Particularly in malignancies that currently lack targeted therapeutic options, autophagy inhibitors are the next hopeful prospects for the treatment of this disease.
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In this review, we discuss the rapid evolution of autophagy inhibitors from early lysosomotropic agents to next-generation lysosome-targeted drugs and beyond. Cancer is the second leading cause of death in the USA by a minute margin expected to close within the next decade [ 1 ]. In , the Surveillance, Epidemiology, and End Results program sponsored by the National Cancer Institute projects 1,, new cancer cases and , cancer-associated deaths in this country alone [ 2 ].
Such statistics are sobering and continue to fuel the work of translational medicine. Although the silver bullets of imatinib in BCR-ABL-expressing leukemia and trastuzumab in HER2-overexpressing breast cancer are encouraging, the vast majority of cancer patients still receive a generic therapeutic regimen consisting of cytotoxic chemotherapy and radiation [ 3 ].
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As biomedical research has progressed, it has become clear that cancer is not a single disease: each malignancy is as unique as the individual hosting it. In reality, several caveats complicate the precision medicine theory and have slowed the development of a corresponding pharmacological toolkit [ 4 ].
First, malignancies are often driven by more than one mutation. The genomic landscape of cancer is incredible, with individual tumors acquiring an average of 50, and as many as , somatic mutations [ 5 ]. Although the majority of these mutations do not support tumorigenesis, it is estimated that as many as eight or more mutations will play leading roles in this process [ 5 ]. As a result, combination therapy approaches are required to treat this disease.
However, within current clinical use, combination strategies often result in toxicities that limit their use in human patients. Second, target-matched therapeutic options are extremely limited. In the case of most tumor suppressors and the prominent oncogene RAS , small molecule inhibitors have been unsuccessful thus far, labeling these genomic drivers of disease undruggable.
With such a limited therapeutic toolbox, the overall impact of precision medicine has slowed.
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Last, patients receiving some form of precision therapy often still experience therapeutic resistance as tumors employ bypass mechanisms for survival [ 7 ]. Although a malignancy may exhibit a dependency upon EGFR signaling, the tumor has the ability to switch signaling dependencies when exposed to a therapeutic insult. This phenomenon has been observed to contribute to the clonal evolution that permits tumor relapse following initial treatment [ 8 , 9 ].
Despite the challenges currently facing precision medicine, biomedical researchers have discovered their own bypass mechanisms in an attempt to outsmart human tumors. One strategy is to target a signaling node common to several pathways in the cancer cell. Since it has been established that tumors display multiple drivers of disease and potential back-up drivers, targeting a single node would seemingly limit toxicity to the patient while still inhibiting several of the tumor's dependencies. The roadblock that has limited the development of this strategy is the lack of a therapeutic margin.
Ideally, precision medicine would minimize the negative effects to nontransformed cells that are often observed with cytotoxic chemotherapy and radiation. Unfortunately, the top prospects for targetable signaling nodes play essential roles in the survival of both transformed and nontransformed cells. A second strategy seeks to target a downstream effector pathway of a currently undruggable target.
Since the RAS isoforms lack small molecule inhibitors, extensive research has identified targetable effector pathways that are preferentially activated by oncogenic RAS mutations [ 10 ]. Among other exciting discoveries, autophagy has been implicated as one such effector pathway. Autophagy is defined as an intracellular recycling process in which cells degrade cytosolic material for reuse. As illustrated in Figure 1 , the process is initiated with the engulfment of cytosolic material such as damaged mitochondria into a double membrane organelle called the autophagosome.
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The process is complete after the fusion of a lysosome with the autophagosome allows the degradation of the engulfed material. Although all cells are thought to undergo a basal level of autophagy to maintain cellular homeostasis, the oncogenic mutations harbored by cancer cells often upregulate this process [ 11 , 12 ]. As in KRAS-mutated non-small-cell lung cancer, the upregulation of autophagy has been synonymous with an increased dependence upon this process, theoretically providing a therapeutic window where a patient's malignancy could be preferentially targeted by autophagy inhibitors.
These recent findings coupled with the existence of FDA-approved autophagy inhibitors has allowed for an expedited preclinical and clinical investigation of autophagy's role in tumorigenesis. In this review, we pay tribute to the lessons learned from the first autophagy inhibitors and discuss the field's rapid evolution toward clinical relevance. Autophagy is categorized into stages defined by the primary organelle present in the process. The induction and elongation stages describe the formation of a double membrane structure called the phagophore, and its subsequent elongation.
Maturation occurs when the phagophore closes to form a cytosolic material-filled autophagosome. The fusion stage defines the formation of the autolysosome, a product of fusion between a mature autophagosome and a functional lysosome.
Clearance describes the active degradation and recycling of engulfed material by lysosomal hydrolases. The first compounds termed autophagy inhibitors were not designed as such, but were rather repurposed from their initial use as antimalarial agents. The development of these autophagy inhibitors has a long, rich history that began with the Peruvian people's use of cinchona tree bark to ameliorate fever and other malaria-associated symptoms in the early s major events are reviewed in Figure 2. In the s, French chemists successfully extracted pure quinine from the cinchona bark and showed its curative effects on malaria patients.
This achievement marked the beginning of the race for antimalarial compounds. Extracted quinine was used extensively throughout the 19th century; in fact, over 25, kg was used by Union troops alone in the American Civil War [ 13 ]. Its use was limited, however, by access to cinchona bark. During World War I, these limitations resulted in casualties experienced by both sides; many sources have even claimed that malaria posed a greater threat to human life than the war itself.
As synthetic chemistry advanced, German scientists at the Bayer pharmaceutical company introduced their first line of quinine-related compounds during World War II [ 14 ]. Included in the line-up was chloroquine, now considered the founder of lysosome-targeted autophagy inhibitors. Interestingly, due to toxicity issues, chloroquine was dismissed for human use by both Germany and the USA in early clinical studies; it took an extensive clinical trial comparing all synthetic antimalarial compounds to show that chloroquine was in fact superior in human patients [ 13 ].
If not for the persistence of scientists, autophagy inhibitors like chloroquine might have never been developed [ 14 ]. The serendipitous identification of the first autophagy inhibitors, CQ and HCQ, has a long, rich history. Events critical to the clinical investigation of HCQ in autophagy research are outlined. Although chloroquine was predominantly used to treat malaria and inflammatory-related diseases in the early and mids, the rise of biomedical research and the identification of autophagy sparked several key observations related to cancer.
In the s, chloroquine was coined as a fibroblast-inhibiting agent following observations of slowed proliferation and migration in vitro [ 15 ]. During the following decade, several instances of lysosomal damage were reported in animals receiving chloroquine treatment, officially labeling the compound as lysosomotropic [ 18—21 ]. The primary discovery at this point was chloroquine's mechanism of action: the compound readily crossed the lysosomal membrane and became protonated, causing its accumulation within the lysosome.
Chloroquine's continued sequestration caused a significant increase in the lysosome's pH, inactivating acid hydrolase enzymes and rendering the lysosome nonfunctional [ 22—24 ]. In the case of malaria, in which parasites hijack the lysosomal system within red blood cells to provide a continuous nutrient supply, the past successes of chloroquine in malaria patients were elucidated.
As the biomedical research field's understanding of autophagy expanded in the s, chloroquine's known effects on the lysosome suggested a connection to the intracellular recycling process. The first studies of chloroquine's effects on autophagy illustrated an accumulation of autophagosomes following treatment, which led researchers to incorrectly conclude that chloroquine was inducing autophagy [ 25 ].
In the s and early s, it was discovered that chloroquine affected autophagy by inactivating the lysosome, just as had been established in malaria research. It was at this point that a more complete picture of autophagy came into view: the accumulation of autophagosomes observed across multiple malignancies both in vitro and in vivo occurred as a result of the process being blocked in the final stages. Although the field had serendipitously uncovered an autophagy inhibitor, chloroquine was not the perfect compound. Although it was FDA approved and well characterized, chloroquine was known for severe side effects in human patients, especially after prolonged use.
In , a hydroxylated version of chloroquine was synthesized to reduce the retinopathy, indigestion and tinnitus effects of treatment, while maintaining the benefits of oral bioavailability and fast gastrointestinal absorption [ 26 ]. Like chloroquine, hydroxychloroquine was primarily investigated in malaria and inflammatory disease research until the s. At the turn of the century, the autophagy field was primed to investigate the next lysosomotropic agent as a potential autophagy inhibitor. In vitro studies were intriguing, showing apoptosis after hydroxychloroquine treatment across numerous cancer cell lines as well as the stalling of growth and proliferation in breast cancer cells [ 27—29 ].
These initial studies paved the way for further investigation of hydroxychloroquine in the context of cancer. The biomedical research field was slow to translate the observations of lysosomotropic agents out of the malaria research field. However, the importance of autophagy in the process of tumorigenesis had been well established.
The first records of neoplastic autophagy occurred in the s in lung tumors, but the phenomenon quickly expanded to both breast and liver tumors as well [ 30—32 ]. These early observations were all made using biochemical techniques, such as acid phosphatase staining of the lysosome and transmission electron microscopy to visualize autophagosomes [ 33 , 34 ]. From the initial observations of basal autophagy in cancer cells, the important discovery that standard chemotherapeutic agents induced autophagy was made.
In the s, the popular cytotoxic therapies vincristine and vinblastine were shown to cause autophagosome accumulation [ 35 , 36 ]. Around the same time, radiation was found to do the same across multiple malignancies [ 37 ].