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  • Clinical trials targeting multiple neoplasms have

    2018-11-14

    Clinical trials targeting multiple neoplasms have been launched to assess the effects of autophagy inhibition in combination with radiation, conventional cytotoxic chemotherapies and targeted agents including DNA damaging agents, HDAC inhibitors, proteasome inhibitors, mitotic inhibitors, antiandrogens, and several kinase inhibitors (ClinicalTrials.gov, Table 2). Additional studies in melanoma, glioblastoma, pancreatic, breast, lung, and prostate cancer are testing CQ/HCQ as a single agent (ClinicalTrials.gov). A major caveat with the current clinical trials is that we have no way to identify patients who are most likely to benefit. At least initially, one strategy to do this may be to focus on tumors with mutations that confer sensitivity to autophagy inhibitors like the BRAF mutant buy KN-93 hydrochloride tumor studies mentioned above (Levy et al., 2014). The first Phase I and I/II trials have been reported testing autophagy inhibition alone or in combination with a proteosome inhibitor (bortezomib), radiation therapy, DNA damaging agents, i.e. temazolomide and doxorubicin, as well as the mTOR inhibitor, temsirolimus, and the HDAC inhibitor vorinostat (Rosenfeld et al., 2014; Rangwala et al., 2014b; Rangwala et al., 2014a; Barnard et al., 2014; Mahalingam et al., 2014; Vogl et al., 2014; Wolpin et al., 2014; Rojas-Puentes et al., 2013; Patel et al., 2016). Doses effective for autophagy inhibition can be reached with minimal side effects, although one study in glioblastoma patients did report grade 3 and 4 neutropenia and thrombopenia (Rosenfeld et al., 2014). Thus far, no studies have reported adverse side effects expected of autophagy inhibition based on pre-clinical animal studies, such as increased incidence of neuropathy, secondary cancers, infections, or metabolic disturbances. Encouragingly, some studies suggest favorable clinical responses. Rangwala et al. reported a partial response and stable disease in 14% and 27%, respectively, of metastatic melanoma patients treated with HCQ in combination with temozolomide, with a complete response and prolonged stable disease seen in 2/6 patients with WT BRAF refractory melanoma (Rangwala et al., 2014b). Moreover, a phase II study of CQ and radiation therapy on brain metastasis in patients with advanced solid tumors report progress free survival after one year in 84% of patients as compared to 55% of patients in the control arm (radiation therapy alone) (Rojas-Puentes et al., 2013).
    Outstanding Questions In this article we have focused on just two types of disease (neurodegenerative disease and cancer) where different approaches to therapeutically manipulate autophagy have been adopted and where clinical studies are underway. However there are still many outstanding questions even for just these two areas. For example, although there is considerable evidence that autophagy inhibition can make other anti-cancer drugs more effective, this may only apply in tumor cells that start off being dependent on autophagy. Indeed, in cancer cells that are not autophagy-dependent the same drug combination may be antagonistic rather than synergistic (Levy et al., 2014; Maycotte et al., 2014); we are currently unable to predict if cancer cells will or won\'t be autophagy-dependent. Some drugs are also thought to require autophagy in order to kill cancer cells (Thorburn et al., 2014). In neurodegenerative diseases it is unclear whether or not different ways of activating autophagy will be more or less effective and we are greatly hampered by the fact that even for laboratory studies we lack good tools to specifically activate autophagy without affecting other cellular processes. In cancer therapy we have poor understanding of when autophagy will increase tumor cell killing and when it will decrease it and we need to better understand the interplay between autophagy and the immune response to cancer. For any therapy involving autophagy manipulation, a major problem is our inability to accurately measure autophagic flux in vivo to assess if the intervention actually worked.