
SPOREs :Organ-Specific SPORE Programs : Prostate

Mayo Clinic Prostate SPORE

Donald J. Tindall, Ph. D., Principal Investigator
Director & Vice Chair of Urologic Research
Mayo Clinic College of Medicine
Department of Urology
Biochemistry Molecular Biology,
Rochester, MN 55905
Phone: 507-284-8139
Fax: 507-284-2384

PROJECT 1

Utility of serum and tissue biomarkers for predicting response to androgen deprivation therapy in the population of men with rising PSA following definitive treatment

Principal Investigator: George G. Klee, M.D., Ph.D.

The majority of men with prostate cancer are now diagnosed with cancers with a low risk of cause-specific mortality.^1-2 Such men are most frequently treated with primary definitive therapy including radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy and are followed by regular serum PSA evaluations thereafter. Over a 5 to 10 year period, 15-30% of these men will be observed to have a rising PSA.^{3, 4, 5}

Of this group, some men will have obvious local recurrence or have clinically detectable metastasis, but many will have no other evidence of recurrent prostate cancer other than a rising or detectable PSA. These PSA relapses are conservatively estimated to affect approximately 50,000 men each year, define a rapidly growing population of major clinical and public health significance. The PSA "doubling time" has been identified as a potential surrogate for cause-specific mortality, and is used by some clinicians to determine which of these men deserve adjuvant hormonal ablation, local radiation therapy, or simple observation.^6-7

Biomarkers that could predict which of these men would benefit from any additional therapy are clearly needed. Genomic studies on prostate cancer tissue provide a good basis not only for tissue markers but also to identify candidates for potential serum biomarkers. Thus in this project we propose a clinical epidemiology study to evaluate and validate comprehensive tissue biomarker panels and to use data from these arrays to develop serum biomarker panels. We will then test both serum and tissue biomarker panels in a clinical trial intended to improve the care of patients with prostate cancer, and ultimately reduce the suffering and early death associated with prostate cancer progression

PROSTATE SPORE PROJECT 2

Prostate Imaging by Vibro-acoustography

Principal Investigator: Mostafa Fatemi, Ph.D.

The long-term goal of this research is to develop and validate a new tool for prostate imaging. The new tool, trans-rectal vibro-acoustography (TRVA), will be noninvasive, and capable of producing high resolution and high contrast images, sensitive to tissue stiffness, suitable for clinical and intra-operative imaging applications. In addition, the new tool will be capable of imaging prostate tissue, malignant lesions, and prostate brachytherapy seeds. It is envisioned that TRVA may be used both as a diagnostic tool and as an intra-operative tool for guidance of minimally invasive prostate cancer therapies. The short-term goal is to develop TRVA as a diagnostic tool for prostate imaging and detection of cancer. The rationale of the proposed work is that prostate imaging is best accomplished by using a non-invasive imaging modality that is sensitive to tissue stiffness, providing the means to detect malignant lesions in the prostate in a way that is conceptually similar to digital rectal examination, but with much higher precision. Preliminary results from laboratory and clinical studies support this hypothesis and provide data for optimizing the technology for clinical use via development of a new 3D imaging device.

PROSTATE SPORE PROJECT 3

Gene Therapy of Prostate Cancer Using Radioactive Iodine

Principal Investigator: John C. Morris, III, M.D.

The specific aims of Project 3 are to:

Evaluate the safety and maximum tolerated dose level of AD5-CMV-NIS as an adenoviral construct for radioiodine treatment as well as obtain preliminary data on clinical outcome in the context of a Phase I clinical trial in patients with locally recurrent prostate cancer following radiation therapy failure. Upon completion of this trial, we will more formally evaluate the efficacy of this treatment regimen at the recommended dose level through a phase II trial.
Develop a second generation adenoviral construct that is specific for prostate tissue, Ad-Pb-NIS, for clinical trial in prostate cancer and evaluate the safety and maximum tolerated dose level of this adenoviral construct as well as obtain preliminary data on clinical outcome through a phase I clinical trial.
Develop and evaluate different constructs for enhanced and systemic delivery of NIS for metastatic prostate cancer.

PROSTATE SPORE PROJECT 4

A Randomized Phase II Clinical Trial to Determine the Safety, Tolerability and Efficacy of an Allogeneic Whole Cell Vaccine Administered With or Without Autologous Myeloid Dendritic Cells to Patients Suffering From Androgen Independent Prostate Carcinoma

Principal Investigator: Stanimir Vuk-Pavlovic, Ph.D.

The specific aims of this study are:

To conduct a two-arm randomized phase II clinical trial of the allogeneic prostate cancer whole-cell vaccine administered alone or in combination with autologous mature DCs and evaluate the clinical endpoints of overall survival, cause-specific survival, progression free survival and PSA-based responses in patients with hormone refractory non-metastatic prostate cancer. From the enrolled patients' sera, we will quantify the levels of human kallikrein-2 (hK2) and pro-hK2 for a preliminary determination of their role as survival predictors in the hormone refractory prostate cancer patients vaccinated as described.
To identify and characterize the type, extent, and duration of the immune response in patients treated by allogeneic prostate cancer whole-cell vaccine alone or in combination with autologous mature DCs.
To transduce dendritic cells with the IL-2 gene and test the effects on expansion of tumor-specific T cells and suppression of T-regulatory cells in vitro.

To execute the clinical trial, we are collaborating with the vaccine manufacturer Onyvax Ltd, Tooting, England. The proposed clinical trial is technically, medically and ethically feasible. It is based on technologies and clinical-grade products that have been approved and tested for human use or are amenable to rapid approval. These cellular products are minimally toxic, particularly in comparison to systemic cytotoxic agents. Our combined resources, expertise, past experience and operating infrastructure provide a unique environment to continue pushing the limits of immunotherapy of prostate cancer.

PROSTATE SPORE PROJECT 5

An Immune-Based Therapeutic Approach for Prostate Cancer

Principal Investigator: Esteban Celis, M.D., Ph.D., H. Lee Moffitt Cancer Center

The primary objective of this application is to translate into the clinic the preclinical scientific achievements derived from the previous funding period. We will utilize CTL and Th cell peptide epitopes identified from prostate-associated antigens, together with a novel topical vaccination technique, to carry out a clinical study in prostate cancer patients. For these studies we have selected two CTL epitopes and two Th cell epitopes derived from the prostate-associated antigens, PSMA and TARP, which will be administered in the form of a topical vaccine. The secondary objective of this proposal will be to further optimize peptide topical vaccines by developing a vaccination strategy that takes into account the immune suppressive environment of the tumor site, which limits the effectiveness of many cancer vaccines. To accomplish these objectives, we propose the following specific aims:

To evaluate the safety and immunogenic effects of a topical formulation of a PSMA/TARP peptide vaccine in prostate cancer patients. We will conduct a clinical study in 30 patients who will receive a topical vaccine consisting of synthetic peptides corresponding to CTL and Th epitopes administered with Aldara cream, which will serve as an immunological adjuvant. Two categories of patients will be accrued and stratified into the protocol:
1. Progressive asymptomatic prostate cancer before initial androgen deprivation therapy
2. Progressive asymptomatic prostate cancer soon after initial androgen deprivation therapy
3. Patients will be repetitively vaccinated and immune responses to the peptides will be measured using peripheral blood lymphocytes obtained prior to each vaccination. Anti-tumor effects of vaccination will be evaluated by assessing plasma PSA levels. Simultaneously, we will monitor the expression levels of the T-cell receptor associated CD3zeta (CD3Z) chain also known as CD247 in blood T lymphocytes, as a parameter related to immune suppressive activity commonly found in cancer patients. An additional parameter associated with immune suppressor activity that will be measured is the level of arginase activity found in peripheral blood mononuclear cells. The main hypothesis for this aim is that the topical vaccine will not only be safe but will be able to induce CTL and Th responses to the immunizing peptides. The secondary hypothesis for this aim is that immune non-responsiveness (or low responsiveness) will most likely occur in those patients exhibiting signs of immunosuppressive activity. We believe that the proposed strategy is unique due to:
4. The use of a topical vaccine formulation using a TLR-ligand (imiquimod) as an adjuvant
5. The generation of both Th cell and CTL responses to antigens expressed by the tumor cells (i.e., an integrated immune response)
6. A multi-antigen strategy that may help prevent antigen-loss variants; and
7. Immunization in the presence of androgen ablation that may to improve the overall immunity. These consider that these attributes make our approach unique, novel and worth pursuing.
To develop a therapeutic strategy to help overcome immune suppressing activities that limit the effectiveness of vaccination against tumors. Since it is well known that established tumors create an immunosuppressive environment that affects the anti-tumor function of T lymphocytes, it is important to study therapeutic approaches that may help overcome this barrier. Myeloid suppressor cells (MSC) constitute one of the most important factors inhibiting effector T cells in the tumor setting. Thus, we will develop an animal tumor model to design a strategy to block the activities of MSC that render the immune system inoperative against the tumor. Using this animal model will also develop a method to block the inhibitory activity of T regulatory (Treg) lymphocytes. This will allow the induction of more effective anti-tumor immune responses to topical peptide vaccination. The results from this aim should facilitate the development of improved vaccination strategies for patients whose immune systems are hampered by these immune suppressor activities.

CORE 1: ADMINISTRATIVE CORE (DONALD J. TINDALL, PH.D.)

The Administrative Core supports the operational structure of this SPORE. It provides coordination of the research projects, scientific cores, and developmental programs of the SPORE. It also serves to enhance communication between SPORE investigators and facilitate all SPORE operations and interactions. The Administrative Core is responsible for coordinating the SPORE Executive Committee and the Advisory Council. Dr. Tindall serves as Director of the Administrative Core, and Dr. Davis as Co-Director. The Administrative Core supports SPORE activities by: (1) providing leadership, organizational support, and financial management for SPORE investigators; (2) coordinating monthly scientific meetings of SPORE investigators, and the ongoing scientific review of SPORE research projects and cores; (3) reviewing progress of the SPORE full and developmental projects; (4) providing for information transfer to the scientific community via professional and public means; (5) providing the structure for nurturing collaborations to facilitate and expand prostate cancer research; and, (6) acting as liaison with leadership of the other Prostate SPOREs and the NCI SPORE Program.

CORE 2: BIOSPECIMEN CORE (JOHN C. CHEVILLE, M.D.)

The Prostate Biospecimen Core of this Specialized Program of Research Excellence (SPORE) provides a coordinated, centralized and dedicated program for procurement and processing of biospecimens obtained from men with prostate cancer. Human biospecimens are one of the most valuable and unique resources available for translational research at Mayo Clinic. The goal of the Biospecimen Core is to collect a full spectrum of biospecimen tissue, blood and urine, from every prostate cancer patient undergoing treatment for their disease. The Biospecimen Core coordinates acquisition of normal and neoplastic prostate tissues, blood and urine for translational research. A portion of normal and prostate cancer tissue from each patient will be obtained fresh and stored frozen to provide investigators with DNA and RNA and the remainder of the tissue will be available in paraffin blocks stored at the Mayo Clinic Tissue Registry. The Biospecimen Core serves as a resource of expertise, collaborative effort and service for pathology, immunohistochemistry, in situ hybridization, laser capture microdissection, reverse-transcriptase polymerase chain reaction (RT-PCR), tissue microarrays and digital image analysis (DIA). The Biospecimen Core provides an interface and be electronically integrated with the Prostate Cancer Patient Registry, Biostatistics Core and the CaBIG initiative. The collection, banking and use of biospecimens will be performed with appropriate patient consent, state and institutional approval. The Biospecimen Core interacts and collaborates with other Prostate SPOREs to promote resource sharing and integrate scientific projects of mutual interest.

CORE 3: CLINICAL CORE (BRIAN J. DAVIS, M.D., PH.D.)

The Clinical Core provides patients to support the translational and clinical portions of all Projects of the Prostate SPORE. Clinical trial management including protocol administration, patient recruitment and data entry will be managed by the Core. Patients will be recruited for participation in the SPORE translational research and clinical trials in this core which will operate jointly in the Departments of Urology, Radiation Oncology, and Medical Oncology. Database managers in each department assist in recruiting patients for these studies, schedule tests and follow-up appointments, and gather data. Prospective follow-up data collection in support of the biomarker Project 1 will include serum prostate specific antigen (PSA), physical examination, and disease status. Data storage and analysis will be conducted by the Biostatistics Core in close coordination with the Clinical Core.

CORE 4: BIOSTATISTICS CORE (ERIC J. BERGSTRALH)

The Biostatistics Core provides statistical collaboration and data management support for each of the SPORE projects, the developmental projects, and the Cores. Each of the projects presented in this application reflects input from members of the Biostatistics Core on study design and analysis plan. The Biostatistics Core provides statistical support across many different fields, including statistical genetics, epidemiological studies, basic sciences including gene array, and clinical trials. This comprehensive nature of the Biostatistics Core assures each SPORE investigator access to statistical expertise that includes collaborative development of study designs and analysis plans, state of the art data analysis and interpretation, data management resources, and abstract and manuscript preparation. The Biostatistics Core also provides a mechanism for the management and integration of both existing and newly collected data through consistent and compatible data handling. Areas of support include database development, data form development and processing, quality control, data collection and entry, and data archiving. This Core complements and assists the efforts of other Cores such as the Clinical and Biospecimen Cores by providing data management expertise and experience with tissue registries such as the Radical Prostatectomy database. The Biostatistics Core builds upon the innovative and time-tested procedures and systems developed by one of the largest statistical groups in the country whose members have collaborated on more than 10,000 clinical and basic science research studies since 1966.

CORE 5: PATIENT ADVOCATE CORE (DONALD D. LAYTON, JR., M.D.)

The overall aims of this Prostate Cancer Advocate Core are to 1) engage researchers and advocates in dialogue that will contribute patient insights to the research programs of the SPORE and 2) to provide information about prostate cancer and prostate cancer research to patients and the community. This is a newly established core.

Meeting these goals means involving advocates in discussion with researchers about the benefits and relevance of their research to patients and on the contribution that will result from a successful completion of their work. The advocates will participate in clinical trial protocol development and consent form reviews for SPORE projects to provide the viewpoint of the patient and enhance the comprehensibility and acceptability of the documents. The advocates will assist in accrual for clinical trials. They will also participate in research proposal reviews to provide a patient/consumer point-of-view.

The community-based aim will focus on persons who have been diagnosed with prostate cancer, their supporting family members, at-risk familial extensions of the patient, and members-at-large of the community. There is both a lack of knowledge and misinformation about prostate cancer among these persons. The work of the advocates will include going into the community to provide information about prostate cancer and its detection and treatment, while providing information about SPORE research and clinical trials, and providing patients and their families with a broad program of education through the established support group. This work is intended to encourage early screening testing, demonstrate access to information resources, and increase awareness of treatment options and clinical trials. This kind of information can contribute directly to earlier diagnosis and treatment and to a higher rate of successful outcomes and patient satisfaction. Mayo Prostate SPORE advocates are now significantly involved with prostate advocates from other Prostate SPOREs and with advocates from other Mayo SPOREs. The prostate advocates also participate with other organizations related to the Mayo Comprehensive Cancer Center. The interests of present and especially those of future prostate cancer patients will be enhanced by the addition of this core to the Mayo Prostate SPORE.



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