Interestingly dataset analyses show that HK

Interestingly, dataset analyses show that HK2 is highly expressed in CRPC compared to the primary prostate cancer. Our findings thus provide preclinical proof-of-concept that co-targeting Warburg effect with 2-DG and autophagy with CQ could be extended to effectively treat CRPC patients whose tumors have elevated HK2 expression. Since recent genetic studies revealed that HK2 is required for oncogenic Kras-driven lung tumorigenesis and ErbB2-driven mammary gland tumorigenesis in vivo (Patra et al., 2013), our therapeutic strategy for HK2-mediated prostate cancers may also be extendable to treating HK2-dependent lung and breast cancers. As far as the tolerability is concerned, accumulating evidence suggests that 2-DG exhibits anti-tumor activity in mouse and rat cancer models in vivo at dosages without toxicity to the host animals, including models of sarcomas, adenocarcinomas, leukemias, melanomas, and bladder, colon, lung, and breast tumors (Xi et al., 2014). A recent Phase I clinical trial (NCT00096707) in prostate cancer patients indicated that 2-DG at 63mg/kg body weight was tolerable dose with anti-tumor effect and was recommended for Phase II clinical Trial (Raez et al., 2013). By allometric scaling, the dosage of 800mg/kg body weight in mice used for our work here could be converted to a human dose of 65mg/kg body weight (Reagan-Shaw et al., 2008). Thus, 2-DG dose used in our animal studies approximates the safe range for b-hydroxybutyrate to patients. The dosage of antimalarial drug CQ and/or its derivatives administrated in our animal studies is also well-tolerated in patients and had been used in patients for decades. Currently, multiple clinical trials targeting autophagy using CQ or its derivate hydroxychloroquine (HCQ) as mono- or combination-therapy for tumors are under way (http://www.cancer.gov/clinicaltrials). Importantly, no notable adverse physiological consequences, monitored by body weight, are observed with long-term administration of 2-DG and CQ in our mouse studies. Thus, building upon insights gained from our findings in the preclinical models and the clinical use knowledge of these two existing drugs, repurposing them for treating CRPC could be expedited from the bench to bedside. Our studies therefore have immediate implications for the design of clinical trials to evaluate the combination treatment with 2-DG and CQ as a novel targeted therapeutic strategy for the subsets of currently incurable CRPC carrying PTEN and TP53 mutations.
Materials and methods
Author contributions
Disclosure of potential conflicts of interest
Introduction Identification of unintended effects of drug therapy is an essential part of post-marketing drug surveillance (pharmacovigilance), as knowledge of rare side-effects is limited at the time of marketing of new medications (Strom et al., 2012). Unintended effects of drugs may involve an increase or a reduction in cancer risk (International Agency for Research on Cancer, 2012; Umar et al., 2012). Although systematic and comprehensive testing of genotoxicity and carcinogenicity is performed for any new drug prior to marketing (Brambilla and Martelli, 2009), both these laboratory assays and the premarketing phase-3 trials are disadvantaged by the typically long latency period of cancer development in humans (Umar et al., 2012; Burstein and Schwartz, 2008). For example, the excess risk of breast cancer induced by use of menopausal or contraceptive hormone therapy first becomes apparent after 5–10years of continued use (Howell and Evans, 2011; Zhu et al., 2012), and the protective effect of aspirin against colorectal cancer requires at least five years of regular use (Chan et al., 2012; Cuzick et al., 2015). Traditional approaches in pharmacovigilance (based primarily on spontaneous reporting of adverse events) rarely detect drug–cancer associations, primarily due to the long induction time of most cancer types, which separate the use of the drug from the diagnosis by several years. As most individual cancer types are rare and have a long latency, pre-marketing clinical trials are unlikely to detect carcinogenic or chemopreventive effects of drugs due to the typically small size and short follow-up of these trials. Since neither spontaneous reporting nor clinical trials would be effective in capturing signals, the primary tool in surveillance of drugs for unintended carcinogenic or cancer preventive effects would be analyses of large administrative databases. Such studies have been instrumental in the identification of carcinogenic effects of several drugs, e.g., female hormone therapy and phenacetin (International Agency for Research on Cancer, 2012).