Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The “treasure trove” of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono- or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

Endoplasmic reticulum (ER) is a dynamic organelle orchestrating the folding and post-translational maturation of almost all membrane proteins and most secreted proteins. These proteins synthesized in the ER, need to form disulfide bridge to acquire specific three-dimensional structures for function. The formation of disulfide bridge is mediated via protein disulfide isomerase (PDI) family and other oxidoreductases, which contribute to reactive oxygen species (ROS) generation and consumption in the ER. Therefore, redox regulation of ER is delicate and sensitive to perturbation. Deregulation in ER homeostasis, usually called ER stress, can provoke unfolded protein response (UPR) pathways with an aim to initially restore homeostasis by activating genes involved in protein folding and antioxidative machinery. Over time, however, activated UPR involves a variety of cellular signaling pathways which determine the state and fate of cell in large part (like autophagy, apoptosis, ferroptosis, inflammation, senescence, stemness, and cell cycle, etc.). This review will describe the regulation of UPR from the redox perspective in controlling the cell survival or death, emphasizing the redox modifications of UPR sensors/transducers in the ER.

As of 2020 the human genome and proteome are both at >90% completion based on high stringency analyses. This has been largely achieved by major technological advances over the last 20 years and has enlarged our understanding of human health and disease, including cancer, and is supporting the current trend towards personalized/precision medicine. This is due to improved screening, novel therapeutic approaches and an increased understanding of underlying cancer biology. However, cancer is a complex, heterogeneous disease modulated by genetic, molecular, cellular, tissue, population, environmental and socioeconomic factors, which evolve with time. In spite of recent advances in treatment that have resulted in improved patient outcomes, prognosis is still poor for many patients with certain cancers (e.g., mesothelioma, pancreatic and brain cancer) with a high death rate associated with late diagnosis. In this review we overview key hallmarks of cancer (e.g., autophagy, the role of redox signaling), current unmet clinical needs, the requirement for sensitive and specific biomarkers for early detection, surveillance, prognosis and drug monitoring, the role of the microbiome and the goals of personalized/precision medicine, discussing how emerging omics technologies can further inform on these areas. Exemplars from recent onco-proteogenomic-related publications will be given. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the hurdles that have to be overcome.

Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids have potential in the treatment of tumors by the modulation of autophagy. In many cases, flavonoids suppress cancer by stimulating excessive autophagy or impairing autophagy flux especially in apoptosis-resistant cancer cells. However, the anti-cancer activity of flavonoids may be attenuated due to the simultaneous induction of protective autophagy. Notably, flavonoids-triggered protective autophagy is becoming a trend for preventing cancer in the clinical setting or for protecting patients from conventional therapeutic side effects in normal tissues. In this review, focusing on the underlying autophagic mechanisms of flavonoids, we hope to provide a new perspective for clinical application of flavonoids in cancer therapy. In addition, we highlight new research ideas for the development of new dosage forms of flavonoids to improve their various pharmacological effects, establishing flavonoids as ideal candidates for cancer prevention and therapy in the clinic.

Rationale: The sustained and severe endoplasmic reticulum (ER) stress in cancer cells may contribute to apoptotic cell death, thus representing a potential target for cancer therapy. Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). However, it remains unclear if brigatinib has alternative model of action to exert antitumor effect in ALK-negative cancers. Methods: ALK-positive NSCLC cells and various human ALK-negative cancer cells, especially human colorectal cancer (CRC) cells were used to examine the tumor suppression effect of brigatinib alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of brigatinib in CRC cells. Results: Here, we show the significant anti-cancer effect of brigatinib in CRC through induction of apoptosis by sustained ER stress. Mechanistically, brigatinib induces ER stress via promoting the interaction between ubiquitin-specific peptidase 5 (USP5), a deubiquitinase, and oxysterol-binding protein-related protein 8 (ORP8), leading to ORP8 deubiquitination, accumulation and growth inhibition. Furthermore, we find that brigatinib-mediated ER stress simultaneously induces autophagic response via ER-phagy that acts as a protective mechanism to relieve excessive ER stress. As such, combination of brigatinib with autophagy inhibitors significantly enhances the anti-CRC effect of brigatinib both in vitro and in vivo, supporting the repurposing of brigatinib in CRC, independently of ALK. Conclusion: The unearthed new molecular action of brigatinib suggests that therapeutic modulation of ER stress and autophagy might represent a valid strategy to treat CRC and perhaps other ALK-negative cancers.