Disulfiram Improves the Anti-PD-1 Therapy Efficacy by Regulating PD-L1 Expression via Epigenetically Reactivation of IRF7 in Triple Negative Breast Cancer.
TL;DR: Wang et al. as discussed by the authors showed that disulfiram (DSF) increased PD-L1 expression in triple negative breast cancer (TNBC) cells and showed that the combination of DSF and anti-PD-1 Ab could activate tumor immune microenvironment (TIME) to show much better antitumor efficacy than monotherapy.
Abstract: Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, disulfiram (DSF) kills tumor cells via regulating multiple signaling pathways and transcription factors. However, its effect on tumor immune microenvironment (TIME) remains unclear. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through bioinformatics analysis, we found that DNMT1 was highly expressed in TNBC tissue and PD-L1 was negatively correlated with IRF7 expression. DSF reduced DNMT1 expression and activity, and hypomethylated IRF7 promoter region resulting in upregulation of IRF7. Furthermore, we found DSF enhanced PD-L1 expression via DNMT1-mediated IRF7 hypomethylation. In in vivo experiments, DSF significantly improved the response to anti-PD-1 antibody (Ab) in 4T1 breast cancer mouse model. Immunohistochemistry staining showed that granzyme B+ and CD8+ T cells in the tumor tissues were significantly increased in the combination group. By analyzing the results of the tumor tissue RNA sequencing, four immune-associated pathways were significantly enriched in the DSF joint anti-PD-1 Ab group. In conclusion, we found that DSF could upregulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate TIME to show much better antitumor efficacy than monotherapy.
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TL;DR: Wang et al. as mentioned in this paper constructed pH-responsive lipid-coated calcium phosphate nanoparticles (LCP NPs) co-loaded with Cu2+ and Disulfiram (DSF).
6 citations
TL;DR: In this paper , peroxidase-like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH•NCs) act as a pH-activatable proenzyme to achieve tumor-selective and synergistic chemodynamic/chemo-immunotherapy against aggressive triple negative breast cancers (TNBCs).
Abstract: Artificial enzymes have demonstrated therapeutic benefits against diverse malignant tumors, yet their antitumor potencies are still severely compromised by non‐selective catalysis, low atomic‐utilization efficiency, and undesired off‐target toxicity. Herein, it is reported that peroxidase‐like biomineralized copper (II) carbonate hydroxide nanocrystals inside single albumin nanocages (CuCH‐NCs) act as a pH‐activatable proenzyme to achieve tumor‐selective and synergistic chemodynamic/chemo‐immunotherapy against aggressive triple‐negative breast cancers (TNBCs). These CuCH‐NCs show pH‐sensitive Cu2+ release, which spontaneously undergoes glutathione (GSH)‐mediated reduction into Cu+ species for catalyzing the evolution of H2O2 into hydroxyl radicals (·OH) in a single‐atom‐like manner to cause chemodynamic cell injury, and simultaneously activates non‐toxic disulfiram to cytotoxic complex for yielding selective chemotherapeutic damage via blocking cell proliferation and amplifying cell apoptosis. CuCH‐NCs exhibit considerable tumor‐targeting capacity with deep penetration depth, thus affording preferable efficacy against orthotopic breast tumors through synergistic chemodynamic/chemotherapy, together with good in vivo safety. Moreover, CuCH‐NCs arouse distinct immunogenic cell death effect and upregulate PD‐L1 expression upon disulfiram combination, and thus synergize with anti‐PD‐L1 antibody to activate adaptive and innate immunities, together with relieving immunosuppression, finally yielding potent antitumor efficacy against both primary and metastatic TNBCs. These results provide insights into smart and high‐performance proenzymes for synergistic therapy against aggressive cancers.
2 citations
TL;DR: In this paper , a review discusses the mechanisms of chemotherapy resistance in cancer cells promoted by ALDH and provides detailed insight into the role of ALDH in cancer stemness, metastasis, metabolism, and cell death.
Abstract: Modern cancer chemotherapy originated in the 1940s, and since then, many chemotherapeutic agents have been developed. However, most of these agents show limited response in patients due to innate and acquired resistance to therapy, which leads to the development of multi-drug resistance to different treatment modalities, leading to cancer recurrence and, eventually, patient death. One of the crucial players in inducing chemotherapy resistance is the aldehyde dehydrogenase (ALDH) enzyme. ALDH is overexpressed in chemotherapy-resistant cancer cells, which detoxifies the generated toxic aldehydes from chemotherapy, preventing the formation of reactive oxygen species and, thus, inhibiting the induction of oxidative stress and the stimulation of DNA damage and cell death. This review discusses the mechanisms of chemotherapy resistance in cancer cells promoted by ALDH. In addition, we provide detailed insight into the role of ALDH in cancer stemness, metastasis, metabolism, and cell death. Several studies investigated targeting ALDH in combination with other treatments as a potential therapeutic regimen to overcome resistance. We also highlight novel approaches in ALDH inhibition, including the potential synergistic employment of ALDH inhibitors in combination with chemotherapy or immunotherapy against different cancers, including head and neck, colorectal, breast, lung, and liver.
1 citations
TL;DR: In this article , the authors found that the addition of disulfiram and copper to alkylating chemotherapy did not significantly improve survival at 6 months, as compared with alkylanating chemotherapy only.
Abstract: Key Points Question Does the addition of disulfiram and copper to chemotherapy improve survival for patients with recurrent glioblastoma? Findings In this randomized clinical trial of 88 patients with recurrent glioblastoma, the addition of disulfiram and copper to alkylating chemotherapy did not significantly improve survival at 6 months, as compared with alkylating chemotherapy only. Significantly more patients receiving disulfiram had adverse events of grade 3 or higher (34% vs 11%) and serious adverse events (41% vs 16%). Meaning These findings suggest that the addition of disulfiram and copper to alkylating chemotherapy should not be recommended for patients with recurrent glioblastoma.
TL;DR: In this article , the immunomodulatory properties of disulfiram (DSF) have been investigated for the management of alcohol addiction, and the authors explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF.
Abstract: More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems.
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TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Abstract: Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.
14,768 citations
TL;DR: In the United States, the cancer death rate has dropped continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment as mentioned in this paper.
Abstract: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
9,661 citations
TL;DR: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express PD-L1 as mentioned in this paper.
Abstract: BackgroundPembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non–small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). MethodsIn this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator’s choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. ResultsMedi...
7,053 citations
The Royal Marsden NHS Foundation Trust1, European Institute of Oncology2, University of Colorado Denver3, Aix-Marseille University4, Baylor University5, University of Michigan6, University of Zurich7, Cross Cancer Institute8, Peter MacCallum Cancer Centre9, Netherlands Cancer Institute10, Hospital General Universitario Gregorio Marañón11, Memorial Sloan Kettering Cancer Center12, Huntsman Cancer Institute13, Yale University14, University of Melbourne15, University of Sydney16, Cornell University17, Ludwig Institute for Cancer Research18, University of Utah19, Yale Cancer Center20, Odense University Hospital21, Bristol-Myers Squibb22, Harvard University23
TL;DR: Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipILimumab alone, and in patients with PD-L1-negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone.
Abstract: The median progression-free survival was 11.5 months (95% confidence interval [CI], 8.9 to 16.7) with nivolumab plus ipilimumab, as compared with 2.9 months (95% CI, 2.8 to 3.4) with ipilimumab (hazard ratio for death or disease progression, 0.42; 99.5% CI, 0.31 to 0.57; P<0.001), and 6.9 months (95% CI, 4.3 to 9.5) with nivolumab (hazard ratio for the comparison with ipilimumab, 0.57; 99.5% CI, 0.43 to 0.76; P<0.001). In patients with tumors positive for the PD-1 ligand (PD-L1), the median progression-free survival was 14.0 months in the nivolumab-plus-ipilimumab group and in the nivolumab group, but in patients with PD-L1–negative tumors, progression-free survival was longer with the combination therapy than with nivolumab alone (11.2 months [95% CI, 8.0 to not reached] vs. 5.3 months [95% CI, 2.8 to 7.1]). Treatment-related adverse events of grade 3 or 4 occurred in 16.3% of the patients in the nivolumab group, 55.0% of those in the nivolumab-plus-ipilimumab group, and 27.3% of those in the ipilimumab group. CONCLUSIONS Among previously untreated patients with metastatic melanoma, nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone. In patients with PD-L1–negative tumors, the combination of PD-1 and CTLA-4 blockade was more effective than either agent alone. (Funded by Bristol-Myers Squibb; CheckMate 067 ClinicalTrials.gov number, NCT01844505.)
6,318 citations
TL;DR: New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy, and evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways.
Abstract: The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.
3,736 citations