Tumors are composed of non-homogeneous cell populations exhibiting varying degrees of genetic and functional heterogeneity. Cancer stem cells (CSCs) are capable of sustaining tumors by manipulating ...genetic and non-genetic factors to metastasize, resist treatment, and maintain the tumor microenvironment. Understanding the key traits and mechanisms of CSC survival provides opportunities to improve patient outcomes via improved prognostic models and therapeutics. Here, we review the clinical significance of CSCs and results of potential CSC-targeting therapies in various cancers. We discuss barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.
Saygin et al. discuss the clinical significance of cancer stem cells (CSCs) and results of potential CSC-targeting therapies in various cancers. They highlight barriers to translating cues from pre-clinical models into clinical applications and propose new strategies for rational design of future anti-CSC trials.
The Clinical Impact of Cancer Stem Cells Lathia, Justin; Liu, Huiping; Matei, Daniela
The oncologist (Dayton, Ohio),
February 2020, Letnik:
25, Številka:
2
Journal Article
Recenzirano
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Patients with cancer can go though many stages in their disease, including diagnosis, recurrence, metastasis, and treatment failure. Cancer stem cells (CSCs) are a subgroup of cells within tumors ...that may explain the mechanism by which tumors recur and progress. CSCs can both self‐renew and produce progenitor cells of more differentiated cancer cells as well as heterogeneously demonstrate resistance and the abilities to migrate and metastasize. These “stemness” characteristics are often the result of dysregulation of one or more pathways, which can be detected by various biomarkers. Although there has been considerable laboratory research conducted on CSCs, its relevance to the practicing oncologist may seem questionable. We sought to determine the clinical impact of CSCs on patients. A systematic literature search was conducted to identify analyses containing survival information based on the expression of known CSC biomarkers in any cancer. Overall, 234 survival analyses were identified, of which 82% reported that high expression of CSC biomarker(s) resulted in poor overall survival and/or disease‐free survival compared with low or no expression of the biomarker. Elevated stemness biomarker levels were also associated with decreased tumor differentiation, altered TNM stage, and increased metastasis. This analysis would suggest that CSCs have a clinical impact on patients and that practicing oncologists need to start considering incorporating CSC‐targeting therapies into their patients’ treatment regimens.
Implications for Practice
Cancer stem cells (CSCs) may occur at any stage of cancer and are implicated in the occurrence of resistance, recurrence, and metastasis. A systematic literature analysis has shown that the presence of CSCs, identified via the upregulation of stemness pathway biomarkers, results in reduced survival across all cancers studied. Several CSC‐targeting agents are currently approved, and several others are in clinical trials. Future treatment regimens will likely include CSC‐targeting agents to enable the elimination of these holdouts to current therapies.
Cancer stem cells are a subgroup of cells within tumors that may explain the mechanism by which tumors recur and progress. This article reports on the clinical evidence to support cancer stem cells as a critical phenomenon that needs to be considered in clinical practice.
Ovarian cancer is an aggressive epithelial tumor that remains a major cause of cancer morbidity and mortality in women. Epigenetic alterations including DNA methylation and histone modifications are ...being characterized in ovarian cancer and have been functionally linked to processes involved in tumor initiation, chemotherapy resistance, cancer stem cell survival, and tumor metastasis. The epigenetic traits of cancer cells and of associated tumor microenvironment components have been shown to promote an immunosuppressive tumor milieu. However, DNA methylation and histone modifications are reversible, and therapies targeting the epigenome have been implicated in potential reinvigoration of the antitumor immunity. In this review, we provide an overview specifically of DNA methylation and histone modifications as "clothes of the ovarian cancer genome" in relationship to their functional effects and highlight recent developments in the field. We also address the clinical implications of therapeutic strategies to remove or alter specific articles of genomic "clothing" and restore normal cellular function. As the clothes of the genome continue to be deciphered, we envision that the epigenome will become an important therapeutic target for cancer.
Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after ...third-line therapy of 5–9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.
QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.
Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3–5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7–22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6–42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 24% of 463 patients) and thrombocytopenia (95 21% of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 7% of 463 patients), thrombocytopenia (34 7% of 463 patients), and vomiting (27 6% of 463 patients). One death due to gastric haemorrhage was considered treatment related.
We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.
Tesaro.
Studies show that the autonomic nervous system (ANS) has an important impact on health in general. In response to environmental demands, homeostatic processes are often compromised, therefore ...determining an increase in the sympathetic nervous system (SNS)'s functions and a decrease in the parasympathetic nervous system (PNS)'s functions. In modern societies, chronic stress associated with an unhealthy lifestyle contributes to ANS dysfunction. In this review, we provide a brief introduction to the ANS network, its connections to the HPA axis and its stress responses and give an overview of the critical implications of ANS in health and disease-focused specifically on the immune system, cardiovascular, oxidative stress and metabolic dysregulation. The hypothalamic-pituitary-adrenal axis (HPA), the SNS and more recently the PNS have been identified as regulating the immune system. The HPA axis and PNS have anti-inflammatory effects and the SNS has been shown to have both pro- and anti-inflammatory effects. The positive impact of physical exercise (PE) is well known and has been studied by many researchers, but its negative impact has been less studied. Depending on the type, duration and individual characteristics of the person doing the exercise (age, gender, disease status, etc.), PE can be considered a physiological stressor. The negative impact of PE seems to be connected with the oxidative stress induced by effort.
Epidemiologic and histopathologic associations between endometriosis and epithelial ovarian cancer have been reported; however, the underlying molecular and cellular mechanisms are not well ...understood. A possible genetic link has been suggested in recent publications. Driver mutations in PIK3CA, KRAS, ARID1A, and other genes have been found in the epithelium of intrauterine endometrial tissue, ovarian and extraovarian pelvic endometriosis tissue, ovarian cancers associated with endometriosis (i.e., clear cell and endometrioid type), and other epithelial ovarian cancers. This makes sense because pelvic endometriosis occurs primarily as a result of retrograde menstruation and implantation of endometrial tissue fragments in ovarian inclusion cysts or extraovarian peritoneal or subperitoneal sites. Unlike epithelial cells, endometriotic stromal cells are mutation free but contain widespread epigenetic defects that alter gene expression and induce a progesterone-resistant and intensely inflammatory environment, driven by estrogen via estrogen receptor-β. The resulting increased estrogenic action in the stroma drives inflammation and sends paracrine signals to neighboring epithelial cells to enhance proliferation. In addition, massively high concentrations of estrogen in the ovary may exert an additional and direct genotoxic effect on DNA and cause accumulation of additional mutations and malignant transformation in initially mutated endometriotic epithelial cells in an ovarian endometrioma, which may initiate epithelial ovarian cancer. The same epithelial mutations and inflammatory processes in stroma are seen in extraovarian deep-infiltrating endometriosis, but carcinogenesis does not occur. We provide a focused review of the literature and discuss the implications of recent genetic breakthroughs linking endometriosis and ovarian cancer.
Lack of sensitive single-cell analysis tools has limited the characterization of metabolic activity in cancer stem cells. By hyperspectral-stimulated Raman scattering imaging of single living cells ...and mass spectrometry analysis of extracted lipids, we report here significantly increased levels of unsaturated lipids in ovarian cancer stem cells (CSCs) as compared to non-CSCs. Higher lipid unsaturation levels were also detected in CSC-enriched spheroids compared to monolayer cultures of ovarian cancer cell lines or primary cells. Inhibition of lipid desaturases effectively eliminated CSCs, suppressed sphere formation in vitro, and blocked tumor initiation capacity in vivo. Mechanistically, we demonstrate that nuclear factor κB (NF-κB) directly regulates the expression levels of lipid desaturases, and inhibition of desaturases blocks NF-κB signaling. Collectively, our findings reveal that increased lipid unsaturation is a metabolic marker for ovarian CSCs and a target for CSC-specific therapy.
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•Ovarian cancer stem cells have high levels of unsaturated lipids•Blocking lipid desaturation impairs cancer stemness and tumor initiation capacity•The NF-κB pathway directly regulates the expression of lipid desaturases•Lipid desaturase inhibitors inactivate the NF-κB pathway
Cheng and colleagues using Raman spectroscopic imaging find that ovarian cancer stem cells contain unusually high levels of unsaturated lipids and show evidence that this metabolic difference could be used as a marker for these cells and as a new target for CSC-specific therapy.
Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput ...stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors.
Summary Background Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ...ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. Methods We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov , number NCT00753545. Findings Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months 95% CI 8·3–not calculable vs 4·3 months 3·0–5·4; HR 0·18 0·10–0·31; p<0·0001); similar findings were noted for patients with wild-type BRCA , although the difference between groups was lower (7·4 months 5·5–10·3 vs 5·5 months 3·7–5·6; HR 0·54 0·34–0·85; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 95% CI 0·64–1·21; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 0·45–1·17; p=0·19) and wild-type BRCA (HR 0·99 0·63–1·55; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten 7% patients in the olaparib group vs four 3% in the placebo group) and anaemia (seven 5% vs one <1%). Serious adverse events were reported in 25 (18%) patients who received olaparib and 11 (9%) who received placebo. Tolerability was similar in patients with mutated BRCA and the overall population. Interpretation These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. Funding AstraZeneca.
Olaparib (AZD2281) is an oral poly(adenosine diphosphate ADP-ribose) polymerase inhibitor that has shown antitumor activity in patients with high-grade serous ovarian cancer with or without BRCA1 or ...BRCA2 germline mutations.
We conducted a randomized, double-blind, placebo-controlled, phase 2 study to evaluate maintenance treatment with olaparib in patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer who had received two or more platinum-based regimens and had had a partial or complete response to their most recent platinum-based regimen. Patients were randomly assigned to receive olaparib, at a dose of 400 mg twice daily, or placebo. The primary end point was progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines.
Of 265 patients who underwent randomization, 136 were assigned to the olaparib group and 129 to the placebo group. Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval CI, 0.25 to 0.49; P<0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P=0.75).
Olaparib as maintenance treatment significantly improved progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer. Interim analysis showed no overall survival benefit. The toxicity profile of olaparib in this population was consistent with that in previous studies. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT00753545.).
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