Cancer therapeutic antibodies come of age: targeting minimal residual disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Ben-Kasus T
PROVIDER: S-EPMC5543854 | biostudies-other | 2007 Jun
REPOSITORIES: biostudies-other
Similar Datasets
Project description:BackgroundCutaneous melanoma is a lethal form of skin cancer with morbidity and mortality rates highest amongst European, North American and Australasian populations. The developments of targeted therapies (TTs) directed at the oncogene BRAF and its downstream mediator MEK, and immune checkpoint inhibitors (ICI), have revolutionized the treatment of metastatic melanoma, improving patient outcomes. However, both TT and ICI have their limitations. Although TTs are associated with high initial response rates, these are typically short-lived due to resistance. Conversely, although ICIs provide more durable responses, they have lower initial response rates. Due to these distinct yet complementary response profiles, it has been proposed that sequencing ICI with TT could lead to a high frequency of durable responses whilst circumventing the toxicity associated with combined ICI + TT treatment. However, several questions remain unanswered, including the mechanisms underpinning this synergy and the optimal sequencing strategy. The key to determining this is to uncover the biology of each phase of the therapeutic response.Aims and methodsIn this review, we show that melanoma responds to TT and ICI in three phases: early response, minimal residual disease (MRD) and disease progression. We explore the effects of ICI and TT on melanoma cells and the tumour immune microenvironment, with a particular focus on MRD which is predicted to underpin the development of acquired resistance in the third phase of response.ConclusionIn doing so, we provide a new framework which may inform novel therapeutic approaches for melanoma, including optimal sequencing strategies and agents that target MRD, thereby ultimately improving clinical outcomes for patients.
| S-EPMC10040726 | biostudies-literature
Project description: Not available
| S-BSST713 | biostudies-other
Project description:The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.
| S-EPMC8978805 | biostudies-literature
Project description:Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer-related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here, we integrated multi-omics data from a tractable organoid system with a metabolic modeling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzyme reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small-molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.
| S-EPMC8543468 | biostudies-literature
Project description:<p>Tumor relapse from treatment-resistant cells (minimal residual disease, MRD) underlies most breast cancer related deaths. Yet, the molecular characteristics defining their malignancy have largely remained elusive. Here we integrated multi-omics data from a tractable organoid system with a metabolic modelling approach to uncover the metabolic and regulatory idiosyncrasies of the MRD. We find that the resistant cells, despite their non-proliferative phenotype and the absence of oncogenic signaling, feature increased glycolysis and activity of certain urea cycle enzymes reminiscent of the tumor. This metabolic distinctiveness was also evident in a mouse model and in transcriptomic data from patients following neo-adjuvant therapy. We further identified a marked similarity in DNA methylation profiles between tumor and residual cells. Taken together, our data reveal a metabolic and epigenetic memory of the treatment-resistant cells. We further demonstrate that the memorized elevated glycolysis in MRD is crucial for their survival and can be targeted using a small molecule inhibitor without impacting normal cells. The metabolic aberrances of MRD thus offer new therapeutic opportunities for post-treatment care to prevent breast tumor recurrence.</p>
2021-09-14 | MTBLS1507 | MetaboLights
Project description:Serum markers and bone marrow examination are commonly used for monitoring therapy response in multiple myeloma (MM), but this fails to identify minimal residual disease (MRD), which frequently persists after therapy even in complete response patients, and extra-medullary disease escape. Positron emission tomography with computed tomography using 18F-deoxyglucose (FDG-PET/CT) is the reference imaging technique for therapeutic assessment and MRD detection in MM. To date, all large prospective cohort studies of transplant-eligible newly diagnosed MM patients have shown a strong and independent pejorative prognostic impact of not obtaining complete metabolic response by FDG-PET/CT after therapy, especially before maintenance. The FDG-PET/CT and MRD (evaluated by flow cytometry or next-generation sequencing at 10-5 and 10-6 levels, respectively) results are complementary for MRD detection outside and inside the bone marrow. For patients with at least a complete response, to reach double negativity (FDG-PET/CT and MRD) is a predictive surrogate for patient outcome. Homogenization of FDG-PET/CT interpretation after therapy, especially clarification of complete metabolic response definition, is currently underway. FDG-PET/CT does not allow MRD to be evaluated when it is negative at initial workup of symptomatic MM. New PET tracers such as CXCR4 ligands have shown high diagnostic value and could replace FDG in this setting. New sensitive functional magnetic resonance imaging (MRI) techniques such as diffusion-weighted MRI appear to be complementary to FDG-PET/CT for imaging MRD detection. The goal of this review is to examine the feasibility of functional imaging, especially FDG-PET/CT, for therapeutic assessment and MRD detection in MM.
| S-EPMC7432032 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-08-06 | GSE242746 | GEO
Project description:Tumor cell dissemination in bone marrow or other organs is thought to represent an important step in the metastatic process. The detection of bone marrow disseminated tumor cells is associated with worse outcome in early breast cancer. Moreover, the detection of peripheral blood circulating tumor cells is an adverse prognostic factor in metastatic breast cancer, and emerging data suggest that this is also true for early disease. Beyond enumeration, the characterization of these cells has the potential to improve risk assessment, treatment selection and monitoring, and the development of novel therapeutic agents, and to advance our understanding of the biology of metastasis.
| S-EPMC3262191 | biostudies-literature
Project description:Progression from localized to metastatic disease requires cancer cells spreading to distant organs through the bloodstream. Only a small proportion of these circulating tumor cells (CTCs) survives dissemination due to anoikis, shear forces and elimination by the immune system. However, all metastases originate from CTCs capable of surviving and extravasating into distant tissue to re-initiate a tumor. Metastasis initiation is not always immediate as disseminated tumor cells (DTCs) may enter a non-dividing state of cell dormancy. Cancer dormancy is a reversible condition that can be maintained for many years without being clinically detectable. Subsequently, late disease relapses are thought to be due to cancer cells ultimately escaping from dormant state. Cancer dormancy is usually associated with minimal residual disease (MRD), where DTCs persist after intended curative therapy. Thus, MRD is commonly regarded as an indicator of poor prognosis in all cancers. In this review, we examine the current understanding of MRD and immunity during cancer progression to metastasis and discuss clinical perspectives for oncology.
| S-EPMC7909268 | biostudies-literature
Project description:BackgroundObesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models.MethodsDoxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR.ResultsHFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52-4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42-3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001).ConclusionThese studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.
| S-EPMC6416940 | biostudies-literature