FGFR4 and β-Klotho in Metastatic Prostate Cancer by Derek LaMar Shenefelt Fibroblast growth factors and fibroblast growth factor receptors have been associated with the aggressiveness and progression of Prostate Cancer (PCa). Also, β-Klotho is a known co-receptor with FGFR4 for FGF19 in the liver however, the role of this co-receptor pair remains unclear in the setting of PCa. I demonstrated that FGFR4 and KLB mRNA and protein are highly expressed in PCa cells when compared to bone marrow stromal cells, a common site of metastasis. I also provide support for the association of FGFR4 and KLB in PCa, suggesting a functional co-receptor pair capable of altering cellular signaling. FGFR4-KLb may also provide some level of protection to PCa cells from chemotherapeutics. This analysis of FGFR4 and KLB expression and signaling in PCa has provided novel insights into phenotypic alterations during PCa progression while also providing new avenues of study to further explore the role and importance of this exciting co-receptor complex.

published_or_final_version / Anatomy / Master / Master of Philosophy

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Hyperthermia based cancer treatments delivered under various modalities have the potential to become an effective option to eradicate the disease, maintain functionality of infected organs, and minimize complications and relapse. Moreover, hyperthermia therapies are a form of minimally invasive cancer treatment which are key to improving the quality of life post-treatment. Many modalities are available for delivering the heat source. However, the ability to control the energy deposition to prevent damage to adjacent healthy tissue is a limiting factor in all forms of thermal therapies, including cryotherapy, microwave, radio-frequency, ultrasound, and laser. The application of a laser heat source under the guidance of real-time treatment data has the potential to provide unprecedented control over the temperature field induced within the biological domain. The computational infrastructure developed in this work combines a computational model of bioheat transfer based on a nonlinear version of the Pennes equation for heterogeneous media with the precise timing and orchestration of the real-time solutions to the problems of calibration, optimal control, data transfer, registration, finite element mesh refinement, cellular damage prediction, and laser control; it is an example of Dynamic-Data-Driven Applications System (DDDAS) in which simulation models interact with measurement devices and assimilates data over a computational grid for the purpose of producing high-fidelity predictions of physical events. The tool controls the thermal source, provides a prediction of the entire outcome of the treatment and, using intra-operative data, updates itself to increase the accuracy of the prediction. A precise mathematical framework for the real-time finite element solution of the problems of calibration, optimal heat source control, and goal-oriented error estimation applied to the equations of bioheat transfer is presented. It is demonstrated that current finite element technology, parallel computer architecture, data transfer infrastructure, and thermal imaging modalities are capable of inducing a precise computer controlled temperature field within a biological domain. The project thus addresses a set of problems falling in the intersection of applied mathematics, imaging physics, computational science, computer science and visualizations, biomedical engineering, and medical science. The work involves contributions in the three component areas of the CAM program; A, Applicable Mathematics; B, Numerical Analysis and Scientific Computing; and C, Mathematical modeling and Applications. The ultimate goal of this research is to provide the medical community a minimally invasive clinical tool that uses predictive computational techniques to provide the optimal hyperthermia laser treatment procedure given real-time, patient specific data. / text

Messenger RNA (mRNA) posttranscriptional regulation has been implicated in the development and/or progression of several diseases including many types of cancer, rheumatoid arthritis, vascular disease, and Alzheimer's disease. Differential regulation of Androgen Receptor (AR) mRNA has been associated specifically with prostate cancer progression. In this thesis, molecular beacons were developed to allow for the detection of the expression and localization of AR mRNA in live prostate cancer cells. These beacons were then applied as a tool for studying how AR mRNA regulation is involved in prostate cancer growth and advancement. Two AR mRNA targeted beacons were designed and tested in solution and in live cells to determine their functionality. The beacon-based approach for AR mRNA detection was then optimized through the use of the two beacons in tandem and alteration of their backbone chemistry. A series of validation tests were performed on these beacons, including testing their abilities to: 1) produce a feasible localization pattern, 2) discriminate between AR positive (AR+) and AR negative (AR-) prostate cancer cell lines and 3) follow stimulus-induced changes in AR mRNA expression. Based on these results, a dual chimeric beacon approach was selected to determine the role of AR mRNA regulation in two systems that represent important stages in prostate cancer growth and progression: 1) hormone stimulation of androgen-dependent prostate cancer cells and 2) progression of androgen-dependent prostate cancer cells to the androgen-independent state. Our results suggest that changes in AR mRNA expression, organization, and localization may be indicative of molecular mechanisms involved in these critical transitions associated with prostate cancer progression. Taken together, this work provides a feasibility study for visualizing changes in AR mRNA state as a diagnostic measure for evaluating the aggressiveness of the disease and demonstrates the possible utility of therapeutically targeting AR mRNA regulation in order to prevent prostate cancer advancement.

The field of systems biology has become very popular as a means to deal with cancer as well as other complex biological issues. It enables scientists to gain an insight into difficult conditions through mathematical approaches that have been developed. Prostate cancer is the second leading cause of death among men after skin cancer and its heterogeneity makes it a complex disease. In this study we focus on three pathways known to play crucial roles in the formation of prostate cancer. By using a mathematical model that combines all of them we describe the interactions taking place during signal transduction in the prostate under normal and cancer conditions.

Indiana University-Purdue University Indianapolis (IUPUI) / In this thesis, I investigated the preclinical utility and antitumor efficacy of TRAIL delivered by Ad-IU2, a prostate-specific replication-competent adenovirus (PSRCA), against androgen-independent prostate cancer. Through transcriptional control of adenoviral early genes E1a, E1b and E4, as well as TRAIL by two bidirectional prostate-specific enhancing sequences (PSES), expression of TRAIL as well as adenoviral replication was limited to prostate-specific antigen and prostate-specific membrane antigen (PSA/PSMA)-expressing cells. Ad-IU2 replicated efficiently in and was restricted to PSA/PSMA-positive prostate cancer cells and induced 5-fold greater apoptosis in androgen-independent CWR22rv and C4-2 prostate cancer cells than the PSRCA control not expressing TRAIL. Ad-IU2 exhibited superior killing efficiency in PSA/PSMA-positive prostate cancer cells at doses 5 to 8-fold lower than that required by a non-TRAIL expressing PSRCA to produce a similar effect. This enhanced cytotoxic effect was not observed in non-prostatic cells, however. As an enhancement of its therapeutic efficacy, Ad-IU2 exerted a bystander effect through either direct cell-to-cell contact or soluble factors present in conditioned media from Ad-IU2-infected cells. In vivo, Ad-IU2, as compared to a control PSRCA, markedly suppressed the growth of subcutaneous CWR22rv xenografts at six weeks post-treatment (3.1 vs. 17.1-fold growth of tumor). The treatment of androgen-independent prostate cancer with Ad-IU2 prior to external beam radiation therapy (EBRT) significantly reduced clonogenic survival with dose reduction factors of 4.91 and 2.43 for CWR22rv and C4-2 cells, respectively. Radio-sensitization by Ad-IU2 was restricted to PSA/PSMA-positive cells. Combinatorial radio-gene therapy resulted in accumulation of cells in G1 phase and a perturbation of the radiation-induced G2 phase arrest. This multi-modal approach combining viral lysis, apoptosis-inducing gene therapy, and radiation therapy could have great impact in achieving complete local tumor control while reducing radiation dose and associated treatment morbidities. This would result in improvement of the clinical outcome of patients with high risk prostate cancer.

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