Use of yeast chemigenomics and COXEN informatics in preclinical evaluation of anticancer agents.

Bladder cancer metastasis is virtually incurable with current platinum-based chemotherapy. We used the novel COXEN informatic approach for in silico drug discovery and identified NSC-637993 and NSC-645809 (C1311), both imidazoacridinones, as agents with high-predicted activity in human bladder cancer. Because even highly effective monotherapy is unlikely to cure most patients with metastasis and NSC-645809 is undergoing clinical trials in other tumor types, we sought to develop the basis for use of C1311 in rational combination with other agents in bladder cancer. Here, we demonstrate in 40 human bladder cancer cells that the in vitro cytotoxicity profile for C1311 correlates with that of NSC-637993 and compares favorably to that of standard of care chemotherapeutics. Using genome-wide patterns of synthetic lethality of C1311 with open reading frame knockouts in budding yeast, we determined that combining C1311 with a taxane could provide mechanistically rational combinations. To determine the preclinical relevance of these yeast findings, we evaluated C1311 singly and in doublet combination with paclitaxel in human bladder cancer in the in vivo hollow fiber assay and observed efficacy. By applying COXEN to gene expression data from 40 bladder cancer cell lines and 30 human tumors with associated clinical response data to platinum-based chemotherapy, we provide evidence that signatures of C1311 sensitivity exist within nonresponders to this regimen. Coupling COXEN and yeast chemigenomics provides rational combinations with C1311 and tumor genomic signatures that can be used to select bladder cancer patients for clinical trials with this agent.

The relationship of palliative transurethral resection of the prostate with disease progression in patients with prostate cancer.

OBJECTIVES: To test, in a prostate-cancer population-based database, the validity of the finding that in single-institution series, palliative transurethral resection of prostate (TURP) is associated with an increased risk of progression. PATIENTS AND METHODS: Using the Surveillance Epidemiology and END Results Registry, we identified men who had a TURP subsequent to their diagnosis of prostate cancer, from 1998 or 1999. The outcome of interest was disease progression, as defined by the initiation of androgen-deprivation therapy or procedures indicating progressive urinary obstruction. Multivariable logistic regression analysis was used to assess the adjusted odds of signal events related to disease progression adjusting for the concurrent effect of the covariates. RESULTS: There were 29,361 men with prostate cancer and 2742 (9.3%) had a TURP after the diagnosis. These men had a mean age of 75 years and were unlikely to undergo definitive primary treatment. Men receiving TURP were more likely to undergo orchidectomy than men who did not have a TURP (odds ratio 1.64; 95% confidence interval 1.03-2.60) even after adjusting for differences in cancer-directed treatment, tumour stage and grade, prostate-specific antigen level, race, and age at diagnosis. These men were also more likely to have malignant urinary obstruction (ureteric and bladder outlet) than were men who did not have TURP. CONCLUSION: The requirement for TURP is an adverse prognostic marker even when this is adjusted for classical tumour characteristics. Although the exact reasons for this finding are unclear, consideration should be given to adjuvant treatment in patients undergoing TURP.

Cancer incidence after localized therapy for prostate cancer.

BACKGROUND: Second cancers may occur in patients who have undergone radiation therapy. The risk for these adverse events after therapy is uncertain. In this study, the authors examined the size and significance of the observed association between occurrences of secondary cancers 5 years after radiotherapy in a large population of men with incident prostate cancer. METHODS: Men with incident prostate cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) registry and were distinguished by the type of treatment received, tumor stage, tumor grade, and age at diagnosis. SEER data also were used to identify occurrences of secondary cancer beginning 5 years after the date patients were diagnosed with prostate cancer. Multivariate logistic regression analysis was used to estimate the adjusted odds of the subsequent occurrence of other cancers associated with types of radiation therapy received and was adjusted for the type of surgery, tumor grade, stage, and patient age. RESULTS: Compared with men who received no prostate cancer-directed radiation, men who received external beam radiation therapy (EBRT) as their only form of radiation therapy had statistically significant increased odds of developing secondary cancers at several sites potentially related to radiation therapy, including the bladder (odds ratio [OR], 1.63; 95% confidence interval [95% CI], 1.44-1.84) and rectum (OR, 1.60; 95% CI, 1.29-1.99). Men who received EBRT also had statistically significant higher odds of developing secondary cancers at sites in the upper body and other areas not potentially related to radiation therapy, including the cecum (OR, 1.63; 95% CI, 1.10-1.70), transverse colon (OR, 1.85; 95% CI, 1.30-2.63), brain (OR, 1.83; 95% CI, 1.22-2.75), stomach (OR, 1.38; 95% CI, 1.09-1.75), melanoma (OR, 1.29; 95% CI, 1.09-1.53), and lung and bronchus (OR, 1.25; 95% CI, 1.13-1.37) compared with the odds among men who received no radiation therapy. Men who received radiation therapy in the form of radioactive implants or isotopes, either in isolation or combined with beam radiation, did not have significantly different odds of secondary cancer occurring at any of the 20 most common sites. CONCLUSIONS: Patients who received with EBRT had significantly higher odds of developing second cancers both overall and in the areas that were exposed to radiation. It is noteworthy that, to the authors' knowledge, this report shows for the first time that, despite the higher doses of radiation delivered, patients who received radioactive implants had the lowest odds of developing second cancers.