Deborah Bradley

Mechanisms Underlying the Development of Androgen-Independent Prostate Cancer

Prostate cancer continues to be the most common lethal malignancy diagnosed in American men and the second leading cause of male cancer mortality. The American Cancer Society estimates that during 2005, ∼232,090 new cases of prostate cancer will be diagnosed in the United States and 30,350 men

The Lethal Phenotype of Cancer: The Molecular Basis of Death Due to Malignancy

The last decade has seen an explosion in knowledge of the molecular basis and treatment of cancer. The molecular events that define the lethal phenotype of various cancers—the genetic and cellular alterations that lead to a cancer with a poor or incurable prognosis—are being defined. While these studies describe the cellular events of the lethal phenotype of cancer in detail, how these events result in the common clinical syndromes that kill the majority of cancer patients is not well understood. It is clear that the central step that makes most cancers incurable is metastasis. Understanding the traits that a cancer acquires to successfully grow and metastasize to distant sites gives insight into how tumors produce multiple factors that result in multiple different clinical syndromes that are lethal for the patient.

Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): Trial results and interleukin-6 analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago phase 2 consortium

This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy‐pretreated patients with metastatic castration‐resistant prostate cancer.

Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862)

This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy‐pretreated patients with metastatic castration‐resistant prostate cancer.

Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases

Nested urothelial carcinoma (UC) is a rare histologic variant of UC, characterized by deceptively bland histologic features resembling von Brunns nests but usually with a poor outcome. In our experience, this variant is frequently misclassified or underrecognized as its clinicopathologic spectrum is not well defined. In addition, its relationship to usual UC and response to traditional bladder cancer management are largely unknown. Herein we report the largest series to date of 30 UC cases with pure or predominant nested morphology to identify its associated histopathologic findings, clinical outcome, and immunophenotype. Patient age ranged from 41 to 83 years (average, 63 years) with a male-female ratio of 2.3:1. The architectural pattern of the nested component ranged from a predominantly disorderly proliferation of discrete, small, variably sized nests (90%) to focal areas demonstrating confluent nests (40%), cordlike growth (37%), and cystitis cystica-like areas (33%) to tubular growth pattern (13%). The deep tumor-stroma interface was invariably (100%) jagged and infiltrative. Despite overall banal cytology, tumor nests demonstrated focal random cytologic atypia (90%) and focal high-grade cytologic atypia centered within the base of the tumor (40%). The tumor stroma ranged from having minimal stromal response to focally desmoplastic and myxoid. A component of usual UC was present in 63% of cases. The nested component demonstrated an immunophenotype identical to usual UC, with CK7, CK20, p63, and CK903 expression in 93%, 68%, 92%, and 92% of cases, respectively. At resection, all but 1 case demonstrated invasive carcinoma-9% into lamina propria, 4% into muscularis propria, 65% into perivesical fat, and 17% into adjacent organ(s). When compared with pure high-grade UC, nested UC was associated with muscle invasion at transurethral resection (31% versus 70%; P < .0001), extravesical disease at cystectomy (33% versus 83%; P < 0.0001), and metastatic disease (19% versus 67%; P < .0001). Follow-up was available on 29 patients (97%) with a median of 12 months (range, 1-31 months) of follow-up; 3 (10%) died of disease, 16 (55%) are alive with persistent or recurrent disease, and 10 (34%) are alive without disease. Response to neoadjuvant chemotherapy was observed in 2 (13%) of 15 patients. Nested UC seen either in pure form or with a component of usual UC had similarly unfavorable outcomes (P = .78). Increased awareness and familiarity with the clinicopathologic spectrum is critical for confident recognition and adequate management of this very aggressive variant of UC.

Randomized, double-blind, placebo-controlled phase II trial of maintenance sunitinib versus placebo after chemotherapy for patients with advanced urothelial carcinoma: Scientific rationale and study design

Systemic chemotherapy is the primary treatment modality for patients with advanced urothelial cancer. However, despite a high initial response rate, durable responses are rare. Angiogenesis has been shown to be important in the development and progression of urothelial cancer. Sunitinib, an oral, multi-targeted, small-molecule inhibitor of multiple tyrosine kinases, is known to inhibit angiogenesis and therefore might decrease progression of urothelial cancer. This phase II trial was designed to investigate the role of sunitinib as maintenance therapy in patients with advanced urothelial cancer. The specific hypothesis of this trial is that sunitinib will decrease progression rates in patients with advanced urothelial cancer who have obtained stable disease or better after standard chemotherapy.

Neoadjuvant Docetaxel and Capecitabine in Patients with High Risk Prostate Cancer

PURPOSE Docetaxel is the most active cytotoxic agent in hormone refractory prostate cancer. Preclinically docetaxel increases expression of thymidine phosphorylase, an enzyme responsible for activation of capecitabine to 5-fluorouracil resulting in increased antitumor activity. We assessed activity and safety of neoadjuvant docetaxel and capecitabine in patients with high risk prostate cancer. MATERIALS AND METHODS Patients with either clinical stage greater than T2, prostate specific antigen 15 ng/ml or more, or Gleason sum 8 or greater received 3 to 6 cycles of docetaxel (36 mg/m2 intravenously on days 1, 8 and 15) and capecitabine (1,250 mg/m2 per day orally divided twice a day on days 5 to 18) every 28 days, followed by local therapy. The primary end point was rate of 50% or greater prostate specific antigen decrease. Correlative studies included qualitative changes in histology, tissue thymidine phosphorylase and survivin expression, and CK18Asp396 (serum apoptosis marker). RESULTS A total of 15 patients were treated, of whom 6 (40%) experienced a 50% or greater decrease in prostate specific antigen with infrequent diarrhea or hand-foot syndrome. Eleven patients underwent radical prostatectomy. There were no pathological complete responses and 4 patients demonstrated mild histological changes, including focal necrosis and vacuolated cytoplasm. While there was no discernable pattern of increased thymidine phosphorylase expression, 4 specimens showed decreased survivin expression, suggesting a possible mechanism for chemotherapy induced apoptosis. There was no correlation of prostate specific antigen response and survivin expression, and no increase in serum CK18Asp396. CONCLUSIONS Neoadjuvant docetaxel and capecitabine is well tolerated but is not associated with significant pathological and prostate specific antigen responses.

CDX-1307: a novel vaccine under study as treatment for muscle-invasive bladder cancer

Cancer vaccines have demonstrated clinical benefit, however greater efficacy could be achieved by enhancing their immunogenicity. Owing to cancer vaccines depending on uptake and cross-presentation of tumor antigens by antigen-presenting cells (APCs), we hypothesized that greater immunogenicity would accompany strategies that direct antigen to APC-expressed mannose receptors, initiating a pathway increasing class I and II presentation to T cells. CDX-1307 consists of a human monoclonal antibody targeting the mannose receptor, fused to the human chorionic gonadotropin-β chain (hCG-β), a tumor antigen frequently expressed by epithelial cancers including bladder cancer. In Phase I studies of cancer patients, CDX-1307 was well tolerated and induced significant hCG-β-specific cellular and humoral immune responses when co-administered with GM-CSF and the Toll-like receptor agonists resiquimod and poly-ICLC. An ongoing Phase II trial evaluates CDX-1307 in patients with newly diagnosed, resectable, hCG-β-expressing bladder cancer, where low tumor burden and early intervention may provide greater potential for benefit.

Promising novel cytotoxic agents and combinations in metastatic prostate cancer

Interest in investigating cytotoxic therapy has increased dramatically since a survival advantage was demonstrated in 2 phase III trials investigating docetaxel-based therapy in hormone-refractory prostate cancer. This result led to an expansion in research in this area with several ongoing trials evaluating docetaxel-based combinations and new cytotoxic agents.

Vorinostat in Advanced Prostate Cancer Patients Progressing on Prior Chemotherapy (NCI Trial # 6862): Trial results and IL-6 analysis. A study by the DOD Prostate Cancer Clinical Trial Consortium and University of Chicago Phase II Consortium

This phase 2 trial was designed to evaluate the efficacy of vorinostat in chemotherapy‐pretreated patients with metastatic castration‐resistant prostate cancer.