Targeting DNA Repair Response Promotes Immunotherapy in Ovarian Cancer: Rationale and Clinical Application
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ABSTRACT:
SUBMITTER: Xie H
PROVIDER: S-EPMC8546337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Reinvigorating the antitumor immune response using immune checkpoint inhibitors (ICIs) has revolutionized the treatment of several malignancies. However, extended use of ICIs has resulted in a cancer-specific response. In tumors considered to be less immunogenic, the response rates were low or null. To overcome resistance and improve the beneficial effects of ICIs, novel strategies focused on ICI-combined therapies have been tested. In particular, poly ADP-ribose polymerase inhibitors (PARPi) are a class of agents with potential for ICI combined therapy. PARPi impairs single-strand break DNA repair; this mechanism involves synthetic lethality in tumor cells with deficient homologous recombination. More recently, novel evidence indicated that PAPRi has the potential to modulate the antitumor immune response by activating antigen-presenting cells, infiltrating effector lymphocytes, and upregulating programmed death ligand-1 in tumors. This review covers the current advances in the immune effects of PARPi, explores the potential rationale for combined therapy with ICIs, and discusses ongoing clinical trials.
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Project description:Over the last decades, the growing understanding on DNA damage response (DDR) pathways has broadened the therapeutic landscape in oncology. It is becoming increasingly clear that the genomic instability of cells resulted from deficient DNA damage response contributes to the occurrence of cancer. One the other hand, these defects could also be exploited as a therapeutic opportunity, which is preferentially more deleterious in tumor cells than in normal cells. An expanding repertoire of DDR-targeting agents has rapidly expanded to inhibitors of multiple members involved in DDR pathways, including PARP, ATM, ATR, CHK1, WEE1, and DNA-PK. In this review, we sought to summarize the complex network of DNA repair machinery in cancer cells and discuss the underlying mechanism for the application of DDR inhibitors in cancer. With the past preclinical evidence and ongoing clinical trials, we also provide an overview of the history and current landscape of DDR inhibitors in cancer treatment, with special focus on the combination of DDR-targeted therapies with other cancer treatment strategies.
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Project description:DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675-93. ©2017 AACR.
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Project description:Defect in DNA damage response (DDR) is a common feature of cancer cells, which regulates tumor growth and therapeutic response. Recently, the approval of immune checkpoint blockade (ICB) for tumors with defective mismatch repair has paved the way for investigating the role of other DDR defects in sensitizing cancer to ICB therapy. Despite great progress in understanding DDR pathways, the mechanisms that link DDR defects and ICB response remain incompletely understood. Further, the clinical activity of ICB in patients with DDR defective tumors has not been well described. Here, we discuss recent studies demonstrating that biomarkers in DDR pathways may serve as potential predictors to guide the selection of patients for ICB therapy. A better understanding of the relationship between deficiency in DDR and response to ICB would facilitate efforts in optimizing the efficacy of immunotherapy.
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Project description:Immune checkpoint inhibitors(ICIs) that activate tumor-specific immune responses bring new hope for the treatment of hepatocellular carcinoma(HCC). However, there are still some problems, such as uncertain curative effects and low objective response rates, which limit the curative effect of immunotherapy. Therefore, it is an urgent problem to guide the use of ICIs in HCC based on molecular typing. We downloaded the The Cancer Genome Atlas-Liver hepatocellular carcinoma(TCGA-LIHC) and Mongolian-LIHC cohort. Unsupervised clustering was applied to the highly variable data regarding expression of DNA damage repair(DDR). The CIBERSORT was used to evaluate the proportions of immune cells. The connectivity map(CMap) and pRRophetic algorithms were used to predict the drug sensitivity. There were significant differences in DDR molecular subclasses in HCC(DDR1 and DDR2), and DDR1 patients had low expression of DDR-related genes, while DDR2 patients had high expression of DDR-related genes. Of the patients who received traditional treatment, DDR2 patients had significantly worse overall survival(OS) than DDR1 patients. In contrast, of the patients who received ICIs, DDR2 patients had significantly prolonged OS compared with DDR1 patients. Of the patients who received traditional treatment, patients with high DDR scores had worse OS than those with low DDR scores. However, the survival of patients with high DDR scores after receiving ICIs was significantly higher than that of patients with low DDR scores. The DDR scores of patients in the DDR2 group were significantly higher than those of patients in the DDR1 group. The tumor microenvironment(TME) of DDR2 patients was highly infiltrated by activated immune cells, immune checkpoint molecules and proinflammatory molecules and antigen presentation-related molecules. In this study, HCC patients were divided into the DDR1 and DDR2 group. Moreover, DDR status may serve as a potential biomarker to predict opposite clinical prognosis immunotherapy and non-immunotherapy in HCC.
| S-EPMC8320764 | biostudies-literature
Project description:Ovarian cancer (OC) has been the most fatal gynecological disease that threatens women's health. Surgery and platinum-based chemotherapy are the basic ovarian cancer treatments that can improve survival, but the five-year survival rate has not improved because of delayed diagnosis, drug resistance, and recurrence. Novel treatments are needed to improve the prognosis and survival rate of ovarian cancer patients. In recent years, adoptive cell therapy (ACT) has received increasing attention as an emerging therapeutic strategy in the treatment of solid tumors including OC. ACT has shown promising results in many preclinical and clinical trials of OC. The application of ACT depends on different effector cells, such as lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), and genetically modified T cells. In this review, we focus on adoptive immunotherapies in ovarian cancer and summarize completed and ongoing preclinical/clinical trials. The future development directions and obstacles for ACT in OC treatment are discussed.
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Project description:Ovarian clear cell carcinoma (OCCC) is one of the major types of ovarian cancer and is of higher relative prevalence in Asians. It also shows higher possibility of resistance to cisplatin-based chemotherapy leading to poor prognosis. This may be attributed to the relative lack of mutations and aberrations in homologous recombination-associated genes, which are crucial in DNA damage response (DDR), such as BRCA1, BRCA2, p53, RAD51, and genes in the Fanconi anemia pathway. On the other hand, OCCC is characterized by a number of genetic defects rendering it vulnerable to DDR-targeting therapy, which is emerging as a potent treatment strategy for various cancer types. Mutations of ARID1A, PIK3CA, PTEN, and catenin beta 1 (CTNNB1), as well as overexpression of transcription factor hepatocyte nuclear factor-1β (HNF-1β), and microsatellite instability are common in OCCC. Of particular note is the loss-of-function mutations in ARID1A, which is found in approximately 50% of OCCC. ARID1A is crucial for processing of DNA double-strand break (DSB) and for sustaining DNA damage signaling, rendering ARID1A-deficient cells prone to impaired DNA damage checkpoint regulation and hence sensitive to poly ADP ribose polymerase (PARP) inhibitors. However, while preclinical studies have demonstrated the possibility to exploit DDR deficiency in OCCC for therapeutic purpose, progress in clinical application is lagging. In this review, we will recapitulate the preclinical studies supporting the potential of DDR targeting in OCCC treatment, with emphasis on the role of ARID1A in DDR. Companion diagnostic tests (CDx) for predicting susceptibility to PARP inhibitors are rapidly being developed for solid tumors including ovarian cancers and may readily be applicable on OCCC. The potential of various available DDR-targeting drugs for treating OCCC by drawing analogies with other solid tumors sharing similar genetic characteristics with OCCC will also be discussed.
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Project description:Despite significant improvements in surgical and medical management, high grade serous ovarian cancer (HGSOC) still represents the deadliest gynecologic malignancy and the fifth most frequent cause of cancer-related mortality in women in the USA. Since DNA repair alterations are regarded as the "the Achille's heel" of HGSOC, both DNA homologous recombination and DNA mismatch repair deficiencies have been explored and targeted in epithelial ovarian cancers in the latest years. In this review, we aim at focusing on the therapeutic issues deriving from a faulty DNA repair machinery in epithelial ovarian cancers, starting from existing and well-established treatments and investigating new therapeutic approaches which could possibly improve ovarian cancer patients' survival outcomes in the near future. In particular, we concentrate on the role of both Poly (ADP-ribose) Polymerase (PARP) inhibitors (PARPis) and immune checkpoint inhibitors in HGSOC, highlighting their activity in relation to BRCA1/2 mutational status and homologous recombination deficiency (HRD). We investigate the biological rationale supporting their use in the clinical setting, pointing at tracking their route from the laboratory bench to the patient's bedside. Finally, we deal with the onset of mechanisms of primary and acquired resistance to PARPis, reporting the pioneering strategies aimed at converting homologous-recombination (HR) proficient tumors into homologous recombination (HR)-deficient HGSOC.
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Project description:Platinum-based chemotherapy is the cornerstone of ovarian cancer treatment, and its efficacy is dependent on the generation of DNA damage, with subsequent induction of apoptosis. Inappropriate or aberrant activation of the DNA damage response network is associated with resistance to platinum, and defects in DNA repair pathways play critical roles in determining patient response to chemotherapy. In ovarian cancer, tumor cell defects in homologous recombination?-?a repair pathway activated in response to double-strand DNA breaks (DSB)?-?are most commonly associated with platinum-sensitive disease. However, despite initial sensitivity, the emergence of resistance is frequent. Here, we review strategies for directly interfering with DNA repair pathways, with particular focus on direct inhibition of non-homologous end joining (NHEJ), another DSB repair pathway. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a core component of NHEJ and it has shown considerable promise as a chemosensitization target in numerous cancer types, including ovarian cancer where it functions to promote platinum-induced survival signaling, via AKT activation. The development of pharmacological inhibitors of DNA-PKcs is on-going, and clinic-ready agents offer real hope to patients with chemoresistant disease.
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Project description:Simple Summary The incidence of biliary tract cancers (BTCs) is rising. Although therapeutic weapons are still limited, a better knowledge of the molecular landscape of these tumors has established the conditions for several phase I and II clinical trials in which molecular targeted drugs are combined with chemotherapy. Clinical research is investing great efforts in immunotherapy, which has recently transformed the treatment of many cancers. In BTCs, the efficacy of immunotherapy is limited by the high percentage of patients presenting immunosuppressive features in the tumor microenvironment. Angiogenesis is known to play a key role in modulating the microenvironment by excluding cytotoxic immune cells from the tumor bed, favoring an immunosuppressive activity. Therefore, blocking angiogenesis could create the conditions for more efficacious immunotherapy. This review considers clinical trials based on therapy combining angiogenesis and immune cell inhibitors, highlighting the clinical need for phase III studies in a precision-medicine era. Abstract Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone.
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