Karen E. Knudsen - US grants

prostate neoplasms; hormone regulation /control mechanism; androgens; cyclins; androgen receptor; cell line;

DESCRIPTION (provided by applicant): Environmental and commercially prevalent estrogenic compounds (xenoestrogens) have been classified as endocrine disruptors, or agents capable of disrupting normal hormone function in the human body. Exposure to xenoestrogens has been shown to result in diverse biological outcomes, such as infertility and developmental defects. Although considerable effort has been directed toward delineating the effect of xenoestrogens on the female reproductive system, few studies have examined the effect of such agents on growth and maintenance of the prostate gland. Prostatic epithelia and the cells of primary prostatic adenocarcinomas are dependent on androgen for proliferation and survival. This critical dependence of the prostate on androgen is exploited in the treatment of prostatic proliferative diseases (e.g. benign prostatic hyperplasia and prostatic adenocarcinoma). Increasing evidence also demonstrates a role for estrogen in the prostate cell proliferation. For example, exposure to estrogen has been shown to directly induce prostate hyperplasia animal model systems. Additionally, the anti-estrogen Tamoxifen is used clinically to reduce prostate growth. Despite these observations, the mechanism by which estrogen stimulates prostate cell growth has not been determined. Moreover, the effect of xenoestrogens on prostate proliferation and growth has not been explored. Here we show that the xenoestrogen bis-phenol A (BPA) provides inappropriate mitogenic stimuli to prostatic epithelial cells. This mitogenic activity is associated with nuclear receptor activity, and allows prostate cells to bypass their requirement for androgen. Based on our preliminary data, we hypothesize that BPA activates specific nuclear receptors in prostate cells to propagate inappropriate mitogenic signaling pathways and initiate cellular proliferation. This action of BPA likely facilitates the development of prostate hyperplasias and neoplasias. The experiments outlined herein will determine the mechanism by which BPA activates nuclear receptors in prostate epithelia, define the mitogenic signaling pathway for BPA in this cell type, and assess the influence of these agents on the formation and treatment of prostate hyperplasias and neoplasias.

DESCRIPTION (provided by applicant): Prostatic adenocarcinomas are treated based on their androgen dependence. The goal of standard therapy for this tumor type is ablation of androgen receptor (AR) function, either through direct AR inhibition or through inhibition of androgen synthesis. Although these lines of treatment are initially effective, recurrent tumors ultimately arise which are refractory to androgen/AR ablation. Clinical evidence suggests that the AR is inappropriately activated in these recurrent tumors, through largely undefined mechanisms. Given the importance of AR activity in prostate cancer growth, considerable effort is being undertaken to delineate the function and regulation of AR modulatory proteins. Cyclin D1 is an integral component of the cell cycle machinery that is induced by androgen in prostatic adenocarcinoma cells. However, we and others have shown that Cyclin D1 has a second role in regulation of androgen dependent proliferation, manifested through its ability to modulate AR activity. We have shown that Cyclin D1 binds the AR directly and through interaction with the N-terminus inhibits AR transactivation potential. Interaction between AR and Cyclin D1 has been shown with endogenous proteins. The repressor function of Cyclin D1 occurs independently of its role in the cell cycle, is dominant to the effects of known AR co-activators, and attenuates the rate of androgen dependent proliferation. Our data put forth the hypothesis that Cyclin D1 is a critical mediator of AR activity that could be exploited to inhibit androgen-mediated proliferation. Initially, we will delineate the precise mechanism of Cyclin D1 action (Aim 1). Subsequent analyses are designed to test the specificity of Cyclin D1 regulation, with a specific emphasis on multiple AR targets and alternate mechanisms through which AR is inappropriately activated in tumorigenesis (Aim 2). Lastly, we will evaluate the impact of the Cyclin D1-AR interaction on androgen dependent tumor proliferation, using a well-defined model system (Aim 3). Collectively, these studies will define the action of a potent AR regulator in the context of prostate cancer. Given the importance of AR activity in the prostate tumor formation and progression, it is our belief that a better understanding of AR regulation is critical for the design of novel, effective therapeutics.

[unreadable] DESCRIPTION (provided by applicant): Loss of specific SWI/SNF subunits is associated with compromised differentiation, aberrant proliferation and tumorigenesis. SWI/SNF chromatin remodeling complexes are recruited to DNA by selected sequence-specific transcription factors, and use the power of ATP hydrolysis to alter chromatin structure and gene transcription. Each SWI/SNF complex is composed of a combinatorial assembly of a central ATPase (either BRM of BRG1), and approximately 8-10 associated proteins (deemed BAFs, for BRG1 associated factors), which lend specificity to SWI/SNF action. Animal models have revealed that BRM is typically expressed in differentiated cells, whereas BRG1 is preferentially expressed in undifferentiated cell types. Accordingly, prostatic luminal epithelial cells express BRM but not BRG1. Although alterations of the BRM locus have not been studied, the region containing BRM (9p22-24) is known to be lost in human prostate cancer. Moreover, monosomy of chromosome 9 has been observed with high frequency. We have previously demonstrated that BRM-associated SWI/SNF complexes regulate critical transcription factors associated with prostate cancer progression and development. First, we demonstrated that BRM is required for the ability of the androgen receptor (AR) to stimulate target gene transcription. Second, we and others demonstrated that the retinoblastoma tumor suppressor protein (RB) requires SWI/SNF to halt cell cycle progression. Given the important roles of AR and RB in governing androgen dependent proliferation and differentiation, we probed the impact of BRM loss in vivo on cellular proliferation in the prostate. Using Brm -/- mice we demonstrate that ablation of BRM function results in early, significant hyperplasia with potential invasion and hypersensitivity to androgen. We also present data to demonstrate that BRM expression is reduced in prostate cancer. These data support the hypothesis that BRM serves an important growth suppressive function in the prostate. Given the paucity of models for prostatic hyperplasia and cancer, this exploratory R21 proposal is designed to: 1) characterize the hyperplastic lesions observed in Brm -/- mice and 2) directly establish the impact of BRM loss on prostatic epithelial cells using tissue recombination. The studies described will establish the utility of this model for analysis of prostate cancer, and reveal the biological consequence of BRM loss in the prostate. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the second leading cause of cancer death amongst men in the United States, as effective therapy for advanced cancers remains elusive. Disseminated prostatic adenocarcinomas are initially dependent on androgen for growth and survival; thus, the mainstay of therapy for this tumor type is ablation of androgen receptor (AR) function, either through direct AR inhibition or through inhibition of androgen synthesis. Although these lines of treatment are initially effective, recurrent tumors ultimately arise which are refractory to androgen ablation and AR inhibition. Clinical evidence strongly supports the concept that the AR is inappropriately reactivated in these recurrent tumors, which occurs via multiple mechanisms (e.g. AR amplification, AR mutation, de-regulation of AR co-activators, and/or activation by alternate pathways). Given the importance of AR activity for CaP growth, considerable effort is being undertaken to delineate the function and regulation of AR modulatory proteins. Through elucidation of AR action in both early and late stage tumors, it is hoped that therapeutic targets will emerge to permanently ablate AR function and thus prevent recurrence/relapse. We and others have shown that activation of SWI/SNF chromatin remodeling complex(es) is required for AR function. SWI/SNF represents a large class of chromatin remodeling complexes, wherein unique combinations of associated subunits are hypothesized to lend specificity to SWI/SNF action. Here, we demonstrate that a non-essential SWI/SNF subunit, BAF57, interacts directly with the AR and potently regulates both AR and AR co-activator function. This function of BAF57 not only governs AR transactivation potential, but also regulates androgen dependent proliferation in prostatic adenocarcinoma cells. Therefore, our studies support the hypothesis that BAF57 regulates AR activity through discrete mechanisms that could be targeted in CaP therapy. The studies proposed herein challenge this hypothesis by dissecting the mechanisms through which BAF57 controls AR activity (Aim 1), revealing specificity of the BAF57 requirement in CaP (Aim 2) and assessing the impact of BAF57 in the growth and progression of CaP in vivo (Aim 3). Together, these studies will reveal the efficacy of BAF57 as a therapeutic target in both early and late stage prostate cancer. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Prostatic adenocarcinomas are treated based on their androgen dependence. The goal of standard therapy for this tumor type is ablation of androgen receptor (AR) function, either through direct AR inhibition or through inhibition of androgen synthesis. Although these lines of treatment are initially effective, recurrent tumors ultimately arise which are refractory to androgen/AR ablation. Clinical evidence suggests that the AR is inappropriately activated in these recurrent tumors, through largely undefined mechanisms. Given the importance of AR activity in prostate cancer growth, considerable effort is being undertaken to delineate the function and regulation of AR modulatory proteins. Cyclin D1 is an integral component of the cell cycle machinery that is induced by androgen in prostatic adenocarcinoma cells. However, we and others have shown that Cyclin D1 has a second role in regulation of androgen dependent proliferation, manifested through its ability to modulate AR activity. We have shown that Cyclin D1 binds the AR directly and through interaction with the N-terminus inhibits AR transactivation potential. Interaction between AR and Cyclin D1 has been shown with endogenous proteins. The repressor function of Cyclin D1 occurs independently of its role in the cell cycle, is dominant to the effects of known AR co-activators, and attenuates the rate of androgen dependent proliferation. Our data put forth the hypothesis that Cyclin D1 is a critical mediator of AR activity that could be exploited to inhibit androgen-mediated proliferation. Initially, we will delineate the precise mechanism of Cyclin D1 action (Aim 1). Subsequent analyses are designed to test the specificity of Cyclin D1 regulation, with a specific emphasis on multiple AR targets and alternate mechanisms through which AR is inappropriately activated in tumorigenesis (Aim 2). Lastly, we will evaluate the impact of the Cyclin D1-AR interaction on androgen dependent tumor proliferation, using a well-defined model system (Aim 3). Collectively, these studies will define the action of a potent AR regulator in the context of prostate cancer. Given the importance of AR activity in the prostate tumor formation and progression, it is our belief that a better understanding of AR regulation is critical for the design of novel, effective therapeutics.

DESCRIPTION (provided by applicant): Prostate cancer is the most frequently diagnosed cancer and second leading cause of cancer death in the United States. Androgen receptor (AR) activity is required for prostate cancer growth, and therapeutic regimens for prostatic adenocarcinoma (CaP) are directed toward ablation of AR activity. Despite the initial efficacy of these therapies, recurrent tumors ultimately arise wherein AR has been inappropriately re-activated. No effective treatment exists for recurrent tumors, which lead to patient death. As such, there is an urgent need to identify the comprehensive set of factors that contribute to AR re-activation and tumor recurrence. We have shown that selected endocrine disrupting compounds (EDCs) prevalent in the environment can impinge on the most common mutant of AR that arises during tumor progression (AR-T877A) to stimulate receptor activity and concomitant cellular proliferation. Our new data demonstrate that this action of EDCs has clinical consequence, wherein a known EDC (bisphenol) increased tumor growth and shortened the time to tumor recurrence. Moreover, we showed that several tumor-derived AR mutants gain sensitivity to selected EDCs. Thus, these findings strongly support the central hypothesis of the present proposal, wherein secondary mutations known to occur during tumor progression can sensitize cells to EDC activity, and through these mechanisms EDCs can significantly impact the response to prostate cancer therapy. Here, we delineated 3 specific aims which challenge this hypothesis by first discerning the molecular mechanisms by which EDCs impinge on mutant AR function (Aim 1), identifying the comprehensive cohort of secondary alterations that sensitize cells to EDC activity (Aim 2), and challenging the biological consequence of EDC exposure in the presence of these secondary alterations using new models of disease (Aim 3). Combined, it is our belief that this proposal rigorously addresses the molecular and biological significance of EDC exposure on prostate cancer management and outcome. Given the persistence of each studied EDC in the American population, these studies may have significant impact on understanding the factors that impinge upon prostate cancer growth.

DESCRIPTION (provided by applicant): Prostate cancer (PCa) cells are dependent on androgen receptor (AR) function for growth and survival;this dependence is exploited in treatment of disseminated cancers, wherein ablation of AR activity is the first line of therapeutic intervention. While initially effective, recurrent tumors ultimately arise as a result of inappropriately restored AR function. AR is a master regulator of G1-S phase transitions in PCa, and interrogation of this mechanism led to the discovery of significant cross-talk mechanisms between the AR and cell cycle pathways. Cyclin D1 is a major effector of androgen action, and serves specialized functions in PCa that were delineated during the first funding period. Active AR induces cyclin D1 accumulation, thereby stimulating cyclin dependent kinase 4 (CDK4) activity and G1 progression. However, we and others showed that accumulated cyclin D1 binds and inhibits AR activity, thereby engaging a negative feedback loop to attenuate subsequent mitogenic response in AR-positive PCa cells. These actions of cyclin D1 contribute to the observed cell cycle dependence of AR activity in PCa, wherein AR activity is inversely correlated with cyclin D1 expression. Thus, cyclin D1 serves as a "rheostat" that controls the strength and duration of the androgen response. The achieved goals of the first funding period were to dissect the mechanism and regulation of this cross-talk pathway in PCa. Our published and unpublished data demonstrate that cyclin D1 is a major effector of AR activity, and acts through defined mechanisms to alter both AR activity and androgen-dependent proliferation in PCa. Moreover, we demonstrated that aberrations in this process facilitate unleashed AR activity. Thus, this renewal application is based on the hypothesis that abrogation of cyclin D1 transcriptional regulatory function promotes unchecked AR activity in PCa cells, and provides a mechanism to promote tumor development and/or progression. The present renewal application will directly challenge this concept by dissecting the molecular impact of cyclin D1 action (and aberrations thereof) under conditions associated with tumor progression (aim 1), defining the consequence of cyclin D1b, a splice variant of cyclin D1 that is deficient in AR control and is induced in PCa, on androgen mediated gene regulation (aim 2), and determining the oncogenic capacity of cyclin D1b in the prostate (aim 3). PUBLIC HEALTH RELEVANCE: Fatal prostate cancer arises as a result of inappropriate androgen receptor (AR) activity, a protein that controls the action of testosterone. We discovered that aberrations in a second gene product (cyclin D1) serve to promote unchecked AR activity and tumor growth. Here, we will determine molecular mechanisms through which cyclin D1 controls AR and determine the importance of this protein in prostate cancer, with the long term goal of devising new therapies to treat this deadly disease.

DESCRIPTION (provided by applicant): Dysregulation of individual SWI/SNF subunits plays tissue and subunit-specific roles in tumorigenesis, disease progression, and therapeutic resistance. This application will assess the role of the BAF57 SWI/SNF subunit in the context of prostate development and prostate cancer (PCa). In PCa, fatal disease arises as a failure to control androgen receptor (AR) activity, and BAF57 is a known effector of AR. Notably, first line therapy for disseminated PCa relies on AR-directed therapeutics. While initially effective, recurrent, incurable tumors form within 2-3 years. Substantive evidence shows that the incurable, castration-resistant stage (referred to as castration-resistant prostate cancer, CRPC) is driven by resurgent AR activity. Major lines of investigation support the hypothesis that BAF57 deregulation induces alterations in SWI/SNF that support aberrant AR activity and progression to CRPC. This application will challenge the in vivo impact of BAF57 in prostate development and disease: First, we showed that BAF57 binds directly to AR, is recruited to in the presence of androgen to sites of AR function, and promotes androgen- dependent gene expression in a SWI/SNF-reliant manner. These BAF57 functions proved critical, as ablation of BAF57-AR interaction nullified ligand-dependent AR activity. Parallel studies showed that even modest changes in SWI/SNF subunit expression can have potent effects on SWI/SNF function, molecular output, and cellular phenotypes. Thus, our data underscore the importance of delineating the precise role of BAF57 in SWI/SNF and AR signaling. Strikingly, there is no understanding as to means by which BAF57 influences SWI/SNF activity (in any tissue) under conditions of tumorigenesis or homeostasis. Here, we will use novel genetic models of BAF57 depletion to delineate the molecular impact of BAF57 on SWI/SNF assembly, androgen-dependent AR cistromes, and prostate development (Aim 1). Second, our data indicate that BAF57 is significantly deregulated in high-grade PCa and CRPC. New models mimicking this event revealed a role for BAF57 in promoting for castration-resistant AR signaling. As AR binds to and modulates differential targets in CRPC, it is essential to assess the impact of tumor-associated BAF57 deregulation on the AR cistrome, the consequence for transcriptional regulation, and the clinical relevance of these observations (Aim 2). Third, tumor-associated BAF57 deregulation was predominant in lymph node deposits of CPRC, and deregulation of BAF57 in cells derived from lymph node metastases rendered cells resistant to androgen ablation in vitro. Thus, it is critical to challenge the in vivo consequence of tumor- associated BAF57 deregulation on tumor aggressiveness, lymph node metastasis, and therapy-resistance (Aim 3). Together, these novel aims will illuminate the means by which BAF57 influences SWI/SNF signaling and AR function, assess the in vivo consequence of both events, and define the consequence of tumor-associated BAF57 deregulation on disease progression.

DESCRIPTION (provided by applicant): This proposal for a Cancer Center Support Grant (CCSG) requests funding to support the cancer research activities of the Kimmel Cancer Center (KCC), in order to increase the survival and quality of life of cancer patients by translating basi research discoveries into new strategies to prevent, diagnose, monitor and cure human cancer. The major thrust of the Kimmel Cancer Center is in discovery and translation of the latest findings in the genetics, cell biology, biochemistry and immunology of cancer into novel modalities to cure cancer. The Kimmel Cancer Center consists of six programs and ten shared resources to support the research programs. Investigators in each program are involved in intra-programmatic and inter-programmatic collaborations and have been extremely successful in obtaining peer-reviewed funding for these collaborative studies. The environment within the KCC has facilitated numerous collaborative studies and publications that have contributed to important advances in cancer research. The KCC programs are supported by $56.3 million in total peer-reviewed sponsored funding. Funding comes from NCI sponsored projects totals $23.3 million. The efforts of the Director and his recruits have resulted in increased philanthropic University and Hospital support. The importance of cancer research and care at Thomas Jefferson University is reflected in the Director's authority over clinical and research activities at the Institution, encompassing 196,936 sq. ft. which includes the Breast Center, Oncology Center and research space. These state of the art KCC facilities enhance the translational cancer research effort of the Kimmel Cancer Center. The KCC has included the Lankenau Institute of Medical Research as part of the endorsed Consortium Cancer Center since 2007. The current submission also includes Drexel University cancer researchers. The inclusion of Drexel University cancer researchers extends a long-standing history of collaborative research publications and grants between consortium investigators.

DESCRIPTION (provided by applicant): Prostatic adenocarcinoma (PCa) is the most frequently diagnosed malignancy and 2nd leading cause of cancer death in American men. PCa is resistant to standard chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR, a ligand-dependent transcription factor) for growth, survival, and progression. As such, AR is the first line therapeutic target for all patients with disseminated disease. AR- directed therapies entail the use of androgen deprivation therapy (ADT), which suppresses testicular androgen synthesis; these modalities prevent AR from binding chromatin and inducing gene expression, and are often used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed castration-resistant prostate cancer (CRPC) is the incurable phase, and underpins the significant morbidity associated with PCa. Thus, there is an urgent need to identify the diverse mechanisms utilized by tumors to reactivate AR, and to develop mechanisms of thwarting this process. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is upregulation of AR. Consonantly, preclinical modeling of even modest AR upregulation showed that this event alone is sufficient to drive progression to incurable CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, our recently reported findings identify perturbation of the RB tumor suppressor as a major mechanism by which AR deregulation occurs and induces CRPC formation, independent of AR amplification. Our collective data have potentially dramatic clinical implications, and strongly support the hypothesis that perturbations of the RB/E2F1/AR axis play a major role in the transition to CRPC, and that RB status can be developed as a metric to direct personalized therapeutic intervention in prostate cancer. Three aims are proposed to challenge this hypothesis: Three aims are proposed will: 1) Define the molecular mechanisms and clinical consequence of RB dysfunction in CRPC; 2) Delineate the impact of RB loss on aberrant AR signaling; and 3) Examine targeting the RB/E2F1/AR axis to suppress PCa progression.

PROJECT SUMMARY (See instructions): The X-ray Crystallography and Molecular Characterization Facility provides access to state-of-the-art x-ray crystallography instrumentation and computational resources, and a wide variety of biophysical approaches lo understanding important molecular interactions. The Facility maintains the equipment and technical expertise to carry out all stages of macromolecular structure determination, and to measure molecular binding parameters such as association and dissociation rates as well as secondary and tertiary structure of biological samples. This facility was used by 6 KCC members.

Program 2, the Molecular Biology and Genetics of Cancer Program (MBG), integrates fundamental studies in the control of gene transcription and regulation with the genetic and molecular mechanisms underlying the most common types of solid tumors and hematological malignancies. An integral part of the KCC since 1991, this program focuses on gene discovery and gene function analyses in order to exploit the translational potential of these studies for cancer diagnosis, assessment, prevention and therapy. The long-term goal of this program is to discover information useful in designing personalized therapies for cancer patients. The Molecular Biology and Genetics of Cancer Program brings together 22 faculty members from 10 academic departments (including the Lankenau Institute for Medical Research and the Department of Biochemistry and Molecular Biology of Drexel University) who are supported by NCI ($3.25 million total costs) and other peer-reviewed grants ($7.80 million total costs). Many members of this program have made important discoveries that have been translated into improved cancer diagnosis and assessment, and into novel therapeutic approaches. In the last five years, program members have continued to interact productively, publishing approximately 100 papers/year in some of the best known and more influential journals such as Nature, Mol.Cell, J.Clin.Invest., Immunity, PNAS. Of papers published since 2007, 21.0% have been the result of intra-programmatic collaborations and 31.3% the result of inter-programmatic collaborations. The program has 15-20 graduate students and more than 80 postdoctoral fellows. Their training and the interactions, both intra- and inter-programmatic, among all members are supported by monthly meetings that enhance the program's translational focus.

? DESCRIPTION (provided by applicant): Prostatic adenocarcinoma (PCa) is resistant to chemotherapy, but is exquisitely dependent on the activity of the androgen receptor (AR), for growth, survival, and progression. As such, AR is the first line therapeutic target for all patient with disseminated disease. AR-directed therapies entail the use of androgen deprivation therapy (ADT), used in combination with direct AR antagonists. While initially effective, recurrent tumors arise within 2-3 years wherein the AR has been inappropriately reactivated. This stage of disease, termed castration-resistant prostate cancer (CRPC) is the incurable phase. Examination of human CRPC revealed that the major mechanism leading to therapy-resistance is inappropriately restored AR activity. Consonantly, preclinical modeling of AR upregulation showed that this event alone is sufficient to drive progression to CRPC. The mechanisms by which AR upregulation occurs during disease progression remained incompletely defined - while amplification of the AR locus accounts for a fraction of these observations, a significant proportion of CRPCs show upregulation of AR without gene amplification. Strikingly, collaborative efforts between the Knudsen and McMahon labs unexpectedly identified deregulation of the SAGA complex member USP22, a known deubiquitylase, as a master regulator of AR levels and output that is sufficient to induce CRPC formation. Moreover, USP22-dependent SAGA activity proved requisite for c- Myc function in prostate cancer, suggesting that USP22 activity is critical for the two major oncogenic pathways that drive prostate cancer progression. Our collective findings have potentially dramatic clinical implications, and strongly support the hypothesis that deregulation of USP22 plays a major role in the transition to CRPC via regulation of the AR/Myc axis, and that targeting the enzymatic function of USP22 can be developed as a novel means of therapeutic intervention. The novel aims herein will illuminate the means by which USP22 modulates the two major pathways that govern prostate cancer development and progression, delineate the mechanisms through which USP22 promotes lethal tumor phenotypes, and comprehensively assess the in vivo and ex vivo impact of USP22 on tumor development and progression. On balance, the studies described will challenge the transformative concept that underpins aggressive prostate cancer phenotypes that can be targeted for therapeutic benefit.

The Kimmel Cancer Center carries out a number of program planning and evaluation activities, and incorporates the resulting recommendations when charting future directions. Major planning activities include: (1) the annual meeting of the External Scientific Advisory Committee (ESAC); (2) the b-monthly meetings of the Executive Committee, which includes the Senior Leaders as well as the Program Leaders; (3) the periodic meetings of the Clinical Science Advisory Committee and the Basic Science Advisory Committee; and (4) the annual retreat and periodic faculty meetings

Protocol Review and Monitoring System Principal Investigator: Pestell, Richard G., M.D., Ph.D. (P30 CA056036) PROJECT SUMMARY (See Instructions): PROTOCOL REVIEW AND MONITORING SYSTEM The Protocol Review and Monitoring System (PRMS) of the Kimmel Cancer Center (KCC) is an integral component of the KCC clinical investigations activities. The KCC PRMS is named the Cancer Clinical Research Review Committee (CCRRC). The CCRRC reviews all new research proposals involving human subjects and neoplastic diseases. Protocols receive a first review by the pertinent Multidisciplinary Disease Group, which provides a written evaluation of protocol feasibility, lack of competitive protocols or stratification if overlap with other protocols exists, and compatibility with KCC research and accrual goals. This evaluation is signed off by the specific Multidisciplinary Disease Group Leader. The Clinical Research Management Office (CRMO) staff prepares the documentation and coordinates meetings and communications for the CCRRC. The specific aims of the CCRRC are: (1) to maintain a review committee of Kimmel Cancer Center investigators (with representation from basic science and clinical areas) responsible for the initial scientific review and monitoring of all ongoing clinical trials; (2) to evaluate the scientific merit of new proposals (study value, methods, statistical merit, investigator experience, and patient resources); (3) to establish criteria for the prioritization of competing Kimmel Cancer Center studies; (4) to monitor trials for patient accrual metrics; (5) to maintain a collaborative relationship with the Thomas Jefferson University Institutional Review Board and the Kimmel Cancer Center Data and Safety Monitoring Committee (DSMC) to facilitate interaction between the three review committees; and (6) to assure protocol compliance through the monitoring of ongoing review scientific progress. The CCRRC initial scientific review of each proposed study focuses on: (1) study value; (2) methods; (3) investigator(s) experience (4) risk and (5) data and safety monitoring plans.

The Protocol Specific Research program provides data management and other infrastructure support of novel clinical trials designed and implemented by Kimmel Cancer Center members. These trials are innovative, early phase (I or II), and/or pilot studies testing concepts that are likely to lead to expanded, externally funded studies. Since the last grant submission, the investigators at the Kimmel Cancer Center have been committed to the development of investigator-initiated trials. Institutional funds cover experienced support staff for these trials. Funds are being requested to provide financial support for additional clinical research coordinators for the planned investigator initiated trials (IIT). The area of greatest emphasis has been in the development of innovative first-in-man trials of new agents, in conjunction with therapeutic radiation. These trials are conducted with multi-disciplinary leadership including radiation oncologists, medical oncologists, surgical oncologists, and translational scientists.

PROJECT SUMMARY (See instructions); The Radiation Research and Translational Biology, (RRTB) program goal is to improve combination radiation therapies by 1) designing and testing new molecular targets identified by mechanistic studies, and 2) addressing tumor resistance to therapy and bypass of immune surveillance, and 3) designing, assessing and improving technologies that diagnose, stage, and deliver therapies for cancer patients. Program members address these goals with multidisciplinary efforts in biochemistry, immunology, drug design, preclinical models, and clinical experience, to accelerate translation from bench to bedside. The Program has been strengthened by integration of members from the former Program in Cancer Immunology. The current RRTB program, comprised of 34 basic, translational and clinical investigators from eleven departments, thus combines basic and clinical research strengths to conduct bench to bedside research and can reverse translate clinical data to inform further translational innovations. This work is supported by 36 peer-reviewed grants totaling direct funds of $13.2 million ($5.3 million from NCI). The total number of publications generated by Program members from 2007 to 2012 is 543 of which 11% are Intra-programmmatic and 22% are Inter-programmatic, with 4.6% being both. The specific research themes ofthe RRTB Program are: (1) Improve RT therapies by defining and characterizing molecular targets for ionizing radiation and for combined therapies, vaccine development and BMT (2) Immune tolerance and strategies for immune surveillance. (3) Tumor resistance: Microenvironment, hypoxia and angiogenesis. (4) Protecting normal tissues: normal tissue injury/genotoxic stress. (5) Clinical translation of diagnostic and therapeutic innovations, and (6) Improving clinical practice: Biomedical/Bioinformatics and Comparitive Effectiveness Research (CER). This program will continually generate new collaborations, intra- and interprogrammatically, and fresh research directions with other research programs in the cancer center.

PROJECT SUMMARY (See instructions): The Senior Leadership of the Kimmel Cancer Center (KCC) is responsible for the overall operation, management, and planning for the Cancer Center. This includes the administrative and management oversight of activities in support of research within the Center, including the research programs, shared resources, and clinical activities. The Senior Leadership includes: Director of the KCC ~ Richard G. Pestell, M.D., Ph.D., MBA Deputy Director for Basic Science -Erik Knudsen, Ph.D. Deputy Director for Clinical Science ? Neal Flomenberg, M.D. Co-Deputy Director for Basic Science -Timothy Block, Ph.D. Associate Director for Translational Research -Wm. Kevin Kelly, D.O. Associate Director for Education ~ Marja Nevalainen, M.D., Ph.D. Associate Director for Clinical Investigations ~ Matthew Carabasi, M.D. Associate Director for Clinical Affairs ~ Leonard Gomella, M.D. Associate Director for Shared Resources - Richard L. Davidson, Ph.D. Associate Director for Diversity Affairs - Edith Mitchell, M.D. Associate Director for Population Science - Ronald Myers, Ph.D. Chief Financial Officer ~ Richard Haldeman, MBA, CPA

PROJECT SUMMARY (See Instructions): The Small Animal Imaging Shared Resource provides state-of-the-art in vivo molecular imaging capabilities to the investigators of the Kimmel Cancer Center. It was established under the direction of Dr. Mathew Thakur in April 2004 supported, to date, by the Thomas Jefferson University and the Department of Radiology. This resource provides non-invasive small animal imaging, with PET, SPECT, CT and optical imaging. These modalities offer innovative basic, as well as pre-clinical translational, research capabilities for studying patho-physiology and genesis of cancer. In addition to providing comprehensive imaging services the expertise exists to a) custom synthesize probes specific for targeted bio-markers; b) develop new image generation and analysis techniques; and c) train cancer investigators to harness the strengths of molecular imaging. The facility is supported by three AALAC accredited animal houses and two veterinarian staff members. Thus far this shared resource has supported fifteen federally funded investigations related to oncology and enhanced productivity as depicted by several publications in peer-reviewed journals. The facility was used by seven cancer center members.

PROJECT SUMMARY (See instructions): Since the inception of the Translational Research Shared Resource its mission has been to provide tissue processing, slide preparation, histochemical staining, and immunohistochemical staining for human neoplastic tissue and experimental animal model tissue being utilized by KCC researchers. This shared resource has also provided procurement, banking and distribution of human neoplastic tissue in order to facilitate translational research. The caBlG caTissue biospecimen management application has been used by tissue bankers since 2007 to enter clinical and pathogical specimen annotation, as well as track specimen storage and distribution. This biospecimen database integrates access to 7 campus specimen collections having about 440,000 specimens from 170,000 individuals. In addition, the Translational Research Shared Resource provides tissue microarrays construction service with paraffin archive material from the resource tumor/tissue bank. Laser microdissection of distinct cell and tissue types for molecular analysis can be performed on the resource's Laser Microdissection system. For all of the capabilities offered by the Translational Research Shared Resource, staff is available to provide technical support and pathology expertise to KCC investigators. Between 2008 and 2011 23 principal investigators from all programs of the KCC benefited from this shared resource.

PROJECT SUMMARY (See instructions): The goal of the Kimmel Cancer Center (KCC) - Cancer Genomics Shared Resource (CGSR) is to provide genomics and bioinformatics leadership to KCC members to facilitate projects in basic, translational and clinical research thus assisting investigators to achieve their overall goals. By serving as a centralized resource with a variety of platforms, a significant computational infrastructure for data analysis and storage, and experienced professionals in genomics-based methods, the CGSR offers a wide spectrum of services and high quality control at cost-effective prices to investigators for DNA and RNA analysis. Services include: 1) nucleic acid isolation and purification, and related molecular biological services including PCR, cloning, sub-cloning and site-directed mutagenesis; 2) cost-effective, reliable, long-read, automated Sanger sequencing with fast turnaround; 3) microsatellite-based genotyping and fragment analysis; 4) high-quality genome-wide SNP genotyping, copy number variation, aCGH and DNA methylation profiling analysis; 5) genome-wide mRNA and microRNA expression profiling on Affymetrix microarrays as well as custom made disease- and/or pathway-targeted arrays; 6) independent validation of candidate loci/genes by quantitative PCR analysis; 7) assisting investigators with experimental design and analyzing results providing web-based pathway analysis software; and, 8) archiving of both Sanger sequencing and Affymetrix array data. Recently added services based on Applied Biosystems SOLID 4 and 5500x1 and lon Torrent PGM include: 1) whole genome sequencing as well as targeted resequencing of human and model organisms; 2) chromatin-IP sample sequencing; 3) measuring RNA expression with both digital gene expression and RNA-sequencing (whole transcriptome) including short and long non-coding RNA; and, 4) genome-wide DNA methylation sequencing. In addition, CLIA certification was received recently to facilitate molecular profiling for clinical research-oriented studies. The range of services mentioned above coupled with the expertise of the resource director, enables the CGSR to provide full support to KCC investigators to facilitate gene discovery, functional characterization and other basic research efforts to elucidate the molecular pathogenesis of human cancers. 63 KCC members have used this Shared Resource in the last year. KCC members' usage represents 90% of the total Shared Resource usage and KCC support represents 91% of the proposed operating budget with the remaining funding coming from charge-backs and institutional support.

PROJECT SUMMARY (See instructions): The Kimmel Cancer Center (KCC) Administration serves to meet the operational and financial needs of the Center, providing cost-effective management and helping to ensure that the goals of the Center are realized. Administration provides key support to the Center Director and Senior Leaders, the Programs and Shared Resources, the Executive Committee, the internal Basic Science and Clinical Science Advisory Committees, and the External Scientific Advisory Committee. KCC Administration participates in the planning and implementation of all activities throughout the programs and shared resources of the Center. Overall responsibility for the operation of Administration lies with the Executive Director, Richard L. Davidson, Ph.D., who has over 35 years' experience in the administration and management of large-scale academic units. Dr. Davidson also serves as Associate Director for Shared Resources, overseeing the activities of all the KCC shared resources. The administrative team under Dr. Davidson includes individuals for financial analysis and management, for liaison and integration with the clinical research enterprise, and for clerical assistance. Administration serves as the link between the Center and the University and Hospital offices for administration, financial affairs, space management, maintenance, construction, human resources, intellectual property, information technology, and legal counsel. The major activities of Administration involve the following areas; 1) financial management of all CCSG accounts 2) operational and financial management of the shared resources; 3) space management, maintenance, and renovation; 4) strategic planning activities; 5) Center retreats, symposia, seminars, and meetings; 6) clinical trials activities; 7) KCC Grand Rounds; 8) faculty recruitment; 9) human resources; 10) educational and training programs; and 11) planning for and preparation of CCSG submissions.

PROJECT SUMMARY (See instructions): Among the keys to deciphering normal physiological processes and their derangements in neoplasia are an understanding of the relationship in spatial and temporal terms of different cellular components to each other, and the related ability to correlate structure with function. Providing these capabilities of visualization is the goal of the KCC Bioimaging Facility/Shared Resource by having available powerful, reliable, and readily accessible light microscopic image acquisition and analysis capabilities for KCC investigators. The Facility is Cancer Center-managed and operates with well-trained staff and a faculty supervisor. Dr. James Keen, and provides training in operation of all instruments as well as consultation in operation, methodology, experimental approach, and interpretation. It is open for scheduled use at any time by trained investigators, or the Facility operator can perform imaging and analysis with laboratory personnel. Through the operation of this Shared Resource, individual KCC investigators are assured of state-of-the-art and reliable facilities operated with a high degree of technical expertise, and are relieved of the obligation for substantial outlay for equipment, maintenance and personnel training. The facility has provided service for more than 90 laboratories and several hundred individuals during the past award period, of which more than 80% are Cancer Center members. Major support for the Facility has been derived from successful competition for extramural funding, from institutional and Cancer Center sources, and from user chargebacks tied to services rendered.

PROJECT SUMMARY (See instructions): The Informatics Shared Resource (ISR) serves as a biomedical research informatics resource for KCC's basic, clinical, and translational investigators. This support includes infrastructure! provisioning, software development or acquisition, and consultative collaboration. ISR services are available directly to peer reviewed funded cancer investigators, or indirectly to other cancer center core facilities, thereby providing services to all program members. The ISR also provides informatics support for the clinical research activities of the Jefferson Kimmel Cancer Center Network of community hospitals. More specifically, the ISR supports cancer center research by developing and/or deploying: 1) Clinical trials applications to give clinical researchers the tools to manage clinical trials data, including mandated reporting. 2) Biospecimen repository applications to help tissue bank staff manage specimen accessioning and distribution, and provide investigators with an ordering mechanism and information characterizing specimens available for research. 3) Data warehousing and mining applications to provide cancer researchers with a research data mart that integrates clinical, biospecimen, cancer registry, clinical trials, and experimental data for cohort identification and hypothesis generation. 4) Infrastructure and applications for other KCC shared resources to facilitate access to their services. The ISR thus provides KCC investigators with ready access to integrated comprehensive information on clinical trials, cancer patients, and research specimens, as well as providing a single portal for requesting equipment and services from KCC shared resources. In all its activities, the ISR recognizes interoperability as crucial to the sharing of research data and resources to promote efficient cancer research, and utilizes standards articulated by the NCI and the biomedical informatics community. Software applications are hosted on servers with networked storage located at a commercial data center contracted by the University, providing professional data center security and disaster recovery services. The ISR employs best practices with regard to data privacy and security complying with the Common Rule, HIPAA, and state regulations.

PROJECT SUMMARY (See instructions): The overall goal of the Biology of Breast Cancer (BBC) Program is to bring together multidisciplinary expertise for collaborative discovery of molecular alterations and signatures of breast cancer and to translate these findings into new strategies for effective detection, diagnosis, and treatment Central thematic aims are 1) Exploit hormonal pathways in preclinical models for molecular target identification and new strategies for therapy and prevention; 2) Improve diagnostic tumor classification and establish new prognostic and predictive molecular signatures to facilitate tailored treatment; 3} Develop innovative strategies and technologies for early detection of cancer and for monitoring of therapy response and disease recurrence. The BBC Program is the renamed continuation of the Endocrine Mechanisms and Hormone Action in Cancer (EMHAC) Program, funded since 2007. During the first four years the EMHAC program grew by successful external recruitment and internal mentored development of junior faculty, with total peer-reviewed funding rising from $4.2 million to $9.3 million in 2011. This growth ofthe EMHAC Program, with a number of productive and leading investigators studying breast cancer or prostate cancer, allowed KCC to strategically split off a subgroup of investigators to form the new Biology of Prostate Cancer (BPC) Program in 2011. Current BBC Program members have authored more than 400 publications between 2007 and 2012, including publications in high impact journals such as Cell, Science, JCO, JNCI, Mol Cell, JCI, MCB, and PNAS. Collaborative interactions by BBC members have been high during the past funding period as documented by 45% intra-programmatic and 28% inter-programmatic publications. The BBC program includes seventeen members from 10 departments and three schools at TJU and Drexel. Dr. Hallgeir Rui (Cancer Biology) has served as Program Leader since 2006, and Dr. Russell Schilder (Medical Oncology) was recruited as Co-Leader in 2011. A series of collaborative and interdisciplinary program initiatives have been supported by extensive cancer center pilot funding. Current annual peer-reviewed program funding of BBC members totals $5.9 million with NCI funding of $ 3.8 million. Multi-investigator grants, including a 5-year Komen Promise program grant for therapy-relevant stratification of breast cancer patients, extensive program meetings, and a high proportion of programmatic collaborative publications attest to successful program activities and interactions.

PROJECT SUMMARY (See instructions): The Blology of Prostate Cancer (BPC) Program at the Kimmel Cancer Center (KCC) is a new program that emanated from the former Endocrine Mechanisms and Hormone Action in Cancer (EMHAC) Program, and represents the section of the EHMAC that focused on prostate cancer. From 2007 to 2011, EMHAC increased the number of highly productive investigators studying either breast/gynecological malignancies or prostate/genitourinary cancers, allow^ing the strategic creation of the BPC program in 2011. During this same interval, the Greater Philadelphia Prostate Cancer Working Group was founded by new recruit Dr. Karen Knudsen, and served as a basis for development of the BPC and the associated consortium. The BPC program consists of 18 investigators from 10 departments and 3 institutions. The Program currently brings in $2.3 million/year in total costs from NCI grants and $4.1 million/year total peer-reviewed costs. Since 2007, the program produced 343 publications of which, 10% of publications were intra-programmatic, 43% were inter-programmatic, and 5% were both inter- and intra-programmatic. Dr. Karen E. Knudsen (Leader) is an accomplished investigator with expertise in basic and translational prostate cancer research. Dr. Gomella, the Co-Leader (TJU) of BPC, provides clinical expertise in genitourinary malignancies. Dr. Fatatis the Co-leader (Drexel University) of BPC is an accomplished physician scientist with expertise in cancer metastasis at the basic and clinical level. He will play a pivotal role integrating Drexel University and TJU cancer researchers in the BPC Program. The goals of the BPC program are to leverage the significant translational and clinical expertise in genitourinary oncology (most especially with regard to prostate cancer) with the intent to: delineate the mechanisms that underpin prostate cancer development and progression, identify novel means to treat advanced disease, and improve disease management by translating these findings into clinical trials. Studies within the program are directed at developing new strategies for effective detection,diagnosis,and cure. Specific aims of this program are to;1. Develop new strategies for prevention, detection, and subtyping of early stage prostate malignancies; 2. Define the impact of hormone action in malignant disease development and prostate cancer progression; 3. Develop novel treatment strategies for prostate malignancies;4. Develop predictive markers for rational therapy delivery.

PROJECT SUMMARY (See Instructions): DESCRIPTION OF SHARED RESOURCE The Biostatistics Shared Resource (BSR) consists of partial effort from six PhD-level faculty biostatisticians and six MS-level or higher technical support staff to collaborate and consult with Kimmel Cancer Center investigators in the design, conduct, and analysis of cancer-related clinical, translational and scientific investigations, and to review clinical trial proposals for cancer-related studies within the Cancer Clinical Research Review Committee (CCRRC). The Division of Biostatistics consists of six PhD faculty, 2 PhD technical senior staff, and 4 MS-level staff, all participate at least partial effort to cancer research, but the Division also serves as the research resource for the entire University. The BSR provides consultation and expertise regarding study design (including validity of the overall design, feasibility of meeting objectives, sample size, study duration, and planned data analysis), recommendations for staffing (data management and analysis support), data analysis, preparation of reports and assistance with manuscript writing, and development of new biostatistical methods, when applicable. The general goal of the BSR is to ensure that study designs, monitoring, and analyses use state-of-the-art methods, and to help developmental studies supported by the Center successfully achieve peer reviewed funding. The BSR has experienced growth during the recent grant cycle, particularly by adding faculty and staff with mathematical programming and robust methods expertise. Plans for the future of Biostatistics include continued growth to meet the needs of the KCC, development in key areas including clinical trials design, and continued strength in methodological development that informs cancer research. The Biostatistics Shared Facility was used by 49 KCC members.

PROJECT SUMMARY (See instructions): The mission of the Cancer Cell Biology and Signaling (CCBS) Program is to elucidate the role of cell signaling in regulating cell growth, differentiation, apoptosis and migration, and to assist Cancer Center members in their efforts to harness this understanding into approaches to cancer detection, prognosis and treatment. Program members focus on three major areas of research: 1) understanding the molecular mechanisms involved in the regulation of cell growth and differentiation with an emphasis on the role of tyrosine kinase and G protein-coupled receptor signaling pathways; 2) elucidating the molecular mechanisms regulating cell apoptosis; and 3) addressing the role of the extracellular matrix in regulating cell growth and migration. The Program is led by Drs. Jeffrey Benovic and George Prendergast, both of whom have extensive administrative experience and established research programs focused on cell signaling and cancer. The Program is comprised of twenty-three members and one associate member from nine departments and three Institutions (Jefferson, Lankenau Institute for Medical Research and Drexel). Program members currently have $3.4 million of NCI support and $12.0 million of total, peer-reviewed support and have published a total of 650 manuscripts (11% intra-programmatic and 26% inter-programmatic) during the last funding period.

PROJECT SUMMARY (See instructions): CLINICAL RESEARCH MANAGEMENT OFFICE The Clinical Research Management Office (CRMO) is the shared resource ofthe Kimmel Cancer Center (KCC) that supports physicians, scientists and other staff in the development, implementation, and conduct of clinical trials. The CRMO provides a broad range of services tailored to the specific needs of investigators, the KCC, and consortium partners. These services include supervision of activities related to trial registration and conduct, quality assurance, and monitoring of KCC institutional, pharmaceutical and cooperative group clinical trials. The CRMO also serves as a resource for the KCC community and patients by providing relevant information regarding clinical trial availability. Specific aims of the CRMO include: Orientation of new faculty to KCC, CRMO and (TJU) policies and procedures related to clinical research cilitate the development of KCC investigator initiated clinical trials Coordinate the preparation and submission of studies for review by the Multidisciplinary Groups (MDG), Clinical Cancer Research Review Committee (CCRRC) and the Thomas Jefferson University Institutional Review Board (IRB) Collect, abstract, maintain and update data specific to patients entered on clinical trials Coordination of study visits and procedures related to clinical trials Assure timely and accurate preparation and submission of all regulatory reviews (e.g. new submissions, amendments, annual reports, safety information, etc. to the IRB and FDA) Serve as a liaison between the TJU IRB, FDA or other regulatory bodies, and KCC investigators Assure accurate entry of patients participating in KCC clinical trials in a centralized database Assist in the maintenance of an accurate shared drive repository for complete protocols and informed consents. To improve easy access to viewing clinical trials Participate in the integration and activation of OnCore clinical trials management system Assure appropriate integration of consortium partners into the conduct of clinical research

DATA AND SAFETY MONITORING The Data and Safety Monitoring Plan (DSMP) of the Kimmel Cancer Center (KCC) provides for the oversight and monitoring of clinical trials to ensure the: 1. Safety of patients; and 2. Validity and integrity of the data collected on these trials. Responsibility for data and safety monitoring at Thomas Jefferson University (TJU) resides in: 1. The Clinical Cancer Research Review Committee (CCRRC) which oversees the scientific review of all new and ongoing cancer-related clinical trials within the KCC; 2. The Clinical Research Management Office (CRMO) which provides strategic assistance and support to the CCRRC, DSMC, and continuous monitoring; 3. The Institutional Review Board (IRB) which has primary responsibility for the protection of the welfare of human subjects involved in biomedical and behavioral research. The IRB has full authority to approve, request modifications prior to approval, disapprove, suspend, or terminate for cause all research activities that fall within its jurisdiction; and 4. The Data and Safety Monitoring Committee (DSMC), which is responsible for data and safety monitoring of Kimmel Cancer Center investigator-initiated trials (KCC IIT).

For the next 5 year cycle of the Cancer Center Support Grant, the Kimmel Cancer Center is requesting Developmental Funds to foster collaborative research projects among KCC consortium cancer center members. During the past grant cycle, no developmental funds were available from the CCSG. However, through a combination of philanthropy, ARRA funding, and an American Cancer Society Institutional Research Grant, 60 projects were funded. These funds are a critical source of flexible funding for the KCC, and provide a vital source of support for new research opportunities through pilot project funding. In addition funds are requested to facilitate recruitment of new faculty. Center-wide recruitment needs have been identified in several areas: Translational Breast Cancer Research (BBC), Radiation Research (RRTB), Epigenetics in Cancer (MBG) and Molecular Epidemiology (Gl). The KCC Basic Science Advisory Committee will play a central role in determining which pilot projects requests will be funded. Therefore, it is important to note that the Committee which will be making the decision will include faculty from all the consortium partners (TJU, LIMR, Drexel), and faculty from all the consortium partners will be eligible to apply for pilot project funding. Members of the developing program in Population Science will be eligible to apply for pilot project funding under a somewhat altered process.

CANCER CENTER FACILITIES The Kimmel Cancer Center is located on the campus of Thomas Jefferson University (TJU) and is part of Jefferson Medical College, founded in 1824. Jefferson Medical College is one of the largest private medical schools in the nation and is located in Center City Philadelphia (Fig. 3). The facilities strategic plan of TJU and TJUH has been developed. The KCC and its facilities are a centerpiece of the campus. The Biostatistical and Administrative offices of the Radiation Therapy Oncology Group (RTOG) are located a few blocks from KCC. as are the headquarters of the Coalition of Cancer Cooperative Groups (CCCG). The RTOG Translational Research Program Committee is co-chaired by Dr. Dicker, leader of the KCC's RRTB program. Dr. Comis, a new KCC Member, who is a faculty member of Drexel University, is the President and CEO of the CCCG and Group Chair of the Eastern Cooperative Oncology Group (ECOG). (Drexel University has a medical school and hospital campus in addition to strengths in biomedical engineering). Philadelphia has four medical schools and four NCI-designated Cancer Centers (University of Pennsylvania, Wistar Institute, Fox Chase Cancer Center and Kimmel Cancer Center). The Cancer Centers at Penn and Wistar are, approximately 20 blocks away from the KCC on the west side of the Schuylkill River. Because of this small distance, Penn and Wistar investigators often attend KCC seminars and functions and vice versa.

PROJECT SUMMARY (See instructions): The Kimmel Cancer Center (KCC) Flow Cytometry Shared Resource (FCSR) provides state-of-the-art cell sorting, phenotypic analysis and related services to the members of the KCC at Thomas Jefferson University (TJU). The facility is located in a dedicated laboratory space on the sixth floor of the Bluemle Life Sciences Building, which is centrally located on the TJU campus. The FCSR operates a fully upgraded Beckman Coulter MoFlo cell sorter capable of 10-color high-speed cell sorting ranging from single cell deposition up to 4-population purification. In 2010 the FCSR purchased a Becton Dickinson LSR 11 analyzer. The LSRll analyzer is equipped with 4 lasers and is capable of 12-color phenotypic analysis. The facility also utilizes a dual laser Becton Dickinson FACSCalibur, which is capable of 4-eolor phenotypic analysis. In addition, the facility offers use of an Invitrogen Countess automated cell counter, one Nikon Labophot-2 fluorescence microscope, and a 4?C refrigerator with -20?C freezer. Data analysis and figure generation are performed on either a Mac Pro workstation with a Dual-Core Intel Xeon processor or a Dell Optiplex 990 with Intel Core 15 processor and the latest version of FlowJo analysis software. An on-line scheduling system facilitates investigators' planning of experiments using analytical cytometers as well as billing and usage tracking. The FCSR is managed by KCC and directed by Dr. Jianke Zhang a faculty and KCC member. All FCSR instruments are maintained and managed by a dedicated facility manager and a technician. The most commonly used applications are cell surface and intracellular phenotyping and sorting, intracellular cytokine and cell signaling molecule detection, analysis of Ca^ mobilization kinetics, apoptosis studies, cell cycle analysis, sorting of rare and stem cell populations, and single cell sorting for cloning assays or monoclonal antibody generation. The FCSR facility plays a critical role in assisting KCC investigators as they conduct research directly related to the understanding and treatment of cancer and other diseases. 39 Cancer Center Members utilize the Flow Cytometry Shared Facilty.

PROJECT SUMMARY (See Instructions): The Gastrointestinal (Gl) Cancer Program (Program #6), one of the original programs of the Kimmel Cancer Center at Jefferson, is a multidisciplinary program composed of 25 full and 5 associate members representing 8 departments within Jefferson Medical College (Pathology; Cancer Biology; Family Medicine; Internal Medicine; Medical Oncology; Pharmacology; Radiology; Surgery), the Christiana Care Health System (Helen F. Graham Cancer Center), and Drexel University, whose over-arching goal is to define fundamental mechanisms underlying Gl malignancies which can be translated into diagnostic and therapeutic innovations for managing cancer in patients and populations. Their work is supported by ?~$7.7M in peer-reviewed funding, representing an increase of -75% from $4.4M during the past funding period. Also, program members have published 561 papers, representing almost a doubling compared to the previous funding period. Of those, >17% were intra-programmatic, representing a tripling of the previous rate, and >16% were inter-programmatic. Program members pursue parallel efforts organized along organ based disease processes from discovery through translation to clinical development and application. Members employ common and collaborative experimental paradigms with the goals of (1) defining previously unappreciated molecular, genetic, and epigenetic mechanisms underlying Gl organ-based tumorigenesis, (2) translating defined mechanisms into novel in vitro and in vivo tools to improve prevention, early detection, prognosis, prediction, and risk-stratification in Gl malignancies, (3) defining molecularly targeted therapeutic approaches for cancer prevention, treatment, and control, (4) advancing novel laboratory discoveries into development for clinical trials, and (5) advancing clinically successful diagnostic and therapeutic trials into evidence-based practice for cancer prevention and control across populations. In that context, enrollment of patients in Gl cancer-based clinical trials has increased ~15-fold compared to the past funding period. Members are interactive and cohesive and, under the direction of Program Leaders, coordinate research planning and new research directions with other research programs in the Cancer Center.

PROJECT SUMMARY (See instructions): LABORATORY ANIMAL SHARED RESOURCE The primary purpose of the Laboratory Animal Shared Resource is to provide the resources and environment with which animal models of cancer can be created and analyzed for the Kimmel Comprehensive Cancer Center. This shared resource provides housing and high quality maintenance and care for laboratory animals. The facility also provides technical expertise in small animal surgery, and administration of chemical and radiological reagents. A critical component of the facility is the maintenance of a high quality barrier facility to generate a specific pathogen-free environment that ensures the accurate interpretation of experimental results. The in-colony health surveillance program ensures the fidelity of the facility. The Laboratory Animal Shared Resource has maintained full AAALAC accreditation since 1977. The facility is operated as a partial barrier system in which all animals are housed in sterile ventilator cages on ventilated racks. The facility is composed of 29 animal rooms, along with the requisite cage and food storage area, a dedicated necropsy room, and a tunnel cage washer. This shared resource also provides cryopreservation of valuable mouse strains and recovery of mice from frozen germplasm as well as a range of assisted reproductive techniques that can be applied to maintaining mouse strains in a cost- and time effective manner. This shared resource has consistently maintained the highest level of expertise and proficiency, greatly enhancing the work of Kimmel Cancer Center members. This facility was used by 46 Cancer Center Members.

Abstract Recent advances in understanding progression to castration-resistant prostate cancer (CRPC) has led to development of therapeutics that slightly increase overall survival; however, the majority of patients with CRPC succumb to disease within 2-3 years, indicating the need for metrics of precision medicine, and development of additional therapeutics. Here, we propose an ambitious approach to stratify and enhance treatment for metastatic CRPC to improve therapeutic outcomes, based on cell cycle alterations that we recently discovered. The studies described will explore untouched territory with regard to PCa targeted therapy based management, and will provide the first assessment of treatment based on subtyping in this disease context. Moreover, the studies described could provide the first biomarker with which to stratify prostate cancer treatment, and to improve therapy for patients with advanced disease. Our collective findings strongly suggest that alterations in the RB-cyclin D1/CDK4 axis play major roles in disease progression, and molecular investigation of these alterations provide a rational basis for disease stratification and improved management of advanced PCa. This postulate will be challenged in carefully planned specific aim. First, building on 2 funded clinical trials, we will use biopsy material, novel models of disease, and co-clinical trials to challenge the hypothesis that the RB-cyclin D1/CDK4 axis can be developed as biomarkers of response and as metrics for treatment stratification (Aim 1). These studies have the potential for near-term patient benefit, and could identify the first biomarker for personalized medicine in advanced PCa. Second, robust models will be used to interrogate the molecular basis of responsiveness to therapeutic directed toward alterations in RB and/or cyclin D1 status (Aim 2). Studies planned will provide critical information as to specificity and clinical placement of RB and cyclin D1- alteration dependent interventions. Finally, targeting the Rb-cyclin D1/CDK4 axis forces reliance of tumor cells on G2/M cyclin dependent kinases?plans were thereby developed to leverage this cell cycle dependence, with a goal toward discovery of new means to maximize efficacy of treatment for cells with RB-cyclin D1/CDK4 alterations (Aim 3). These collective aims build off the unique collaboration amongst a leader in clinical management of advanced PCa and a pioneer of novel clinical trials (Dr. Kelly), and a leading AR biologist with significant expertise in studying cell cycle regulation and PCa-associated cell cycle alterations (Dr. Knudsen), and an expert in clinical targeting of cell cycle alterations (Dr. O?Dwyer). As proposed, this project has the capacity to illuminate the means by which perturbations Rb-cyclin D1 alterations alter disease progression and therapeutic response in human disease, and to dramatically alter PCa management.

Leadership, Planning, and Evaluation ABSTRACT: The Sidney Kimmel Cancer Center (SKCC) utilizes a well-established system for Leadership, Planning, and Evaluation efforts that engage Institutional Leaders, Senior Leaders, Program Leaders, Shared Resources Directors, Cancer Center members and staff, advisors, and patient advocates. This effort includes well-tested and integrated mechanisms to monitor, evaluate, and adjust the Center?s Research Program activities, Shared Resources services, funding allocations, and strategic directions to ensure alignment with SKCC vision and goals. Planning and Evaluation ensures that future directions are achievable and that resources and investments are targeted effectively while providing the ability to respond to new opportunities and changes in the cancer research field. Our Planning and Evaluation process is also highly integrated with institutional planning and resource allocation activities to ensure alignment and ability to capitalize on institutional investments. Under Dr. Knudsen, leadership roles/structures, strategic and programmatic planning, and evaluation processes have been transformed and have become embedded in our culture. We have instituted a multi- year strategic plan that guides Leadership decisions and investments. Leadership has been increasingly effective in defining and realizing the Cancer Center?s vision, using planning and evaluation mechanisms to guide decisions, assess progress, and make changes to ensure success. In addition, the Executive Committee now conducts intensive annual Program and Shared Resource reviews, through which they carefully assess progress against milestones, future relevance, leadership, and future aims. Senior Leadership serves to: 1) Establish a vision for the Center and oversee implementation of strategic processes that ensure effective resource allocation, development and management of Programs, Shared Resources, and other relevant components; 2) Foster a collaborative scientific environment that facilitates high-impact research and clinical care; 3) Enable a focus on cancer problems applicable to the catchment area served by the Center, informed by the TIPS (Transdisciplinary Integration of Population Science) platform and senior leadership; and 4) Develop effective training and educational programs that integrate the training of biomedical scientists and health care professionals. Planning and Evaluation processes serve to: 1) Develop and oversee action plans that align with the SKCC vision and mission to achieve Center goals; 2) Implement well-organized internal, external, and institutional planning and evaluation processes that engage leaders, members, and advisors and enable the Center to achieve goals; 3) Provide ongoing mechanisms to monitor, evaluate, and improve Programs, Shared Resources, Developmental Funds, clinical research resources, new initiatives, funding priorities and allocations, and strategic directions to ensure alignment with the Center?s vision and goals.