proliferation remain ill-defined. The oncoprotein c-MYC, which governs neoplastic proliferation, is overexpressed in pancreatic tumors at the metastatic site as compared to primary tumors, with the overexpression of c-MYC indicative of a poor clinical outcome for patients with cancer. At present, the oncogenic pathways mediating c-MYC upregulation in metastatic cancer cells are largely unknown. Our exciting preliminary data demonstrate for the first time that platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells, suggesting a novel prometastatic role for platelets in pancreatic cancer.
Aims: To define the mechanisms by which platelets upregulate c-MYC protein levels in PANC-1 pancreatic cancer cells.
Methods: We utilized a co-culture platform to examine the effect of resting and thrombin-stimulated human platelets as well as platelet fractions (platelet-derived membrane bound molecules and soluble molecules) on c-MYC expression in PANC-1 cancer cells. Platelet inhibitors, including the GPIIbIIIa blocker Integrilin, were used to study the molecular mechanisms by which platelets upregulate c-MYC expression in cancer cells. Changes in c-MYC oncoprotein were detected by Western Blotting. The physical association between platelets and PANC-1 cancer cells was quantified by immunoblotting with an anti-GPIIb antibody against the platelet-specific integrin GPIIbIIIa.
Results: Resting and activated platelets as well as platelet fractions induced an upregulation of c-MYC expression in PANC-1 cancer cells. The effect of platelets on c-MYC expression was largely dependent on direct contact with the cancer cells, as the preincubation of platelets with Integrilin reduced platelet-induced c-MYC expression.
Conclusion: We show that the expression of c-MYC in PANC-1 cancer cells can be upregulated by platelets, revealing a novel mechanism of platelet action in the progression of cancer and suggesting that the overexpression of c-MYC at the metastatic niche may be inhibited through the use of platelet inhibitors. We are currently characterizing the molecular underpinnings of platelet-mediated c-MYC regulation with respect to the contribution of platelets to cancer cell proliferation and growth.
Citation Format: Annachiara Mitrugno, Katherine Pelz, Rosalie Sears, Owen McCarty. Role of the blood microenvironment in the upregulation of oncoproteins in circulating pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B62.