Targeting Autophagy in Cancer: Update on Clinical Trials and Novel Inhibitors (original) (raw)
Related papers
Principles and Current Strategies for Targeting Autophagy for Cancer Treatment
Clinical Cancer Research, 2011
Autophagy is an evolutionarily conserved, intracellular self-defense mechanism where organelles and proteins are sequestered into autophagic vesicles (AVs) that are subsequently degraded through fusion with lysosomes. Cells thereby prevent the toxic accumulation of damaged or unnecessary components, but also recycle these components to sustain metabolic homoeostasis. Heightened autophagy is a mechanism of resistance for cancer cells faced with metabolic and therapeutic stress, revealing opportunities for exploitation as a therapeutic target in cancer. We summarize recent developments in the field of autophagy and cancer, and build upon the results presented at the Cancer Therapeutics and Evaluation Program (CTEP) Early Drug Development meeting in March, 2010. Herein, we describe our current understanding of the core components of the autophagy machinery, the functional relevance of autophagy within the tumor microenvironment and outline how this knowledge has informed preclinical investigations combining the autophagy inhibitor hydroxychloroquine (HCQ) with chemotherapy, targeted therapy and immunotherapy. Finally, we describe ongoing clinical trials involving HCQ as a first
The Role of Autophagy in Cancer: Therapeutic Implications
Molecular Cancer Therapeutics, 2011
Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are engulfed into autophagosomes, digested in lysosomes and recycled to sustain cellular metabolism. Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Tumor cells activate autophagy in response to cellular stress including hypoxia and increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance, as shown in preclinical models where the inhibition of autophagy can restore chemosensitivity and enhance tumor cell death. These results established autophagy as a therapeutic target and have led to multiple early phase clinical trials in humans evaluating autophagy inhibition using hydroxychloroquine in combination with chemotherapy or targeted agents. Targeting autophagy in cancer provides new opportunities for drug development since more potent and specific inhibitors of autophagy are needed. The role of autophagy and its regulation in cancer cells continues to emerge and studies aim to define optimal strategies to modulate autophagy for therapeutic advantage.
Autophagy Modulation in Cancer: Current Knowledge on Action and Therapy
Oxidative Medicine and Cellular Longevity
In the last two decades, accumulating evidence pointed to the importance of autophagy in various human diseases. As an essential evolutionary catabolic process of cytoplasmatic component digestion, it is generally believed that modulating autophagic activity, through targeting specific regulatory actors in the core autophagy machinery, may impact disease processes. Both autophagy upregulation and downregulation have been found in cancers, suggesting its dual oncogenic and tumor suppressor properties during malignant transformation. Identification of the key autophagy targets is essential for the development of new therapeutic agents. Despite this great potential, no therapies are currently available that specifically focus on autophagy modulation. Although drugs like rapamycin, chloroquine, hydroxychloroquine, and others act as autophagy modulators, they were not originally developed for this purpose. Thus, autophagy may represent a new and promising pharmacologic target for future ...
Autophagy Agents in Clinical Trials for Cancer Therapy: A Brief Review
Current Oncology, 2022
Autophagy has been of novel interest since it was first demonstrated to have effect in Burkitt’s lymphoma. Since that time, the autophagy agents chloroquine and hydroxychloroquine have become the only FDA (Food and Drug Administration)-approved autophagy inhibitors. While not approved for cancer therapy, there are ongoing clinical trials to evaluate their safety and efficacy. Pevonedistat has emerged as a novel inhibitor through the neddylation pathway and is an autophagy activator. This paper summarizes and presents current clinical trials for hydroxychloroquine (HCQ), chloroquine (CQ), and Pevonedistat for the clinician.
Medicinal Chemistry, 2020
Targeting autophagy in cancer has emerged as a promising strategy for drug discovery. Autophagy is a conserved process required for the degradation and recycling of damaged organelles and proteins. Dysregulation of autophagy has been implicated in many diseases including cancer. In breast cancer, studies have demonstrated that activated autophagy promotes cell survival and therapeutic resistance. Chloroquine (CQ), an antimalarial and anti-inflammatory agent, has emerged as a potentialanticancer agent due to its autophagy inhibitory activity; however, it lacks specificity and potency. In this study, we report the synthesis and evaluation of several CQ analogs.Interestingly, the most potent compounds identified 5 and 6, induced autophagy, as they enhanced the accumulation of LC3B-II and induced p62 protein degradation. Cotreatment of MDA-MB-231 cells with compound 5 and bafilomycin A1, an autophagy inhibitor, resulted in blocking apoptosis induction concomitant with partial rescue of ...
ACS Medicinal Chemistry Letters, 2015
The autophagy inhibitors chloroquine (CQ) and hydroxychloroquine (HCQ) have single agent antiproliferative activity against human cancer cell lines; however, low potency may limit their antitumor efficacy clinically. We synthesized a series of chloroquine analogs that retained the 4-aminoquinoline subunit and incorporated different substituted triazoles into the target structure. These compounds were tested for growth inhibition against H460 and HCC827 human lung cancer and BxPC3 pancreatic cancer cells. The most potent compound, EAD1, had an IC 50 of 5.8 μM in the BxPC3 cells and was approximately 8-fold more potent than CQ and HCQ. EAD1 inhibited autophagy, as judged by the cellular accumulation of the autophagy-related autophagosome proteins LC3-II and p62 and induced apoptosis. The increases in LC3-II levels by the analogues were highly correlated with their growth inhibitory IC 50 s, suggesting that autophagy blockade is closely linked to inhibition of cell proliferation. EAD1 is a viable lead compound for evaluation of the antitumor activity of autophagy inhibitors in vivo.
Targeting autophagy with small molecules for cancer therapy
Journal of Cancer Metastasis and Treatment, 2019
Autophagy is a conserved lysosomal-dependent catabolic process that maintains the cellular homeostasis by recycling misfolded proteins and damaged organelles. It involves a series of ordered events (initiation, nucleation, elongation, lysosomal fusion and degradation) that are tightly regulated/controlled by diverse cell signals and stress. It is like a double-edged sword that can play either a protective or destructive role in cancer, by pro-survival or apoptotic cues. Recently, modulating autophagy by pharmacological agents has become an attractive strategy to treat cancer. Currently, a number of small molecules that inhibit autophagy initiation (e.g., ULK kinase inhibitors), nucleation (e.g., Vps34 inhibitors), elongation (e.g., ATG4 inhibitors) and lysosome fusion (e.g., chloroquine, hydroxyl chloroquine, etc .) are reported in pre-clinical and clinical study. Also a number of small molecules reported to induce autophagy by targeting mammalian target of rapamycin (e.g., rapamycin analogs) or adenosine 5'-monophosphate-activated protein kinase (e.g., sulforaphane). The study results suggest that many potential "druggable" targets exist in the autophagy pathway that could be harnessed for developing new cancer therapeutics. In this review, we discuss the reported autophagy modulators (inhibitors and inducers), their molecular mode of action and their applications in cancer therapy.
Autophagy and Cancer Treatment Review
2021
Autophagy is a catabolic process that targets impaired organelles and proteins for lysosomal degradation to maintain cell hemostasis. Autophagy in cancer is dynamic and, more specifically, depending on the stage and type of tumor. Researches in genetically engineered mouse models are agreed with the concept that autophagy can constrain initiation of the tumor by controlling oxidative stress and DNA damage, while in established tumors, autophagy can also be required for tumor survival. As shown in preclinical models, suppression of autophagy restored chemotherapy sensitivity against tumor cells. Targeting autophagy in cancer will develop a new era for anti-cancer drugs, but more specific and potent inhibitors of autophagy are needed. The role of autophagy in cancer cells continues to emerge, and further studying to identify optimum strategies to modulate autophagy for therapeutic advantage.
Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy
Cancers
Autophagy is a physiological cellular process that is crucial for development and can occurs in response to nutrient deprivation or metabolic disorders. Interestingly, autophagy plays a dual role in cancer cells—while in some situations, it has a cytoprotective effect that causes chemotherapy resistance, in others, it has a cytotoxic effect in which some compounds induce autophagy-mediated cell death. In this review, we summarize strategies aimed at autophagy for the treatment of cancer, including studies of drugs that can modulate autophagy-mediated resistance, and/or drugs that cause autophagy-mediated cancer cell death. In addition, the role of autophagy in the biology of cancer stem cells has also been discussed.
Clin Cancer Res, 2014
Purpose: Estrogen receptor-a (ERa)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER þ breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness. Experimental Design: TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER þ breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ. Results: We show that HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICIþHCQ was less effective than HCQ alone in vivo, unlike the TAMþHCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICIþHCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNg were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAMþHCQ treatment increased tumor CD68 þ cells infiltration, whereas ICI and ICIþHCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI. Conclusion: HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAMþHCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER þ ductal carcinoma in situ lesions. Clin Cancer Res; 1-11. Ó2014 AACR. 42 tumors fail to respond (de novo resistance) or acquire 43 resistance over time (2-4). 44 Autophagy is a process by which a double membrane 45 vesicle surrounds cellular contents, such as damaged orga-46 nelles and misfolded or protein aggregates, and recycles 47 the material through lysosomal degradation (5). Studies in 48 breast cancer cells show that the induction of autophagy by 49 various therapeutics is usually prosurvival (6-8). Further-50 more, TAM and ICI both induce autophagy in ER þ breast 51 cancer cells (6, 9-13). Antiestrogen-resistant cell lines 52 exhibit increased basal autophagy when compared with 53 their antiestrogen-sensitive parental cells (10). Inhibiting 54 autophagy through autophagy-related gene 5 (ATG5) 55 silencing potentiated antiestrogen-mediated cell death, 56 indicating that antiestrogen-stimulated autophagy is pro-57 survival and a critical mechanism of therapy resistance (10). 58 Analysis of publically available human datasets indicates 59 that autophagy-related genes, ATG5, ATG7, and p62 60 (SQSTM1), are elevated in early recurring breast cancer 61 when compared with breast cancer that never recurs. More-62 over, elevated p62 is significantly correlated with poor 63 survival in patients with breast cancer (Supplementary Fig. 64 S1), suggesting a role for autophagy in breast cancer reoc-65 currence (14-18).