Platinum Priority – Editorial Referring to the article published on pp. 400–404 of this issue [2_TD$DIFF]Natural [3_TD$DIFF]Compounds [4_TD$DIFF]Targeting [5_TD$DIFF]STAT3 [6_TD$DIFF]Mediated [7_TD$DIFF]Inflammation Edwin E. Morales a , Bharat B. Aggarwal b , Ashish M. Kamat a, * a Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; b Department of Cytokine Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA [1_TD$DIFF]In this issue of European Urology, Bjartell and colleagues from the University of Lund highlight a novel small molecule inhibitor of the STAT3 pathway, which is known to be relevant when constitutively activated in multiple different solid tumors [1,2]. Metastatic prostate cancer (PCa) is known to have a constitutively activated STAT3 factor that is directly involved in androgen independence and locoregional and distant lymphatic metastases [3]. The future of anticancer chemotherapy and immuno- therapy is likely to involve directed and multiple oncogenic pathway inhibition using such small molecule inhibitors as galiellalactone and other naturally derived antineoplastic compounds such as curcumin (diferuloylmethane), a principal constituent of Curcuma longa, the common household spice turmeric. Our own research has demon- strated that the relatively safe and nontoxic compound powerfully inhibits the nuclear factor-kB (NF-kB) nuclear transcription factor pathway, thereby inhibiting angiogen- esis and inflammation [4–6]. Combination treatment with such novel natural and synthetically derived agents is likely to reflect a greater understanding of oncogenic and proliferative pathways such as NF-kB and STAT3. As further research into proliferative pathways increases, novel pathway associations are likely to be discovered and can be used in our antitumor armamentarium. STAT3 has been extensively implicated in PCa oncogen- esis and metastatic potential. Interestingly, loss of STAT3 has been a known marker for PCa aggressiveness and metastatic potential [7] and the STAT3 pathway has been implicated in PCa stem cell senescence. What do the authors postulate is the mechanistic explanation for this effectual dualism, and how would they factor this into translation of their findings to the clinical arena? Indeed, the addition of the small molecule inhibitor galiellalactone by the authors seems to provide a contradictory and rather inflammatory (from a scientific perspective) result: that metastases and oncogenesis are inhibited by galiellalactone rather than increased or worsened. The discovery of new pathways and small molecule inhibitors is often likely to involve the same dualism, that is, normal cell cycle regulation/proliferation and oncogenesis. One example is epidermal growth factor, the dual-sided pathway intricately involved in hepatic regeneration, on the one hand, and hepatocellular carcinogenesis, on the other [8]. Inhibition of these different pathways through different synthetic and natural small molecule inhibitors in a combinatorial approach could allow for a greater antineo- plastic effect than single-pathway inhibition alone. Such pathway inhibition may also be potentiated, as we have shown in urothelial carcinoma, with existing immunother- apeutic or chemotherapeutic technologies such as bacillus Calmette-Gue ´ rin or gemcitabine [9]. By inhibiting the proliferation of the neoplastic cells, we can perhaps allow our existing broadly toxic or immunologic therapies the kick-start to exert a maximal effect. Bjartell and colleagues used a technically challenging orthotopic mouse PCa model [10] and were able to both decrease propensity and volume of lymphatic metastases with galiellalactone therapy. Not only was volume of the tumor decreased, the natural history of disease was altered through direct inhibition of the STAT3 pathway. We applaud the authors for specific use of the clinically relevant model. As we move further into studies of tissue profiling, it is even more evident that the tumor–stromal environment is a crucial part of prognostic and therapeutic response. Consequently, preclinical studies in animal EUROPEAN UROLOGY 69 (2016) 405–406 available at www.sciencedirect.com journal homepage: www.europeanurology.com DOI of original article: http://dx.doi.org/10.1016/j.eururo.2015.06.016. * Corresponding author. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Tel. +1 713 792 3250; Fax: +1 713 794 4824. E-mail address: akamat@mdanderson.org (A.M. Kamat). http://dx.doi.org/10.1016/j.eururo.2015.09.033 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.