Faculty Bibliography

PURPOSE: The development of new effective therapeutic agents with minimal side effects for prostate cancer (PC) treatment is much needed. Indirubin, an active molecule identified in the traditional Chinese herbal medicine-Qing Dai (Indigo naturalis), has been used to treat leukemia for decades. However, the anticancer properties of Natura-alpha, an indirubin derivative, are not well studied in solid tumors, particularly in PC. EXPERIMENTAL DESIGN: The growth kinetics and invasion ability of on human PC cell lines with or without Natura-alpha treatment were measured by cell proliferation and invasion assays. The antitumor effects of Natura-alpha were examined in nude mice tumor xenograft models, and in a patient with advanced hormone-refractory metastatic PC. Signal network proteins targeted by Natura-alpha were analyzed by using proteomic pathway array analysis (PPAA) on xenografts. RESULTS: Natura-alpha inhibited the growth of both androgen-dependent (LNCaP) and androgen-independent (LNCaP-AI, PC-3, and DU145) PC cells with IC(50) between 4 to 10 mmol/L, and also inhibited invasion of androgen-independent PC cells. Its antitumor effects were further evident in in vivo tumor reduction in androgen-dependent and androgen-independent nude mice tumor xenograft models and reduced tumor volume in the patient with hormone refractory metastatic PC. PPAA revealed that antiproliferative and antiinvasive activities of Natura-alpha on PC might primarily be through its downregulation of Forkhead box M1 (FOXM1) protein. Forced overexpression of FOXM1 largely reversed the inhibition of growth and invasion by Natura-alpha. CONCLUSION: Natura-alpha could serve as a novel and effective therapeutic agent for treatment of both hormone-sensitive and hormone-refractory PC with minimal side effects.

Malignant melanoma is fatal in its metastatic stage. It is therefore essential to unravel the molecular mechanisms that govern disease progression to metastasis. MicroRNAs (miRs) are endogenous non-coding RNAs involved in tumourigenesis. Using a melanoma progression model, we identified a novel pathway controlled by miR-214 that coordinates metastatic capability. Pathway components include TFAP2C, homologue of a well-established melanoma tumour suppressor, the adhesion receptor ITGA3 and multiple surface molecules. Modulation of miR-214 influences in vitro tumour cell movement and survival to anoikis as well as extravasation from blood vessels and lung metastasis formation in vivo. Considering that miR-214 is known to be highly expressed in human melanomas, our data suggest a critical role for this miRNA in disease progression and the establishment of distant metastases.

Background: Although the current median survival time of stage-IV melanoma patients is less than 12 months, there is a subset of patients who experience long-term survival. Due to poor response rates to standard cytotoxic agents in metastatic melanoma, patients are encouraged to participate in clinical trials, the overall impact of which has not been studied, however. The aim of our study was to identify the factors associated with long-term survival and to determine the impact of clinical trial enrollment on patient outcome. Methods: We studied stage-IV melanoma patients prospectively enrolled at New York University Medical Center from 2002-2008. Associations between clinicopathologic variables and overall post-stage-IV survival were examined. Kaplan-Meier survival analysis was used to identify univariate predictors of post-stage-IV survival and the independent effect of these variables was assessed in a multivariate Cox proportional hazards regression model. The associations between clinicopathologic variables and long-term survival status (>/=2 vs. <2 years) were examined by chi(2) analysis and the independent effect of these variables on the latter was assessed in a multivariate logistic regression model. Results: Site of metastasis, treatment (systemic vs. localized) and pretreatment lactate dehydrogenase (LDH) level independently correlated with post-stage-IV survival. Participation in clinical trials and normal LDH levels were associated with a long-term survival of >/=2 years. Conclusion: Our data suggest that enrollment in clinical trials independently correlates with prolonged survival after a diagnosis of stage IV melanoma.

MicroRNAs are endogenous non-coding RNAs, proven to regulate biological functions, including tumor progression, by regulating specific target genes post-trancriptionally. Cancer is often a fatal disease in its metastatic stage, hence it is essential to unravel the molecular mechanisms that govern metastasis dissemination. Using a melanoma progression model, represented by a poorly aggressive parental cell line (A375P) and its highly metastatic variants, we identified a novel pathway controlled by miR-214 that coordinates metastatic capability. The genes comprised in the pathway are over 70 and include TFAP2C, homologue of a well-established melanoma tumor suppressor, the adhesion receptor ITGA3 and multiple surface molecules, such as ALCAM, CD9, ADAM9. Modulations of miR-214 significantly alter tumor cell migration, invasion and survival to anoikis, as well as extravasation from blood vessels and metastasis formation in mice. Considering that miR-214 is highly expressed in human melanomas, our data suggest a critical role for this small RNA in the establishment of distant metastases. We are now carrying on a detailed analysis of the molecular mechanisms used by miR-214 to control metastatic dissemination and results will be presented