The Complexity of the Tumor Microenvironment and Its Role in Acute Lymphoblastic Leukemia: Implications for Therapies.
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ABSTRACT:
SUBMITTER: Simioni C
PROVIDER: S-EPMC8131840 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The tumor microenvironment is emerging as an important therapeutic target. Most studies, however, are focused on the protein components, and relatively little is known of how the microenvironmental metabolome might influence tumor survival. In this study, we examined the metabolic profiles of paired bone marrow (BM) and peripheral blood (PB) samples from 10 children with acute lymphoblastic leukemia (ALL). BM and PB samples from the same patient were collected at the time of diagnosis and after 29 days of induction therapy, at which point all patients were in remission. We employed two analytical platforms, high-resolution magnetic resonance spectroscopy and gas chromatography-mass spectrometry, to identify and quantify 102 metabolites in the BM and PB. Standard ALL therapy, which includes l-asparaginase, completely removed circulating asparagine, but not glutamine. Statistical analyses of metabolite correlations and network reconstructions showed that the untreated BM microenvironment was characterized by a significant network-level signature: a cluster of highly correlated lipids and metabolites involved in lipid metabolism (p<0.006). In contrast, the strongest correlations in the BM upon remission were observed among amino acid metabolites and derivatives (p<9.2 × 10(-10)). This study provides evidence that metabolic characterization of the cancer niche could generate new hypotheses for the development of cancer therapies.
| S-EPMC3862732 | biostudies-literature
Project description:The majority of adult patients with acute lymphoblastic leukemia (ALL) will die from the disease. Although the prognosis for pediatric patients is significantly better than for adult patients with ALL, the prognosis for patients with relapsed or refractory disease is poor in all cases. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a related donor offers a significant therapeutic benefit for pediatric patients, although the benefit of this therapy to adults with ALL is less established. Because most patients lack a suitable related donor, alternative approaches to allo-HSCT, including umbilical cord blood, and unrelated and haploidentical allo-HSCT, have been investigated in the clinical setting. Although treatment with donor-derived T-cells, so-called 'donor lymphocyte infusion', has demonstrated poor outcomes in patients with relapsed ALL following HSCT, modified adoptive T-cell regimens, including the infusion of enriched tumor-targeted donor T-cells and genetically targeted T-cells, are currently under clinical investigation. In addition, the resistance of ALL tumor cell lines to NK-cell-mediated lysis may be overcome by the genetic modification of NK cells to target ALL tumor cell antigens, and this approach will be evaluated in an upcoming clinical trial. Whether these novel adoptive cell therapies will ultimately result in improved clinical outcomes remains to be determined.
| S-EPMC4694559 | biostudies-literature
Project description:ALL remains a difficult disease to treat. In the adult setting, most patients will ultimately die of their disease, whereas in the pediatric setting, relapsed and refractory disease remains a therapeutic challenge. Cellular therapy through allo-HSCT remains an option for these patients, and recent advances in alternative forms of allo-HSCT, including unrelated donor transplants, UCB transplants, and haploidentical transplants, have expanded the numbers of patients eligible for allo-HSCT but have not improved outcomes when compared with HLA-matched related allo-HSCTs. In light of this persistent failure, several novel adoptive cellular approaches are being investigated to treat patients with ALL. The use of enriched WT-1–specific donor T cells to treat patients with ALL is currently under investigation in phase I trials at several centers. Treatment of ALL with genetically modified T cells targeted to the CD19 antigen through the expression of a CD19-specific CAR also have entered phase I clinical trials at several centers. Similarly, a clinical trial treating patients with ALL with genetically modified NK cells targeted to the CD19 antigen has recently opened for accrual. Collectively, these ongoing and anticipated trials provide a promising role for adoptive cellular therapies in the treatment of ALL. What remains to be seen is whether this promise will either translate into improved outcomes for these patients or provide significant insights on which to design second-generation adoptive cell therapeutic clinical trials for ALL in the future.
| S-EPMC3551618 | biostudies-literature
Project description:The use of multiagent combination chemotherapy regimens results in cure rates of >90% for children and ?40% for adults with acute lymphoblastic leukemia (ALL) but is associated with extensive toxicity and disappointingly low efficacy in relapsed patients. ALL blast cells express several surface antigens, including CD20, CD22, and CD19, which represent valuable targets for immunotherapy. Monoclonal antibodies, antibody-drug conjugates, and bispecific T-cell-engaging antibodies targeting these antigens offer novel mechanisms of action. Within the last several years, the anti-CD20 antibody rituximab has been added to chemotherapy for newly diagnosed patients <60 years with CD20+ pre-B ALL and significantly improved the 2-year event-free survival from 52% to 65%. In adults with relapsed or refractory CD22+ ALL, the antibody-drug conjugate inotuzumab ozogamicin resulted in a complete response rate of 81% and median overall survival of 7.7 months with reduced toxicity compared with standard chemotherapy. Similarly, the bispecific T-cell-engaging antibody blinatumomab yielded a complete response rate of 44% and a median overall survival of 7.7 months in an extensively treated ALL population. Moreover, ?80% of ALL patients in complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response following treatment with blinatumomab. These results highlight the tremendous promise of antibody-based treatment approaches for ALL. Ongoing and future research is critical to further define the role of the various immunotherapies in the frontline treatment of ALL. Additional challenges include the optimal sequencing of the available antibodies in the relapsed setting as well as their integration with stem cell transplant and chimeric antigen receptor T-cell therapy.
| S-EPMC6246018 | biostudies-literature
Project description:IntroductionThe improvement in outcomes for children with acute lymphoblastic leukemia (ALL) is one of the greatest success stories of modern oncology however the prognosis for patients who relapse remains dismal. Recent discoveries by high resolution genomic technologies have characterized the biology of relapsed leukemia, most notably pathways leading to the drug resistant phenotype. These observations open the possibility of targeting such pathways to prevent and/or treat relapse. Likewise, early experiences with new immunotherapeutic approaches have shown great promise. Areas covered: We performed a literature search on PubMed and recent meeting abstracts using the keywords below. We focused on the biology and clonal evolution of relapsed disease highlighting potential new targets of therapy. We further summarized the results of early trials of the three most prominent immunotherapy agents currently under investigation. Expert commentary: Discovery of targetable pathways that lead to drug resistance and recent breakthroughs in immunotherapy show great promise towards treating this aggressive disease. The best way to treat relapse, however, is to prevent it which makes incorporation of these new approaches into frontline therapy the best approach. Challenges remain to balance efficacy with toxicity and to prevent the emergence of resistant subclones which is why combining these newer agents with conventional chemotherapy will likely become standard of care.
| S-EPMC6028000 | biostudies-literature
Project description:The dynamic interactions of cancer cells with their microenvironment consisting of stromal cells (cellular part) and extracellular matrix (ECM) components (non-cellular) is essential to stimulate the heterogeneity of cancer cell, clonal evolution and to increase the multidrug resistance ending in cancer cell progression and metastasis. The reciprocal cell-cell/ECM interaction and tumor cell hijacking of non-malignant cells force stromal cells to lose their function and acquire new phenotypes that promote development and invasion of tumor cells. Understanding the underlying cellular and molecular mechanisms governing these interactions can be used as a novel strategy to indirectly disrupt cancer cell interplay and contribute to the development of efficient and safe therapeutic strategies to fight cancer. Furthermore, the tumor-derived circulating materials can also be used as cancer diagnostic tools to precisely predict and monitor the outcome of therapy. This review evaluates such potentials in various advanced cancer models, with a focus on 3D systems as well as lab-on-chip devices. Video abstract.
| S-EPMC7140346 | biostudies-literature
Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with T-ALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent T-ALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of T-ALL and gives a comprehensive overview of the novel treatments for patients with T-ALL that are currently under clinical investigation or that are emerging from preclinical research.SignificanceT-ALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.
| S-EPMC8447273 | biostudies-literature
Project description:Purpose of reviewAcute lymphoblastic leukemia (ALL) is a rare hematologic malignancy. Advances in multi-agent chemotherapy have resulted in dramatic improvements in the number of pediatric cases that result in a cure; however, until recently, treatment options for older adults or patients with relapsed and refractory disease were extremely limited. This review seeks to describe in greater detail a number of emerging novel treatment modalities recently approved for this cancer.Recent findingsIn this review, we discuss a number of recently approved novel therapies for ALL, including new approaches with targeted tyrosine kinase inhibitors, novel immune-based therapies including the bispecific antibody blinatumomab and the antibody-drug conjugate inotuzumab ozogamicin, and the role of cellular therapeutics such as chimeric antigen receptor (CAR) T cells. We also discuss the impact that advances in diagnostics and disease classification and monitoring have had on treatment. A number of advances in ALL have resulted in dramatic changes to the treatment landscape and therapeutic options both at the time of diagnosis and in salvage. These findings are reshaping our treatment paradigms throughout the course of disease.
| S-EPMC8889501 | biostudies-literature
Project description:BackgroundDespite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study.MethodsThe effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts.ResultsWe showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation.ConclusionsOur data suggest that WEE1 plays a role in ALL blast's survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
| S-EPMC6090987 | biostudies-literature
Project description:PurposePyrvinium pamoate (PP) is an anthelmintic drug that has been found to have anti-cancer activity in several cancer types. In the present study, we evaluated PP for potential anti-leukemic activity in B cell acute lymphoblastic leukemia (ALL) cell lines, in an effort to evaluate the repurposing potential of this drug in leukemia.MethodsALL cells were treated with PP at various concentrations to determine its effect on cell proliferation. Metabolic function was tested by evaluating Extracellular Acidification Rate (ECAR) and Oxygen Consumption Rate (OCR). Lastly, 3D spheroids were grown, and PP was reformulated into nanoparticles to evaluate distribution effectiveness.ResultsPP was found to inhibit ALL proliferation, with varied selectivity to different ALL cell subtypes. We also found that PP's cell death activity was specific for leukemic cells, as primary normal immune cells were resistant to PP-mediated cell death. Metabolic studies indicated that PP, in part, inhibits mitochondrial oxidative phosphorylation. To increase the targeting of PP to a hypoxic bone tumor microenvironment (BTME) niche, we successfully encapsulated PP in a nanoparticle drug delivery system and demonstrated that it retained its anti-leukemic activity in a hemosphere assay.ConclusionWe have demonstrated that PP is a novel therapeutic lead compound that counteracts the respiratory reprogramming found in refractory ALL cells and can be effectively formulated into a nanoparticle delivery system to target the BTME.
| S-EPMC7021357 | biostudies-literature