Abstract 1056: Inhibition of hexose monophosphate pathway promotes castration resistant prostate cancer
Authors: Kaushik Akash K. , Shojaie Ali , Panzitt Katrin , Sonavane Rajni , Venghatakrishnan Harene , Manikkam Mohan , Zaslavsky Alexander , Putluri Vasanta , Vasu Vihas , Zhang Yiqing , Khan Ayesha , Lloyd Stacy , Szafran Adam , Dasgupta Subhamoy , Bader David , Stossi Fabio , Li Hangwen , Samanta Susmita , Cao Xuhong , Tsouko Efrosini , Huang Shixia , Frigo Daniel , Chan Lawrence , Edwards Dean , Kaipparettu Benny , Mitsiades Nicholas , Weigel Nancy , Mancini Michael , Ittmann Michael , Chinnaiyan Arul , Putluri Nagireddy , Palapattu Ganesh , Michailidis George , Sreekumar Arun 
Published: July 2016

Prostate Cancer (PCa) is the second highest cause of cancer-related death in men in the US. PCa is androgen dependent when organ-confined and is conventionally treated using surgery or using a combination of anti-androgens and radiation therapy. However, in about 30% of the patients tumor recurs and are initially administered androgen deprivation therapy (ADT). Majority of the patients become resistant to ADT and develop hormone-refractory disease also termed castration-resistant prostate cancer (CRPC), which is lethal. Currently, the molecular and biochemical alterations driving CRPC are not well understood. Using a novel network-based integrative approach, we show distinct alterations in the Hexosamine Biosynthetic Pathway (HBP) to be critical for sustaining the castrate resistant state. Our data suggests expression of key HBP enzymes to be significantly elevated in androgen dependent (AD) PCa while interestingly enough, relatively diminished in CRPC. Genetic loss of function experiments for these HBP enzymes in CRPC-like cells had tumor promoting effect both in vitro and in vivo. This was mediated by alterations in either PI3K-AKT pathway or SP1-ChREBP (SP1- carbohydrate response element binding protein) network in CRPC cells containing full length androgen receptor (AR) or its splice variant AR-V7, respectively. Strikingly, addition of HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) or glucosamine (GlcN) to CRPC-like cells attenuated tumor cell proliferation, both in vitro and in animal studies. Interestingly, these metabolites demonstrated additive efficacy when combined with enzalutamide in vitro. These findings are particularly significant given that the CRPC-like cells tested, inclusive of those containing AR-V7 variant, are inherently resistant to enzalutamide. These observations demonstrate the therapeutic value of targeting altered HBP in CRPC.

Citation Format: Akash K. Kaushik, Ali Shojaie, Katrin Panzitt, Rajni Sonavane, Harene Venghatakrishnan, Mohan Manikkam, Alexander Zaslavsky, Vasanta Putluri, Vihas Vasu, Yiqing Zhang, Ayesha Khan, Stacy Lloyd, Adam Szafran, Subhamoy Dasgupta, David Bader, Fabio Stossi, Hangwen Li, Susmita Samanta, Xuhong Cao, Efrosini Tsouko, Shixia Huang, Daniel Frigo, Lawrence Chan, Dean Edwards, Benny Kaipparettu, Nicholas Mitsiades, Nancy Weigel, Michael Mancini, Michael Ittmann, Arul Chinnaiyan, Nagireddy Putluri, Ganesh Palapattu, George Michailidis, Arun Sreekumar. Inhibition of hexose monophosphate pathway promotes castration resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1056.