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impairs recurrence of tumors after chemotherapy78, 79. Clinical trials involving chloroquine- and

hydroxychloroquine-mediated autophagy inhibition for cancer therapy are ongoing and listed at http://www.clinicaltrial.gov/.

In addition to chloroquine derivatives, various other putative autophagy inhibitors have been studied for their antitumor effects in vitro and in vivo (Table 2). However, these agents have nonspecific effects on other cellular functions, such as endocytosis (e.g., 3-methyladenine) and lysosomal function (e.g., bafilomycin A). Targeting key autophagy proteins would be a more potent and specific approach. Several components of the autophagic machinery are druggable and serve as potential therapeutic targets. These include the ULK1 and ULK2 serine-threonine protein kinases, the enzymes involved in ubiquitin-like conjugation systems (e.g., E1-like

ubiquitination enzyme Atg7 and E2-like enzymes Atg3 or Atg10) and the cysteine protease Atg4. Moreover, Vps34, a class III PI3K, could be targeted as it is a key autophagy regulator, although it also regulates normal endocytosis. In addition to pharmacological inhibitors, gene interference

using small interfering RNA against various autophagy proteins has a synergistic effect in combination with other treatments in preclinical studies. Accordingly, a deeper understanding of the molecular basis of autophagy induction and execution could help identify more

therapeutic targets for cancer that can be drugged alone or in combination. Conclusions

Cancer cells display multiple layers of metabolic alterations that affect cell proliferation and survival through dysregulation of oncogenic pathways and tumor

suppressors and through changes in the microenvironment and stromal cells. Increasing evidence indicates that cancer cell metabolism is reprogrammed through expression of specific isoforms of metabolic enzymes that exhibit distinct enzymatic activities and substrate preferences. Preclinical studies suggest that tumor cells may be addicted to these enzyme variants. As metabolic enzymes could be easier to target compared with transcription factors and signaling proteins, it may be possible to develop isoform-specific small-molecule

inhibitors that achieve a greater therapeutic window compared with conventional chemotherapeutics. The identification of patients who may benefit from targeted metabolic therapies will be facilitated by a better understanding of the signaling pathways leading to alternative splicing events that give rise to cancer-specific isoforms of metabolic enzymes. Recent insights into genomic amplification and mutation of metabolic enzymes48, 49, 80, 81 also provide a source of new targets. Finally, clinical application of emerging knowledge about autophagy will require further investigation of the roles of this process in cancer development. For example, identifying the signaling pathways that regulate autophagy activity at different stages of tumor progression should help in deciphering the mechanisms of tumor resistance to targeted therapies and in designing combinatorial therapies that overcome drug resistance. Successful targeting of autophagy in cancer therapy also requires molecular analysis of the components of distinct forms of autophagy, as well as their interactions with other cellular and metabolic processes.

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