Eric J. Small, MD

Research Interests

Advanced Prostate Cancer Clinical Research Program

Our research program has focused on the etiology and treatment of hormone resistant prostate cancer (HRPC). We have been interested in the clonal evolution from hormone sensitive to hormone refractory prostate cancer, and to this end have established a HRPC tissue bank. We have evaluated a variety of markers of prognosis, which may ultimately become treatment targets, including erbB2, EGFR, androgen receptor, FGF, and VEGF. Utilizing this tissue, we have undertaken comparative genomic hybridization (cgh) and loss of heterozygosity (LOH) studies in HRPC tissue in order to begin to define common cytogenetic abnormalities in HRPC tissue. More recently, interest in angiogenesis has resulted in a program evaluating prostatic tissue vascular flow with color doppler ultrasonography, and correlating these findings with fibroblastic growth factor (FGF) and vascular endothelial growth factor (VEGF) levels. We anticipate that clinical trials with anti-VEGF antibody will be forthcoming in the near future.

We have been interested in the development of a new paradigm in the approach to hormone refractory prostate cancer which has resulted from an understanding of second line hormonal therapy in "early" HRPC patients. Small is the chair of a Cancer and Leukemia Group B (CALGB) Phase III randomized trial comparing the efficacy of two different hormonal manuevers, including adrenal androgen deprivation, in patients with HRPC. This trial has been selected by the National Cancer Institute to receive funding for a correlative component which will evaluate these patients for androgen receptor mutations. A separate correlative science companion trial will correlate adrenal androgen levels with clinical outcome. The UCSF therapeutic program for "early" HRPC patients has focused not only on secondary hormonal manipulations, but on immunologic approaches as well. Thus, we are currently evaluating the efficacy of a dendritic cell "vaccine" for specific immune targetting of advanced prostate cancer. We will also be examining the utility of a novel cytokine, Flt3-L, which up-regulates dendritic cell function.

Once immune approaches and second line approaches are exhausted, more agressive cytotoxic approaches to HRPC are warranted. We have reported our results with a dose intensification program (Journal of Clinical Oncology, May, 1996), and are building on this experience with a liposomal doxorubicin and tissue localization program. At the same time, UCSF has become one of the leading suramin centers in the country. Small is the study chair of an Intergroup (CALGB, SWOG, ECOG) phase III trial, currently accruing patients, which compares three different doses of suramin in patients with HRPC. While defining the role of suramin in these patients is important, we are also looking ahead: we have created a drug development program for the treatment of HRPC. Thus, we were selected by the NCI as the sole site to evaluate a novel cytotoxic drug, Pyrazoloacridine, in these patients.

Future directions for the advanced prostate cancer program include the development of immunologic therapy utilizing dendritic cells as outlined above, as well as of gene therapy for prostate cancer. Our gene therapy program is well under way. Small is the principal investigator of a gene therapy trial for the treatment of bladder cancer using recombinant adenovirus containing the retinoblastoma gene. This trial has received Recombinant Advisory Committee (RAC) approval and is the basis for the development of (similar) trials in prostate cancer.

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