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Blood Oct 2022Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo...
Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
Topics: Child; Humans; Mice; Animals; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Dasatinib; Zebrafish; Tyrosine; Cell Line, Tumor; Signal Transduction; Protein Kinase Inhibitors; Mechanistic Target of Rapamycin Complex 1; Receptors, Antigen, T-Cell; T-Lymphocytes; Recurrence; Mammals
PubMed: 35544598
DOI: 10.1182/blood.2021015106 -
EBioMedicine Sep 2019Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at...
BACKGROUND
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans.
METHODS
In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ± 3·1 years old; 2 female; BMI:33·9 ± 2·3 kg/m; eGFR:27·0 ± 2·1 mL/min/1·73m). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed.
FINDINGS
D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16-and p21-expressing cells, cells with senescence-associated β-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16 and p21 cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12.
INTERPRETATION
"Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.
Topics: Adipocytes; Adipose Tissue; Aged; Biomarkers; Biopsy; Cellular Senescence; Clinical Trials, Phase I as Topic; Dasatinib; Diabetic Nephropathies; Drug Therapy, Combination; Female; Humans; Immunohistochemistry; Kidney Function Tests; Macrophages; Male; Middle Aged; Quercetin
PubMed: 31542391
DOI: 10.1016/j.ebiom.2019.08.069 -
Current Hematologic Malignancy Reports Oct 2022Due to lack of pediatric-specific data, the management of chronic myeloid leukemia (CML) in pediatric, adolescents, and young adults is guided by adult CML... (Review)
Review
PURPOSE OF REVIEW
Due to lack of pediatric-specific data, the management of chronic myeloid leukemia (CML) in pediatric, adolescents, and young adults is guided by adult CML evidence-based recommendations. Pediatric CML presents differently than adult CML and is often a more aggressive disease with different biological and host factors, yet there is sparse literature on how to address those differences.
RECENT FINDINGS
Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the way CML is treated. There are currently three FDA-approved TKIs (imatinib, dasatinib, and nilotinib) for pediatric patients. When choosing which TKI to begin treatment with, there are many factors that should be considered on a case-to-case basis to obtain optimal outcomes. The safety profiles for long-term TKI use in pediatrics require further study. Unlike adults, children are still actively growing during TKI use, and the effect on development can be detrimental. TKI therapy is not recommended during pregnancy with variable but significant risk of fetal abnormalities and miscarriage, warranting counseling for young female patients prior to beginning TKIs. Attempts for treatment-free remission (TFR) by planned TKI cessation in eligible adult patients in deep and sustained molecular remission are now done as a standard of practice. However, data is sparse in the pediatric population. There is currently an ongoing Children's Oncology Group (COG) study to determine the feasibility of TFR as a treatment goal. Further research and additional pediatric trials are needed to characterize the unique aspects of CML in children and adolescents and optimize outcomes.
Topics: Adolescent; Child; Dasatinib; Female; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors; Young Adult
PubMed: 35920965
DOI: 10.1007/s11899-022-00673-5 -
Molecular Therapy : the Journal of the... Jan 2023Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR...
Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7 malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.
Topics: Mice; Animals; Humans; T-Lymphocytes; Immunotherapy, Adoptive; Dasatinib; Feasibility Studies; Receptors, Chimeric Antigen; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 36086817
DOI: 10.1016/j.ymthe.2022.09.003 -
Blood Advances Jan 2022The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by... (Clinical Trial)
Clinical Trial
The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
Topics: Acute Disease; Adult; Dasatinib; Humans; Imatinib Mesylate; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence
PubMed: 34516628
DOI: 10.1182/bloodadvances.2021004607 -
Journal of Clinical Oncology : Official... Aug 2018Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic... (Clinical Trial)
Clinical Trial
Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.
Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.
Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Dasatinib; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Survival Rate; Young Adult
PubMed: 29812996
DOI: 10.1200/JCO.2017.76.7228 -
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.EBioMedicine Feb 2019Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a... (Clinical Trial)
Clinical Trial
BACKGROUND
Cellular senescence is a key mechanism that drives age-related diseases, but has yet to be targeted therapeutically in humans. Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal cellular senescence-associated disease. Selectively ablating senescent cells using dasatinib plus quercetin (DQ) alleviates IPF-related dysfunction in bleomycin-administered mice.
METHODS
A two-center, open-label study of intermittent DQ (D:100 mg/day, Q:1250 mg/day, three-days/week over three-weeks) was conducted in participants with IPF (n = 14) to evaluate feasibility of implementing a senolytic intervention. The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.
FINDINGS
Fourteen patients with stable IPF were recruited. The retention rate was 100% with no DQ discontinuation; planned clinical assessments were complete in 13/14 participants. One serious adverse event was reported. Non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent. Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulat.ing SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).
INTERPRETATION
Our first-in-humans open-label pilot supports study feasibility and provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of DQ in larger randomized controlled trials for senescence-related diseases. ClinicalTrials.gov identifier: NCT02874989 (posted 2016-2018).
Topics: Aged; Aged, 80 and over; Biomarkers; Cellular Senescence; Dasatinib; Drug Therapy, Combination; Female; Humans; Idiopathic Pulmonary Fibrosis; Male; Middle Aged; Patient Compliance; Patient Reported Outcome Measures; Pilot Projects; Quality of Life; Quercetin; Respiratory Function Tests; Treatment Outcome
PubMed: 30616998
DOI: 10.1016/j.ebiom.2018.12.052 -
Nature Communications Nov 2022The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as...
The progressive decline of physiological function and the increased risk of age-related diseases challenge healthy aging. Multiple anti-aging manipulations, such as senolytics, have proven beneficial for health; however, the biomarkers that label in vivo senescence at systemic levels are lacking, thus hindering anti-aging applications. In this study, we generate a Glb1‒Glb1-2A-mCherry (GAC) reporter allele at the Glb1 gene locus, which encodes lysosomal β-galactosidase-an enzyme elevated in tissues of old mice. A linear correlation between GAC signal and chronological age is established in a cohort of middle-aged (9 to 13 months) Glb1 mice. The high GAC signal is closely associated with cardiac hypertrophy and a shortened lifespan. Moreover, the GAC signal is exponentially increased in pathological senescence induced by bleomycin in the lung. Senolytic dasatinib and quercetin (D + Q) reduce GAC signal in bleomycin treated mice. Thus, the Glb1-2A-mCherry reporter mice monitors systemic aging and function decline, predicts lifespan, and may facilitate the understanding of aging mechanisms and help in the development of anti-aging interventions.
Topics: Animals; Mice; Aging; Bleomycin; Cellular Senescence; Dasatinib; Longevity; Genes, Reporter; Glycoside Hydrolases
PubMed: 36396643
DOI: 10.1038/s41467-022-34801-9 -
GeroScience Jun 2023Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and...
Ovarian injury caused by chemotherapy can lead to early menopause, infertility, and even premature senility in female cancer patients, impairing the quality of life and overall health of the cancer survivors seriously. However, there is still a lack of effective protection strategies against such injury. Cellular senescence can be induced by chemotherapeutic agents in multiple organs and may corrode the structure and function of normal tissues. We hypothesized that the widely used first-line chemotherapy drug, doxorubicin, could increase senescent cell burden in normal ovarian tissue during the therapeutic process and that elimination of senescent cells with senolytics would ameliorate doxorubicin-induced ovarian injury. Here, we demonstrated an accumulation of cellular senescence in doxorubicin-treated ovaries through detecting p16 and p21 expression levels and senescence-associated β-galactosidase (SA-β-gal) activity as well as senescence-associated secretory phenotype (SASP) factors. Short-term intervention with the classic senolytic combination dasatinib and quercetin (DQ) or fisetin significantly reduced the load of senescent cells in ovaries after doxorubicin treatment. However, neither DQ nor fisetin alleviated doxorubicin-related ovarian dysfunction. Further experiments showed that ovarian apoptosis and fibrosis following doxorubicin exposure could not be improved by senolytics. Collectively, our study shows that senolytic treatment can eliminate accumulated senescent cells, but cannot reverse the massive follicle loss and ovarian stromal fibrosis caused by doxorubicin, suggesting that cellular senescence may not be one of the key mechanisms in doxorubicin-induced ovarian injury.
Topics: Female; Animals; Mice; Senotherapeutics; Quality of Life; Cellular Senescence; Doxorubicin; Dasatinib; Fibrosis
PubMed: 36648735
DOI: 10.1007/s11357-023-00728-2 -
The Journal of Prevention of... 2022Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation,... (Randomized Controlled Trial)
Randomized Controlled Trial
Preclinical studies indicate an age-associated accumulation of senescent cells across multiple organ systems. Emerging evidence suggests that tau protein accumulation, which closely correlates with cognitive decline in Alzheimer's disease and other tauopathies, drives cellular senescence in the brain. Pharmacologically clearing senescent cells in mouse models of tauopathy reduced brain pathogenesis. Compared to vehicle treated mice, intermittent senolytic administration reduced tau accumulation and neuroinflammation, preserved neuronal and synaptic density, restored aberrant cerebral blood flow, and reduced ventricular enlargement. Intermittent dosing of the senolytics, dasatinib plus quercetin, has shown an acceptable safety profile in clinical studies for other senescence-associated conditions. With these data, we proposed and herein describe the objectives and methods for a clinical vanguard study. This initial open-label clinical trial pilots an intermittent senolytic combination therapy of dasatinib plus quercetin in five older adults with early-stage Alzheimer's disease. The primary objective is to evaluate the central nervous system penetration of dasatinib and quercetin through analysis of cerebrospinal fluid collected at baseline and after 12 weeks of treatment. Further, through a series of secondary outcome measures to assess target engagement of the senolytic compounds and Alzheimer's disease-relevant cognitive, functional, and physical outcomes, we will collect preliminary data on safety, feasibility, and efficacy. The results of this study will be used to inform the development of a randomized, double-blind, placebo-controlled multicenter phase II trial to further explore of the safety, feasibility, and efficacy of senolytics for modulating the progression of Alzheimer's disease. Clinicaltrials.gov registration number and date: NCT04063124 (08/21/2019).
Topics: Aged; Alzheimer Disease; Animals; Cellular Senescence; Dasatinib; Humans; Mice; Senotherapeutics; Tauopathies
PubMed: 35098970
DOI: 10.14283/jpad.2021.62