Specific Research Opportunities
Biostatistics/Epidemiology/Outcomes
Ethan Basch, MD, MSc, is a health services researcher in the Department of Epidemiology and Biostatistics who studies clinical informatics and patient symptom self-reporting. As a medical oncologist he treats prostate cancer patients at the Kimmel Center. His recent research has focused on allowing patients to report their own toxicity-related symptoms during routine care and clinical trials. His other involvements include national informatics initiatives such as the cancer Biomedical Informatics Grid (caBIG) and the Clinical Data Interchange Standards Consortium (CDISC). Fellows interested in projects related to symptom assessment or the use of information technology during clinical trials are encouraged to participate in one of these programs.
Andrew Vickers, PhD, is on the Biostatistics Service, the broad focus of which is medical prediction. More specifically, our biostatisticians are interested in how predictions impact decision making. Much of their work concerns biomarkers, of which the best known is prostate-specific antigen (PSA). A typical issue that members of this team might examine is whether PSA levels can predict cancer recurrence, and if so, whether a prediction based on PSA levels is accurate enough to influence a clinical decision -- for example, whether to offer adjuvant therapy. They also conduct research into various aspects of surgical quality, addressing questions such as whether outcomes vary between surgeons and what the "learning curve" is for particular surgical techniques.
Erectile Dysfunction
John P. Mulhall, MD, is a urologist who specializes in sexual dysfunction. His laboratory is focusing on two main endeavors. The first is to analyze the effect of cavernous neurotomy on the structure and function of corpus cavernosal smooth muscle and to explore methods of abrogating the deleterious effect of this nerve damage. Using a rat model, the laboratory is assessing the downstream effects of cavernous neurotomy as well as the impact of neuro protectants on nerve regeneration and survival of nerve grafts. They are also analyzing the utility of neurotracers injected in both antegrade and retrograde fashions to better identify the cavernous nerves. The fellow will work closely with Dr. Mulhall in designing and conducting the experiments, including IACUC liaison, animal microsurgery, and hands on exposure to the molecular techniques involved in the project.
The second main endeavor is to analyze the cellular mechanisms involved in the development of Peyronie's disease. This project involves both animal and molecular biologic research. Using a well-established cell culture model, molecular techniques such as PCR, RT-PCR, and viral transfection are being utilized to better understand this condition. SCID mouse experiments assess the pathobiology of Peyronie's disease plaque-derived fibroblasts that are cultured from patients and also are part of an effort to develop an animal model for this condition.
Immunology/Gene Therapy
Neil H. Bander, MD, developed the first and most successful monoclonal antibody against prostate specific membrane antigen(PSMA). His research focuses on the therapeutic activity of the naked monoclonal antibody, the development of conjugated antibody with cytotoxic compounds or with radio emitters for the therapy of prostate cancer, and the development of imaging tests using the radio labeledor fluorphore-labeled antibody. Both laboratory and clinical trials experience are available for fellows in his lab.
Michel Sadelain, MD, PhD, runs the Gene Transfer and Gene Expression Laboratory in the Immunology Program at SKI. His lab is investigating the use of adoptive immunotherapy in the treatment of prostate cancer. Genetically modified cytotoxic T cells have been generated that express artificial receptors specific for prostate specific membrane antigen (PSMA). This system is currently being investigated in the treatment of local as well as metastatic prostate cancer in an in vivo model. Studies are also ongoing to explore the signaling properties of these receptors, alternative approaches to T cell activation and expansion, and homing properties in a metastatic model. It is hoped that these studies will lead to a novel approach to the treatment of prostate cancer.
Laparoscopic and Minimally Invasive Surgery Laboratory and Clinical Research
Bertrand Guillonneau, MD, Karim A. Touijer, MD, and Jonathan Coleman, MD, supervise clinical and laboratory research in laparoscopic and robotic-assisted surgery and image guided procedures. The Urology Service at MSKCC is committed to determining the most appropriate applications of laparoscopy and minimally invasive techniques in the field of urologic oncology. The goal of the minimally invasive surgical research group, and therefore the research fellow, is to devise and test operative modifications, new techniques, and new technologies that will result in improvements in patient care. Because mastery of the laparoscopic techniques is indispensable to future innovation, dry laboratory facilities are available for every fellow who wants to improve his or her laparoscopic skill. Laparoscopic simulators, perfused-organs models, instrumentation to complete full laparoscopic training, and remote controlled manipulators (da Vinci and other robots) are available at any time. State of the art facilities include a live animal vivarium and allow for the critical evaluation of current laparoscopic and image-guided therapeutics as they apply to surgical outcome. The MIS program collaborates with bio engineering in instrument and bio material development for training, diagnosis, and therapeutics in MIS urologic oncology. Clinical research protocols in minimally invasive procedures explore the range of techniques applicable for the diagnosis and treatment of all urologic cancers, including cryoablation for renal tumors and MRI-directed prostate biopsy. The latter have been initiated, together with our colleagues in diagnostic and interventional radiology, to investigate the effective use of these techniques in urologic oncology care. Interested fellows will play a role in the critical steps of trial design and implementation as well as in the performence of percutaneous image guided procedures.
Molecular Pathology and Molecular Biology of Cancer
Pier Paolo Pandolfi, MD, PhD, is head of the Molecular and Developmental Biology Laboratory. His laboratory studies the molecular events and pathways responsible for the development and progression of human malignancies. The goals of the lab are 1) to identify tumor suppressor and oncogenic pathways essential for human tumorigenesis; 2) to evaluate these pathways in a mammalian system (mouse modeling) and study the role they play in tumorigenesis, in order to evaluate cooperating oncogenic events and potential molecular therapeutic targets as well as the safety and efficacy of anticancer therapies in preclinical trials; and 3) to translate the knowledge gained by modeling human cancer in mice to establish clinical trials for cancer patients.
In recent years Dr. Pandolfi's team has identified and established the role of a number of tumor suppressors in human carcinogenesis and leukemiogenesis (PTEN, PML, p27, p53, TSC2, NPM, etc.). Through mouse modeling they established the impact that the loss of one or more of these tumor suppressors has on tumorigenesis as well as on molecular pathways and the interactions involved in these malignant processes. Their experiments further defined the tumor suppressive pathways that are responsible for the inhibition of tumorigenesis and may serve as potential targets for anticancer therapy.
Through their interaction with the Memorial Sloan-Kettering SPORE in Prostate Cancer, the lab has become increasingly active in identifying the molecular events responsible for prostate cancer development and progression. They are continuing to define cooperating genetic events responsible for human prostate cancer development to and establish the molecular significance of these events through mouse modeling. Through this process they hope to identify molecular markers, which have both prognostic and therapeutic significance. To accomplish these goals the lab actively collaborates with other investigators in the Prostate SPORE program to establish clinical correlates for their findings.
Pathology
William L. Gerald, MD, PhD, Leads a research team whose major efforts are centered on identification and characterization of the molecular alterations in human cancers that are responsible for the clinically relevant features of each form of the disease. Their investigations have focused on alterations in transcriptional regulation and gene expression, which provide detailed information useful for diagnosis, prognosis, and therapeutic design. In recent years, largely due to the increased availability of human genomic information, his laboratory has used high throughput, comprehensive genetic and gene expression analysis to characterize and explore several tumor types, and to identify genes that play important roles in the progression of disease and response to therapy. Through analysis of localized primary tumors and comparison to gene expression profiles of metastatic prostate cancer, the team has identified a large number of differentially expressed genes that may participate in aggressive forms of this disease. In many cases these genes are known to participate in functional pathways that are critically important in tumor biology and may provide useful therapeutic targets and prognostic markers for prostate carcinoma. Individual genes and classification schemes based on their expression are now being explored.
The lab's second objective in their work on prostate cancer is to characterize the androgen response pathway and mechanisms of androgen-independent growth. The androgen receptor transcriptional pathway is critical to the development and progression of prostate cancer, and androgen ablation therapy is a mainstay of therapy. However, responses are temporary and eventually all patients develop resistance to androgen withdrawal. Once this occurs there are few therapeutic options. Dr. Gerald's team has analyzed prostate cancers that have been treated with androgen withdrawal and those that are androgen-independent to identify genes and gene expression profiles that play a major role in response and resistance to this therapeutic regimen. The results are providing new insight into the androgen response pathway in prostate cancer and mechanisms of androgen withdrawal resistance.
The rich data sets from these initiatives will become publicly available and will form an important part of future research efforts into this disease. These efforts are leading to the identification of gene expression profiles and novel individual genes that will need extensive validation and functional analysis to fully establish their role in neoplastic disease.
Victor Reuter, MD, Vice Chairman of the Department of Pathology, manages the Immunohistochemistry Core Laboratory. Fellows in his lab focus on clinical pathological correlations using detailed histologic and IHC analysis of surgical specimens. Dr. Reuter, who is also director of the SPORE Pathology Core, is particularly interested in prognostic features important in the biology and response to treatment of genitourinary cancers.
Radiology/Imaging
Hedvig Hricak, MD, is Chairman of the Department of Radiology. She supervises a broad program of basic and clinical research in imaging urologic cancer, including prostate imaging using MRI and MRS (magnetic resonance spectroscopy). Clinical studies investigate the use of MRI for staging prostate cancer and for identifying features associated with increased perioperative morbidity. Expanding areas of research include molecular imaging, optical imaging, and the role of bladder imaging using MRI and MRS. In the animal lab, Dr. Jason Koutcher has developed a "micro MRI" for the serial measurement of tumors in mice.
Steven Larson, MD, is Chief of the Nuclear Medicine Service in the Department of Radiology and head of the Nuclear Medicine Research Laboratory in the Molecular Pharmacology and Chemistry Program of SKI. Dr. Larson is in charge of the Human PET and SPECT scanning facility and the micro PET scanner, which is designed for use with small animals. Dr. Larson's research goal is to achieve improved tumor diagnosis, treatment, and retreatment follow up through the use of radiotracers. The use of tissue and tumor specific antibodies and novel synthetic compounds, such as the G250 MoAb in renal cell cancer and CC-49 in colon and prostate cancer, is allowing Dr.Larson's team to identify and target solid tumors. His lab is exploring the potential of new antibodies against the external domain of PSMA as a potential prostate tumor radiotracer. Dr. Larson is also able to image the effectiveness of gene therapy using radiotracers and is analyzing this expression in patients.
Tumor Markers
Hans Lilja, MD, PhD, is a member of the Departments of Clinical Laboratories, Surgery, and Medicine. His research focuses on the mechanism of enzymes that are significant for the detection, progression, and monitoring of prostate cancer. Detection of increased extracellular release and sequestering of latent, active, and inactive forms of prostatic kallikreins (e.g., free and complexed PSA and hK2) provide extremely sensitive means to discover changes in tissue architecture that accompany the invasion and progression of prostate cancer lesions at an early stage. Recent studies from the Urologic Oncologic Research Laboratory demonstrate that there are significantly elevated levels of various PSA and hK2 forms in blood up to 20 years before men are diagnosed with clinically significant prostate cancer. The magnitude of extracellular release of active and latent protease forms parallels the invasion and progression of prostate cancer, and results in the activation of specific cascades that modify local regulatory target proteins in the extracellular micro environment of prostate cancer lesions. Data from the lab also suggest that the shedding of prostate cancer cells into the blood occurs at an early stage of disease while the tumor is still confined to the prostate. They hypothesize that the extracellular actions of prostatic kallikreins and related proteases are involved in tissue remodeling that enhances prostate cancer progression and results in the loss of the basal cell layer, basal lamina integrity, and the frequent shedding of prostate cells into blood. Selective, reliable, and early identification of men at high risk for prostate cancer, before they develop frequent shedding of prostate cells into the blood, may be a relevant target population for chemo preventive studies.
The team will use their findings on early disease specific, protease related patterns of prostate cancer to develop early risk group stratification, discriminate clinically significant from insignificant prostate cancer, identify noncurable disease, and monitor therapeutic efficacy. Novel principles of chemo prevention that block the activation of local growth stimulatory factors as a result of the release of latent and active forms of prostatic kallikreins and related proteases will be investigated.
