The goal of this Specialized Program of Research Excellence (SPORE) in pancreas cancer is to translate outstanding hypothesis-driven basic research into clinical treatment that saves lives. Pancreatic cancer is a devastating cancer that kills patients not just because it may be extremely aggressive but also because it is diagnosed late. This SPORE is a unique collaboration between Georgetown University, Geisinger Health System and INDIVUMED a German Research Institute with a German hospital consortium that brings together an outstanding academic institution, a large regional healthcare system and a German basic and clinical research system to address the biology of pancreatic cancer and clinical care. Project 1 focuses on inhibition of pleiotrophin, a novel heparin-binding growth factor that promotes invasion and metastasis in pancreatic cancer. Project 2 focuses on the role of neuregulins and pleiotrophin in an established model of neuron tumor cell interaction with the goal of developing methods to block neural invasion by malignant pancreas cells that may ultimately aid in disease palliation. Project 3 focuses on recent findings that inhibition of the nuclear receptor coactivator AIB1 within pancreas cancer cells and adjacent endothelium may block signaling from multiple growth factors to enhance apoptosis. The activation of the ras/MAP kinase pathway that occurs in up to 90 percent of pancreas cancer is the focus for novel approaches to radiation sensitization in Project 4. Investigators at Georgetown have developed a rafl antisense inhibitor that is already in Phase I trial and have developed other molecular targets in the pathway that are complementary. In addition, this SPORE is developing the infrastructure and resources to acquire tissues and bodily fluids from patients (Pancreatic Tumor Bank and Serum Detection & Molecular Identification Cores) with an expected 120 curative resections a year. The SPORE will utilize a biostatistical core to insure that all projects have appropriate designs, methods of analysis, and an integrated database for reporting patient outcomes. Further, the SPORE will support developmental projects designed to generate new knowledge and approaches to early detection and promote the development of career tracks dedicated to translational research in pancreatic cancer. This SPORE is also establishing interactions with SPOREs in other institutions as well as with other NCI- and NIH-funded programs to promote the aggressive development of novel therapies for the control of pancreas cancer. OVERALL CRITIQUE This SPORE brings to bear appropriate scientific expertise and unique resources to address the molecular mechanisms underlying the development and progression of human pancreatic cancer. Four projects and four cores are proposed whose overarching goal is to improve control, detection and prevention of pancreatic cancer. Several of the proposed studies are novel and have the potential to lead to new insights into the biology and clinical management of the disease. Additional strengths of the application include the excellent leadership and scientific expertise of the Principal Investigator, integration with the Lombardi Cancer Center, and the strong institutional commitment. However, overall merit is diminished by deficiencies in experimental design and rationale, by the uncertainties regarding the administrative cohesion between the various SPORE sites and by the inadequate level of support by some of the Core components. Overall, the strengths of the SPORE are many and, although a number of substantial concerns and deficiencies were identified, the proposed program possesses therapeutic potential. Project 1: Pleiotrophin Modulation of Pancreatic Metastasis (John Jessup, M.D., Anton Wellstein, M.D., Ph.D.) This project focuses on a novel growth regulatory pathway in pancreatic cancer involving the overexpression of the growth factor pleitrophin. The strengths of the project include abundant preliminary data that support an important role for this pathway in tumorigenesis, the clear translational potential of the proposed studies and the excellent track record of the co-leadership team. Weaknesses include the omission of experimental details from some of the proposed studies and the fact that a large proportion of the preliminary results have been derived from non-pancreatic cancers. This project was rated outstanding to excellent. Project 2: Nerve Metastasis and Pancreas Cancer (David Carey, M.D., Farid Fata, M.D.) The goal of this project is to identify cell adhesion and growth factor signaling mechanisms that promote the invasion and growth of pancreatic cancer cells in nerve tissue. The strengths of the project include the clinical relevance of the questions it addresses, the novelty of the experimental approach and the expertise of the basic scientist, Dr. Carey, in tumor and nerve cell biology. Weaknesses include lack of rigor with respect to experimental design and data interpretation, uncertainty with respect to the feasibility of some of the proposed studies and the absence of clearly defined translational end points. This project was rated good. Project 3: Role of the Co-Activator A1B1 in Pancreatic Cancer (Anna Riegel, Ph.D., John Marshall, M.D.) This project is designed to test the hypothesis that the nuclear receptor coactivator AIB1 and its splice variant may serve as diagnostic and prognostic markers of pancreatic cancer. The strengths of the project include the intriguing nature of the preliminary data, the novelty of the central premise underlying the proposed studies, the qualifications of the co-Project Leader (Dr. Riegel) and the well delineated experimental plans. The application is weakened by the relatively premature stage of the preliminary data, which complicates the assessment of the translational potential of the proposed work and by the lack of consideration of the technical and conceptual limitations of some of the proposed studies. For example, potential pitfalls and details of the approach to injecting siRNA are not adequately discussed. This is critical because the siRNA injection is technically difficult and there are concerns about its feasibility. This project was rated excellent. Project 4: Molecular Biological Approaches to Radiosensitization (Anatoly Dritschilo, M.D., Mira Jung, Ph.D.) The overall goal of this project is to identify molecular targets that can be exploited to enhance the radiation sensitivity of pancreatic cancer cells. The proposed studies will focus on cellular components that play critical roles in K-Ras mediated activation of NF-kB. The strengths of the project include the clinical relevance and translational potential of the outlined experiments, and the past accomplishments of the PI in elucidating signal transduction pathways involved in radiation response. The weaknesses include limitations in the experimental design that could have negative impact on both the feasibility and interpretation of the studies. This project was rated very good to good. Core A: Administrative Core (John Jessup, M.D.) The Administrative Core led by the Principal Investigator, Dr. Jessup, constitutes the principal oversight mechanism for the fiscal, clinical and scientific coordination of the SPORE. The core leadership is outstanding, and mechanisms are outlined to promote communications and collaborations among SPORE investigators. The chief weaknesses of the core are that the effort of key personnel, especially at the remote SPORE sites is too low and the paucity of detail in the organizational plans for insuring that the SPORE will be able to manage the remote SPORE sites effectively. This core was rated very good. Core B: Tissue and Pathology Core (Baljit Singh, M.D., John Jessup, M.D) This core proposes to provide comprehensive histology and pathology support, and tumor and tissue resources to all five projects in the program. Pancreatic tissue will be collected from 3 centers in the United States: Georgetown, Geisinger, and INDIVUMED, each of which has multiple sub-sites/participating institutions, and a hospital in Germany. The part of the core which exists at Georgetown is well organized, operates in a cost-effective manner, and benefits from superb leadership. However, the majority of the tissue will come the other sites and the description of the other sites is not as clear. It is not certain that the necessary personnel are in place at those sites and plans for sharing data are not sufficiently detailed in the application. Thus there is a lack of confidence that this core will be able to attain its goals and collect tissues in sufficient numbers to support the needs of the SPORE. This core was rated very good to good. Core C: Serological Detection and Molecular Identification Core (Hartmut Juhl, M.D., Ph.D., Anton Wellstein, M.D., Ph.D.) This core provides two services, procurement of tissue at INDIVUMED and development of prognostic and diagnostic markers biomarkers. The core benefits from well-qualified leaders and the services it intends to provide have strong translational potential. However, the specimen procurement component of this core has a significant overlap with Core B and the coordination of activities between the two geographically disparate cores is not adequately addressed. In addition, the biomarkers studies are not well described and their relevance to the SPORE projects is not apparent. The commercial nature of INDIVUMED and the potential implications for issues pertaining to conflict of interest and intellectual property are serious concerns as these issues are not adequately addressed in the application. This core was rated good. Core D: Biostatistics Core (Edmund Gehan, Ph.D.) Biostatistics Core This core provides centralized patient data base management to the projects and cores together with biostatisitcal consultation and data analysis. The core has strong leadership but is not well integrated with the SPORE projects. There is not sufficient evidence of adequate interactions between the core and the projects. The core is also weakened by the paucity of in-depth considerations of data analysis strategies and study design as well as inadequate resources to achieve its stated goals. As a result of these serious deficiencies, this core was rated only good. DEVELOPMENTAL RESEARCH PROGRAM (Anton Wellstein, M.D., Ph.D.) The goal of the Developmental Research Program is to identify and fund pilot projects for promoting translational pancreatic cancer research. Funds to support 4 pilot projects annually at $75,000 per project are requested, which is adequate. A suitable solicitation process within the institution is described, however, the process for solicitation outside of the SPORE institutions is not adequately described. Review is a two step process with the final decision by Dr. Jessup, the SPORE Principal Investigator, based on recommendations from the SPORE Executive Committee. This is an adequate process of review. The provided examples of the developmental research proposals are of excellent merit. However, the institution commitment is not clearly addressed. This program would have been strengthened by a more detailed discussion of the mentoring process and a brief discussion of a strategy to bring clinical and basic scientists together to perform translational pancreatic cancer research. This program was rated excellent. CAREER DEVELOPMENT PROGRAM (Mira Jung, Ph.D.) The SPORE application describes a strong Career Development Program directed by Dr. Mira Jung. It is focused on the development of junior faculty, advanced post-doctoral fellows and established faculty who wish to conduct pancreatic cancer research. Overall, the selection process is appropriate and the application describes an aggressive plan for recruitment of racial/ethnic minority candidates and women. An excellent group of mentors has been identified, and guidelines for mentoring are appropriate. Additional strengths are the plan for coursework to allow trainees to broaden their knowledge and the leadership of the Program Director, Dr. Jung. One concern is that it is not clear how well the mentoring program will work at such geographically disparate sites (Washington, DC, Pennsylvania, and Germany). Another concern is that although additional institutional support is mentioned, but supporting documentation is not provided in the application. This program was rated excellent. HUMAN SUBJECTS SUMMARY: There are no human subjects concerns. Adequate measures to protect patient populations from research risks are in place. In addition, there are satisfactory plans for data and safety monitoring. Although it is not a concern, it should be noted that this core proposes to use human tissues obtained from a foreign source (Germany). Both men and women will be included in numbers proportionate to the incidence of the disease and there are adequate plans for the inclusion of minority populations. Children will not be included since pancreatic cancer is rare in anyone under 35 years of age. The application was rated acceptable in these categories. SPORE PROGRAM ORGANIZATION AND CAPABILITY The Principal Investigator, Dr. Jessup, has the scientific and administrative credentials to lead this SPORE. He is well funded and well published in the area of GI malignancies. He has been the Principal Investigator for a PO1, the Director of a T-32 training grant, member of several peer review panels, and Chief of Surgical Oncology and UTSA. However, he will devote only 10 percent of his effort, which is not adequate for the predicted administrative burden of this SPORE. The co-Principal Investigator, Dr. Wellstein, will assist him, particularly in the area of developmental projects, although the level of commitment of Dr. Wellstein to the co-leadership of the SPORE has not been clearly specified in the application. The planning and evaluation of the various SPORE activities will be conducted by the Principal Investigator and co-Principal Investigator in close consultation with a steering committee that includes scientists from other SPORES and members of the Internal Advisory Committee which is composed of all Project leaders, Directors and co-Directors of Cores and the Career Development and Developmental Project programs. The advice of an External Advisory Board, yet to be appointed, with respect to progress and direction will be sought once a year. Relatively low numbers of patients with pancreatic tumors are seen at Georgetown. However, it is a plus that the SPORE investigators have sought to increase their patient populations through consortia with other institutions. There is documentation that the SPORE program will have access to approximately 100 operative specimens a year contributed by the participating institutes. In addition, collaborative interactions have been formed to expand the patient population for developing diagnostic and prognostic screens. The close relationship with MedStar will provide the benefit of integrating clinical trials and translational research into a more diverse ethnic population. However, sufficient convincing detail that these consortia will be managed effectively and provide the stated patients, and their tissues, has not been provided. The research programs are diverse and well balanced with respect to scientific approaches and translational potential. The Lombardi Cancer Center offers a number of shared resources that are utilized by the SPORE including Biostatistics, Tissue Culture, Clinical and Molecular Epidemiology, and Familial Cancer Registry. In addition the SPORE program interacts heavily with the Tumor Bank and Biomarker resources of the Lombardi Cancer Center. Similarly, the SPORE's Serological Detection and Molecular identification core is closely allied to the Lombardi Biomarker Shared resources. Institutional commitment from the lead institution, Georgetown University, to this SPORE is evident at three levels: space allocation, recruitment of faculty and discretionary funds to support developmental projects or career development. Institutional support is also provided through partial reimbursement of postdoctoral and graduate student salaries. Institutional commitment from MedStar is reflected primarily by the recruitment of junior academic surgeons with expertise in upper GI tract cancer. Scientific interactions between projects will be promoted through monthly meetings. All components of the SPORE make an effective use, albeit to varying degrees, of the shared SPORE resources. INTERACTION WITH OTHER SPORES The SPORE has an ongoing collaboration with the Johns Hopkins GI SPORE program particularly in the area of Tissue Microarrays. This interaction has resulted in two abstracts for the upcoming AACR meeting. There are also plans to establish interactions with the NIH serum repository whereby the SPORE will be provided with 0.5 ml of serum from a large series of patients with ductal adenocarcinoma with matching controls for serological detection of malignancy. In addition, the SPORE will establish a relationship with the Prostate, Lung, Colorectal and Ovarian screening trial again to integrate screening efforts based on serological markers. The collaboration with PLCO provides opportunity to access a collection of over 150,000 participants who lack familial history but in whom more that 200 people developed pancreatic cancer. Plans are also proposed to establish collaboration with the division of Human Genetics at the University of Oklahoma School of Medicine who has a large familial pancreatic cancer registry. INDIVIDUAL RESEARCH PROJECTS PROJECT 1: Pleiotrophin Modulation of Pancreatic Metastasis (John Jessup, M.D., 10 percent effort and Anton Wellstein, M.D., Ph.D., 15 percent effort) DESCRIPTION (provided by applicant): Adenocarcinoma of the pancreas is the tenth and ninth most common newly diagnosed cancer in men and women, respectively, in the United States and yet is the fourth most common cause of cancer-related death with a 97 percent mortality rate. This project focuses on the development of novel therapies that target pancreatic cancer metastasis and local invasion by inhibiting a growth factor that is important for metastasis as well as tumor-stroma interaction. Pleiotrophin (PTN) is a heparin binding growth factor that controls proliferation, angiogenesis, stromal interactions and metastasis. We have shown that PTN is overexpressed in the majority of human pancreatic cancers, that blood levels are prognostic and that inhibition of PTN production reduces tumorigenicity and cell proliferation in a human pancreas cancer cell line. Furthermore, malignant cells secrete PTN to be a paracrine factor that induces expression of its receptor in adjacent endothelial and stromal cells. We have identified anaplastic lymphoma kinase (ALK) as a receptor for PTN and shown that ALK is expressed in human pancreas carcinomas as well as in other carcinomas and are developing novel reagents to disrupt PTN-ALK signaling. Our hypotheses are that the PTN-ALK axis is an essential component of neoplastic progression by human pancreatic cancer and that disruption of PTN-ALK signaling by novel inhibitors trader development will block growth, local invasion and metastasis of tumor cells. These hypotheses will be tested by the following aims: 1.) determine the role of PTN/ALK in the phenotype of pancreatic cancer cells in culture, 2) determine the effect of PTN/ALK inhibition on tumor growth and spontaneous metastasis in an orthotopic implantation xenograft model of human pancreatic cancer in mice, 3) to correlate the expression of ALK, phospho-ALK and PTN in a cohort of resection specimens from pancreatic cancer vs. normal tissues, as well as determine the levels of PTN in the blood of patients with pancreatic cancer vs. control patients to assure that PTN and/or ALK represent appropriate targets for therapy, and 4) to introduce an inhibitor for PTN or ALK that demonstrates activity in the preclinical studies described in Aim 2 into a Phase I trial with serum-based pharmacodynamic assays for drug dosing.
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