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1.
Acta Haematol ; 2024 May 28.
Article in English | MEDLINE | ID: mdl-38806013

ABSTRACT

BACKGROUND: Identifying patients with high-risk T-cell acute lymphoblastic leukemia (T-ALL) is crucial for personalized therapy, however, the lack of robust biomarkers hinders prognosis assessment. To address this issue, our study aimed to screen and validate genes whose expression may serve as predictive indicators of outcomes in T-ALL patients, while also investigating the underlying molecular mechanisms. METHODS: Differentially expressed genes (DEGs) between T-ALL patients and healthy controls were identified by integrating data from three independent public datasets. Functional annotation of these DEGs and protein-protein interaction were also conducted. Further, we enrolled a prospective cohort of T-ALL patients (n=20) at our center, conducting RNA-seq analysis on their bone marrow samples. Survival-based Univariate Cox Analysis was employed to identify gene expressions related to survival, and an intersection algorithm was sequentially applied. Furthermore, we validated the identified genes using cases from the Therapeutically Applicable Research to Generate Effective Treatments database, plotting Kaplan-Meier curves for secondary validation. RESULTS: Through the integration of survival-related genes with DEGs identified in T-ALL, our analysis revealed six T-ALL-specific genes, the expression levels of which were linked to prognostic value. Notably, the independent prognostic value of SLC40A1 and TES expression levels was confirmed in both an external cohort and a prospective cohort at our center. CONCLUSIONS: In summary, our preliminary study indicates that the expression levels of TES and SLC40A1 genes show promise as potential indicators for predicting survival outcomes in T-ALL patients.

2.
Drug Resist Updat ; 74: 101082, 2024 May.
Article in English | MEDLINE | ID: mdl-38569225

ABSTRACT

Molecular targeted drugs and chimeric antigen receptor (CAR) T cell therapy represent specific biological treatments that have significantly improved the efficacy of treating hematologic malignancies. However, they face challenges such as drug resistance and recurrence after treatment. Combining molecular targeted drugs and CAR-T cells could regulate immunity, improve tumor microenvironment (TME), promote cell apoptosis, and enhance sensitivity to tumor cell killing. This approach might provide a dual coordinated attack on cancer cells, effectively eliminating minimal residual disease and overcoming therapy resistance. Moreover, molecular targeted drugs can directly or indirectly enhance the anti-tumor effect of CAR-T cells by inducing tumor target antigen expression, reversing CAR-T cell exhaustion, and reducing CAR-T cell associated toxic side effects. Therefore, combining molecular targeted drugs with CAR-T cells is a promising and novel tactic for treating hematologic malignancies. In this review article, we focus on analyzing the mechanism of therapy resistance and its reversal of CAR-T cell therapy resistance, as well as the synergistic mechanism, safety, and future challenges in CAR-T cell therapy in combination with molecular targeted drugs. We aim to explore the benefits of this combination therapy for patients with hematologic malignancies and provide a rationale for subsequent clinical studies.


Subject(s)
Hematologic Neoplasms , Immunotherapy, Adoptive , Molecular Targeted Therapy , Tumor Microenvironment , Humans , Hematologic Neoplasms/therapy , Hematologic Neoplasms/immunology , Hematologic Neoplasms/drug therapy , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/trends , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Molecular Targeted Therapy/methods , Drug Resistance, Neoplasm/drug effects , Combined Modality Therapy/methods , Receptors, Chimeric Antigen/immunology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Animals
3.
Front Oncol ; 12: 1057153, 2022.
Article in English | MEDLINE | ID: mdl-36408189

ABSTRACT

Identifying subgroups of T-cell acute lymphoblastic leukemia (T-ALL) with poor survival will significantly influence patient treatment options and improve patient survival expectations. Current efforts to predict T-ALL survival expectations in multiple patient cohorts are lacking. A deep learning (DL)-based model was developed to determine the prognostic staging of T-ALL patients. We used transcriptome sequencing data from TARGET to build a DL-based survival model using 265 T-ALL patients. We found that patients could be divided into two subgroups (K0 and K1) with significant difference (P< 0.0001) in survival rate. The more malignant subgroup was significantly associated with some tumor-related signaling pathways, such as PI3K-Akt, cGMP-PKG and TGF-beta signaling pathway. DL-based model showed good performance in a cohort of patients from our clinical center (P = 0.0248). T-ALL patients survival was successfully predicted using a DL-based model, and we hope to apply it to clinical practice in the future.

4.
Cell Death Dis ; 11(8): 712, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32873786

ABSTRACT

Utilizing oxidative stress has recently been regarded as a potential strategy for tumor therapy. The NUAK family SNF1-like kinase 1 (NUAK1) is a critical component of the antioxidant defense system and is necessary for the survival of tumors. Therefore, NUAK1 is considered an attractive therapeutic target in cancer. However, antioxidant therapy induced elevated ROS levels to activate the Unc-51-like kinase 1 (ULK1) pathway to promote protective autophagy and ULK1-dependent mitophagy. Thus, the combined inhibition of NUAK1 and ULK1 showed a strong synergistic effect in different tumor types. Herein, the potential antitumor activities of a dual NUAK1/ULK1 inhibitor MRT68921 were evaluated in both tumor cell lines and animal models. MRT68921 significantly kills tumor cells by breaking the balance of oxidative stress signals. These results highlight the potential of MRT68921 as an effective agent for tumor therapy.


Subject(s)
Autophagy-Related Protein-1 Homolog/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Repressor Proteins/antagonists & inhibitors , Animals , Autophagy/drug effects , Autophagy-Related Protein-1 Homolog/metabolism , Cell Line, Tumor , China , Female , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Mice , Mice, Inbred BALB C , Mitophagy , Neoplasms/drug therapy , Oxidative Stress/drug effects , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Reactive Oxygen Species/metabolism , Repressor Proteins/metabolism , Xenograft Model Antitumor Assays
5.
Transl Oncol ; 13(4): 100766, 2020 Apr.
Article in English | MEDLINE | ID: mdl-32247263

ABSTRACT

GZD824 is a novel third-generation BCR-ABL inhibitor. It entered Phase II clinical trials in China and Phase Ib clinical trials in USA in 2019 for treatment of patients with resistant chronic myeloid leukemia (CML). We found that at concentrations below 10 nM, GZD824 significantly suppresses FLT3, FGFR1 and PDGFRα kinase activities and inhibits their signal pathways in MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa leukemia cells. It selectively inhibits the growth of MV4-11Flt3-ITD, KG-1FGFR1OP2-FGFR1 and EOL-1FIP1L1-PDGFRa cells, and also effectively suppresses the growth of Ba/F3-FLT3-ITD cells harboring F691I and other mutations with IC50 values <10 nM. GZD824 induces G0/G1 phase arrest and apoptosis in MV4-11, KG-1 and EOL-1 cells and activates cleavage of caspase-3 and PARP. In MV4-11, Ba/F3-ITD-F691I and KG-1 mouse xenograft models, GZD824 at 10 or 20 mg/kg, q2d, p.o. almost completely eradicates tumors. It also inhibits the viability of primary leukemic blasts from a FLT3-ITD positive AML patient but not those expressing native FLT3. Thus GZD824 suppresses leukemia cells of FLT3-ITD-driven AML and other hematologic malignancies driven by FGFR1 or PDGFRa, and it may be considered to be a novel agent for the treatment of leukemia.

7.
J Exp Clin Cancer Res ; 38(1): 211, 2019 May 22.
Article in English | MEDLINE | ID: mdl-31118055

ABSTRACT

BACKGROUND: Epidermal growth factor receptor (EGFR) and epidermal growth factor receptor pathway substrate 8 (Eps8) have been widely reported to be expressed in various tumors. Eps8 is an important active kinase substrate of EGFR that directly binds to the juxtamembrane (JXM) domain of EGFR to form an EGFR/Eps8 complex. The EGFR/Eps8 complex is involved in regulating cancer progression and might be an ideal target for antitumor therapy. This study focused on the screening of small-molecule inhibitors that target the EGFR/Eps8 complex in breast cancer and non-small cell lung cancer (NSCLC). METHODS: In silico virtual screening was used to identify small-molecule EGFR/Eps8 complex inhibitors. These compounds were screened for the inhibition of A549 and BT549 cell viability. The direct interaction between EGFR and Eps8 was measured using coimmunoprecipitation (CoIP) and JXM domain replacement assays. The antitumor effects of the inhibitors were analyzed in cancer cells and xenograft models. An acute toxicity study of EE02 was performed in a mouse model. In addition, the effect of the EE02 inhibitor on the protein expression of elements downstream of the EGFR/Eps8 complex was determined by western blotting and protein chip assays. RESULTS: In this study of nearly 390,000 compounds screened by virtual database screening, the top 29 compounds were identified as candidate small-molecule EGFR/Eps8 complex inhibitors and evaluated by using cell-based assays. The compound EE02 was identified as the best match to our selection criteria. Further investigation demonstrated that EE02 directly bound to the JXM domain of EGFR and disrupted EGFR/Eps8 complex formation. EE02 selectively suppressed growth and induced apoptosis in EGFR-positive and Eps8-positive breast cancer and NSCLC cells. More importantly, the PI3K/Akt/mTOR and MAPK/Erk pathways downstream of the EGFR/Eps8 complex were suppressed by EE02. In addition, the suppressive effect of EE02 on tumor growth in vivo was comparable to that of erlotinib at the same dose. CONCLUSIONS: We identified EE02 as an EGFR/Eps8 complex inhibitor that demonstrated promising antitumor effects in breast cancer and NSCLC. Our data suggest that the EGFR/Eps8 complex offers a novel cancer drug target.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Breast Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Multiprotein Complexes/antagonists & inhibitors , A549 Cells , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Adaptor Proteins, Signal Transducing/chemistry , Animals , Apoptosis/drug effects , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Cell Survival/drug effects , Drug Resistance, Neoplasm/drug effects , Drug Synergism , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/genetics , Erlotinib Hydrochloride/pharmacology , Female , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Multiprotein Complexes/genetics , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Small Molecule Libraries/pharmacology , Xenograft Model Antitumor Assays
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