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Clinical Efficacy and Tumor Microenvironment Influence in a Dose-Escalation Study of Anti-CD19 Chimeric Antigen Receptor T Cells in Refractory B-Cell Non-Hodgkin's Lymphoma

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (23)

Purpose: Anti-CD19 chimeric antigen receptor (CAR) T cells represent a novel immunotherapy and are highly effective in treating relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). How tumor microenvironment influences clinical response to CAR T therapy remains of great interest. Patients and Methods: A phase I, first-in-human, dose-escalation study of anti-CD19 JWCAR029 was conducted in refractory B-NHL (NCT03355859) and 10 patients received CAR T cells at an escalating dose of 2.5 x 10(7) (n = 3), 5 x 10(7) (n = 4), and 1 x 10(8) (n = 3) cells. Core needle biopsy was performed on tumor samples collected from diffuse large B-cell lymphoma patients on Day -6 (1 day before lymphodepletion) and on Day 11 after CAR T-cell infusion when adequate CAR T-cell expansion was detected. Results: The overall response rate was 100%, with 6 of 9 (66.7%) evaluable patients achieving complete remission. The most common adverse events of grade 3 or higher were neutropenia (10/10, 100%), anemia (3/10, 30%), thrombocytopenia (3/10, 30%), and hypofibrinogenemia (2/10, 20%). Grade 1 cytokine release syndrome occurred in all patients and grade 3 neurotoxicity in 1 patient. The average peak levels of peripheral blood CAR T cells and cytokines were similar in 3 different dose levels, but CAR T cells were significantly higher in patients achieved complete remission on Day 29. Meanwhile, RNA sequencing identified gene expression signatures differentially enriched in complete and partial remission patients. Increased tumor-associated macrophage infiltration was negatively associated with remission status. Conclusions: JWCAR029 was effective and safe in treating refractory B-NHL. The composition of the tumor microenvironment has a potential impact in CAR T therapy response.

IF:8.91

Parallel Analyses of Somatic Mutations in Plasma Circulating Tumor DNA (ctDNA) and Matched Tumor Tissues in Early-Stage Breast Cancer

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (21)

Purpose: Early detection and intervention can decrease the mortality of breast cancer significantly. Assessments of genetic/genomic variants in circulating tumor DNA (ctDNA) have generated great enthusiasm for their potential application as clinically actionable biomarkers in the management of early-stage breast cancer. Experimental Design: In this study, 861 serial plasma and matched tissue specimens from 102 patients with early-stage breast cancer who need chemotherapy and 50 individuals with benign breast tumors were deeply sequenced via next-generation sequencing (NGS) techniques using large gene panels. Results: Cancer tissues in this cohort of patients showed profound intratumor heterogeneities (ITHGs) that were properly reflected by ctDNA testing. Integrating the ctDNA detection rate of 74.2% in this cohort with the corresponding predictive results based on Breast Imaging Reporting and Data System classification (BI-RADS) could increase the positive predictive value up to 92% and potentially dramatically reduce surgical overtreatment. Patients with positive ctDNA after surgery showed a higher percentage of lymph node metastasis, indicating potential recurrence and remote metastasis. The ctDNA-positive rates were significantly decreased after chemotherapy in basal-like and Her2(+) tumor subtypes, but were persistent despite chemotherapy in luminal type. The tumor mutation burden in blood (bTMB) assessed on the basis of ctDNA testing was positively correlated with the TMB in tumor tissues (tTMB), providing a candidate biomarker warranting further study of its potentials used for precise immunotherapy in cancer. Conclusions: These data showed that ctDNA evaluation is a feasible, sensitive, and specific biomarker for diagnosis and differential diagnosis of patients with early-stage breast cancer who need chemotherapy.

IF:8.91

Plasma Exchange Can Be an Alternative Therapeutic Modality for Severe Cytokine Release Syndrome after Chimeric Antigen Receptor-T Cell Infusion: A Case Report

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (1)

Background: Tumor immunotherapy with chimeric antigen receptor-T cells (CAR-T) is a promising new treatment for B-cell malignancies and has produced exciting results. However, cytokine release syndrome (CRS) is the most significant toxicity associated with this treatment and can be life-threatening. Case Presentation: A 23-year-old male patient had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia. The patient was recruited into our CAR-T clinical trial, and 1 x 10(6)/kg of engineered anti-CD19 CART cells was administered. After infusion of CAR-T cells (day 0), the patient underwent a typical CRS reaction, with increases in fever, muscle soreness, and inflammatory cytokines. He was treated with antiallergic and antipyretic drugs, glucocorticoids, and tocilizumab (4 mg/kg, days 3 and 5). However, CRS was not under control, and his condition rapidly deteriorated. He was transferred to the intensive care unit, where dexamethasone 10 mg q6h was administered, and plasma exchange was performed, with 3,000 mL of plasma replaced by fresh frozen plasma per day for 3 consecutive days. His symptoms gradually improved, and the CRS-related symptoms were relieved. Additionally, a bone marrow smear showed no lymphoblast cells, and minimal residual disease was negative on day 28. The patient was eventually discharged in a normal condition. Conclusions: CRS is caused by an exaggerated systemic immune response, potentially resulting in organ damage that can be fatal. Although therapeutic plasma exchange is not included in CRS management guidelines, this case shows that plasma exchange is feasible in at least some patients with severe CRS.

IF:8.91

Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-kappa B Signaling

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (22)

Purpose: Long noncoding RNAs (lncRNA) have essential roles in diverse cellular processes, both in normal and diseased cell types, and thus have emerged as potential therapeutic targets. Aspecific member of this family, the SWI/SNF complex antagonist associated with prostate cancer 1 (SChLAP1), has been shown to promote aggressive prostate cancer growth by antagonizing the SWI/SNF complex and therefore serves as a biomarker for poor prognosis. Here, we investigated whether SChLAP1 plays a potential role in the development of human glioblastoma (GBM). Experimental Design: RNA-ISH and IHC were performed on a tissue microarray to assess expression of SChLAP1 and associated proteins in human gliomas. Proteins complexed with SChLAP1 were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis in vitro and in vivo. Results: SChLAP1 was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. SChLAP1 was found to bind heterogeneous nuclear ribonucleoprotein L (HNRNPL), which stabilized the lncRNA and led to an enhanced interaction with the protein actinin alpha 4 (ACTN4). ACTN4 was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The SChLAP1-HNRNPL complex led to stabilization of ACTN4 through suppression of proteasomal degradation, which resulted in increased nuclear localization of the p65 subunit of NF-kappa B and activation of NF-kappa B signaling, a pathway associated with cancer development. Conclusions: Our results implicated SChLAP1 as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.

IF:8.91

TFEB Mediates Immune Evasion and Resistance to mTOR Inhibition of Renal Cell Carcinoma via Induction of PD-L1

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (22)

Purpose: Despite the FDA approval of mTOR inhibitors (mTORi) for the treatment of renal cell carcinoma (RCC), the benefits are relatively modest and the few responders usually develop resistance. We investigated whether the resistance to mTORi is due to upregulation of PD-L1 and the underlying molecular mechanism. Experimental Design: The effects of transcription factor EB (TFEB) on RCC proliferation, apoptosis, and migration were evaluated. Correlation of TFEB with PD-L1 expression, as well as effects of mTOR inhibition on TFEB and PD-L1 expression, was assessed in human primary clear cell RCCs. The regulation of TFEB on PD-L1 was assessed by chromatin immunoprecipitation and luciferase reporter assay. The therapeutic efficacies of mTORi plus PD-L1 blockade were evaluated in a mouse model. The function of tumor-infiltrating CD8(+) T cells was analyzed by flow cytometry. Results: TFEB did not affect tumor cell proliferation, apoptosis, and migration. We found a positive correlation between TFEB and PD- L1 expression in RCC tumor tissues, primary tumor cells, and RCC cells. TFEB bound to PD-L1 promoter in RCCs and inhibition of mTOR led to enhanced TFEB nuclear translocation and PD-L1 expression. Simultaneous inhibition of mTOR and blockade of PD- L1 enhanced CD8(+) cytolytic function and tumor suppression in a xenografted mouse model of RCC. Conclusions: These data revealed that TFEB mediates resistance to mTOR inhibition via induction of PD-L1 in human primary RCC tumors, RCC cells, and murine xenograft model. Our data provide a strong rationale to target mTOR and PD-L1 jointly as a novel immunotherapeutic approach for RCC treatment.

IF:8.91

Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (2)

Purpose: This study assessed the safety and efficacy of SHR-1210 (anti-PD-1 antibody) and apatinib (VEGFR2 inhibitor) as combination therapy in patients with advanced hepatocellular carcinoma (HCC), gastric, or esophagogastric junction cancer (GC/EGJC). Patients and Methods: This was an open-label, dose-escalation (phase Ia) and expansion study (phase Ib). In phase Ia, patients (n = 15) received SHR-1210 200 mg every 2 weeks and apatinib 125-500 mg once daily until unacceptable toxicity or disease progression. In phase Ib, patients (n = 28) received apatinib at the phase Ia-identified recommended phase II dose (RP2D) plus SHR-1210. The primary objectives were safety and tolerability and RP2D determination. Results: At data cutoff, 43 patients were enrolled. In phase Ia, four dose-limiting toxicity events were observed (26.7%): one grade 3 lipase elevation (6.7%) in the apatinib 250 mg cohort and three grade 3 pneumonitis events (20%) in the apatinib 500 mg cohort. The maximum tolerated RP2D for apatinib was 250 mg. Of the 33 patients treated with the R2PD combination, 20 (60.6%) experienced a grade >= 3 treatment-related adverse event; adverse events in >= 10% of patients were hypertension (15.2%) and increased aspartate aminotransferase (15.2%). The objective response rate in 39 evaluable patients was 30.8% (95% CI: 17.0%-47.6%). Eight of 16 evaluable HCC patients achieved a partial response (50.0%, 95% CI: 24.7%-75.4%). Conclusions: SHR-1210 and apatinib combination therapy demonstrated manageable toxicity in patients with HCC and GC./EGJC at recommended single-agent doses of both drugs. The RP2D for apatinib as combination therapy was 250 mg, which showed encouraging clinical activity in patients with advanced HCC.

IF:8.91

Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/beta-catenin/CBP signaling

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (3)

Purpose: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC). Experimental Design: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/beta-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. Themechanism by which RBMS3 loss sustained activation of miR-126-5p/beta-catenin/CBP signaling and the effects of RBMS3 and miR126- 5p competitively regulatingDKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays. Results: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited beta-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/beta-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy. Conclusions: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.

IF:8.91

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (4)

Purpose: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs. Experimental Design: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain-and loss-of-function assays in vitro and in vivo. Results: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. Conclusions: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.

IF:8.91

Cancer-associated Fibroblast-promoted LncRNA DNM3OS Confers Radioresistance by Regulating DNA Damage Response in Esophageal Squamous Cell Carcinoma

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (6)

Purpose: Our study aimed to investigate whether CAF (cancer-associated fibroblasts) were involved in long noncoding RNAs (lncRNA)-regulated radioresponse in esophageal squamous cell carcinoma (ESCC). Experimental Design: By use of lncRNAs PCR array, 38 lncRNAs were screened in esophageal cancer cells and in normal esophageal epithelial cells Het-1A. LncRNA DNM3OS was detected in tumor tissues of patients with ESCC and in matched normal esophageal epithelial tissues by qRT-PCR analysis and in situ hybridization assay. The association of DNM3OS and tumor radioresistance was investigated in vitro and in vivo. The influences of DNM3OS on DNA damage response (DDR) was investigated by Western blotting, immunofluorescence imaging, and comet assay. The mechanisms by which CAFs promoted DNM3OS expression was investigated by kinase inhibitors' screening, luciferase assay, and chromatin immunoprecipitation. Results: Among the 38 lncRNAs tested, DNM3OS was found to have a much higher expression level in esophageal cancer cells than in Het-1A. In tumor tissues of 16 patients with ESCC, the expression level of DNM3OS showed an average increase of 6.3429-fold compared with that in matched normal tissues. DNM3OS conferred significant radioresistance in vitro and in vivo by regulating DDR. CAFs promoted the expression of DNM3OS with a 39.2554-fold and 38.3163-fold increase in KYSE-30 and KYSE-140, respectively. CAFs promoted the expression of DNM3OS in a PDGF beta/PDGFR beta/FOXO1 signaling pathway-dependent manner. FOXO1, a transcription factor downstream of PDGF beta/PDGFR beta signaling pathway, initiated the transcription of DNM3OS by binding to DNM3OS promoter. Conclusions: Our study highlighted CAF-promoted DNM3OS as an attractive target to reverse tumor radioresistance in ESCC.

IF:8.91

Tumor-Contacted Neutrophils Promote Metastasis by a CD90-TIMP-1 Juxtacrine-Paracrine Loop

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (6)

Purpose: The different prognostic values of tumor-infiltrating neutrophils (TIN) in different tissue compartments are unknown. In this study, we investigated their different prognostic roles and the underlying mechanism. Experimental Design: We evaluated CD66b(+) neutrophils in primary tumors from 341 patients with breast cancer from Sun Yat-sen Memorial Hospital by IHC. The association between stromal and parenchymal neutrophil counts and clinical outcomes was assessed in a training set (170 samples), validated in an internal validation set (171 samples), and further confirmed in an external validation set (105 samples). In addition, we isolated TINs from clinical samples and screened the cytokine profile by antibody microarray. The interaction between neutrophils and tumor cells was investigated in transwell and 3D Matrigel coculture systems. The therapeutic potential of indicated cytokines was evaluated in tumor-bearing immunocompetent mice. Results: We observed that the neutrophils in tumor parenchyma, rather than those in stroma, were an independent poor prognostic factor in the training [ HR = 5.00, 95% confidence interval (CI): 2.88-8.68, P < 0.001], internal validation (HR = 3.56, 95% CI: 2.07-6.14, P < 0.001), and external validation set (HR = 5.07, 95% CI: 2.27-11.33, P < 0.001). The mechanistic study revealed that neutrophils induced breast cancer epithelial-mesenchymal transition (EMT) via tissue inhibitor of matrix metalloprotease (TIMP-1). Reciprocally, breast cancer cells undergoing EMT enhanced neutrophils' TIMP-1 secretion by CD90 in a cell-contact manner. In vivo, TIMP-1 neutralization or CD90 blockade significantly reduced metastasis. More importantly, TIMP-1 and CD90 were positively correlated in breast cancer (r(2) = 0.6079; P < 0.001) and associated with poor prognosis of patients. Conclusions: Our findings unravel a location-dictated interaction between tumor cells and neutrophils and provide a rationale for new antimetastasis treatments.

IF:8.91

Neutrophil Extracellular Traps Induced by IL8 Promote Diffuse Large B-cell Lymphoma Progression via the TLR9 Signaling

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (6)

Purpose: More than 30% of patients with diffuse large B-cell lymphoma (DLBCL) experience treatment failure after first-line therapy. Neutrophil extracellular traps (NETs), a pathogen-trapping structure in tumor microenvironment, can promote the transition of autoimmunity to lymphomagenesis. Here, we investigate whether NETs play a novel role in DLBCL progression and its underlying mechanism. Experimental Design: NETs in DLBCL tumor samples and plasma were detected by immunofluorescence and ELISA, respectively. The correlation between NETs and clinical features were analyzed. The effects of NETs on cellular proliferation and migration and mechanisms were explored, and the mechanism of NET formation was also studied by a series of in vitro and in vivo assays. Results: Higher levels of NETs in plasma and tumor tissues were associated with dismal outcome in patients with DLBCL. Furthermore, we identified NETs increased cell proliferation and migration in vitro and tumor growth and lymph node dissemination in vivo. Mechanistically, DLBCL-derived IL8 interacted with its receptor (CXCR2) on neutrophils, resulting in the formation of NETs via Src, p38, and ERK signaling. Newly formed NETs directly upregulated the Toll-like receptor 9 (TLR9) pathways in DLBCL and subsequently activated NFkB, STAT3, and p38 pathways to promote tumor progression. More importantly, disruption of NETs, blocking IL8-CXCR2 axis or inhibiting TLR9 could retard tumor progression in preclinical models. Conclusions: Our data reveal a tumor-NETs aggressive interaction in DLBCL and indicate that NETs is a useful prognostic biomarker and targeting this novel cross-talk represents a new therapeutic opportunity in this challenging disease.

IF:8.91

PRMT5-mediated H4R3sme2 Confers Cell Differentiation in Pediatric B-cell Precursor Acute Lymphoblastic Leukemia

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (8)

Purpose: Little is known about the function of histone arginine methylation in acute lymphoblastic leukemia (ALL). The objective was to evaluate whether protein arginine methyltransferase 5 (PRMT5) plays a role in pediatric ALL and to determine the possible mechanism of epigenetic regulation. Experimental Design: We used bone marrow samples from patients with pediatric ALL, the Nalm6 cell line, mature B-cell lines, and mouse xenograft models to evaluate the function of PRMT5 in ALL tumorigenesis. Results: This study showed that PRMT5 and the symmetric dimethylation of H4R3 (H4R3sme2) were upregulated in most initially diagnosed (n = 15; 100%) and relapsed (n = 4; 75%) bone marrow leukemia cells from patients with pediatric B-cell precursor ALL (BCP-ALL) and were decreased when the disease was in remission (n = 15; 6.7%). Down-regulation of H4R3sme2 by PRMT5 silencing induced BCP-ALL cell differentiation from the pre-B to immature B stage, whereas overexpressed PRMT5 with enhanced H4R3sme2 promoted human mature B cells to dedifferentiate back to the pre-B II/immature B stages in vitro. High PRMT5 expression enhanced the proportion of CD43(+)/B220(+)/sIgM(-) B leukocytes in recipient mice. CLC and CTSB were identified as potential target genes of PRMT5 in BCP-ALL cells and were inhibited by H4R3sme2 in gene promoters. Conclusions: We demonstrate that enhanced PRMT5 promotes BCP-ALL leukemogenesis partially by the dysregulation of B-cell lineage differentiation. H4R3sme2 and PRMT5 may serve as potential sensitive biomarkers of pediatric BCP-ALL. Suppression of the activation of PRMT5 may offer a promising therapeutic strategy against pediatric BCP-ALL.

IF:8.91

Depression-Induced Neuropeptide Y Secretion Promotes Prostate Cancer Growth by Recruiting Myeloid Cells

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (8)

Purpose: Psychologic depression has been shown to dysregulate the immune system and promote tumor progression. The aim of this study is to investigate how psychologic depression alters the immune profiles in prostate cancer. Experimental Design: We used a murine model of depression in Myc-CaP tumor-bearing immunocompetent FVB mice and Hi-myc mice presenting with spontaneous prostate cancer. Transwell migration and coculture assays were used to evaluate myeloid cell trafficking and cytokine profile changes evoked by Myc-CaP cells that had been treated with norepinephrine (NE), a major elevated neurotransmitter in depression. Chemoattractant, which correlated with immune cell infiltration, was screened by RNA-seq. The chemoattractant and immune cell infiltration were further confirmed using clinical samples of patients with prostate cancer with a high score of psychologic depression. Results: Psychologic depression predominantly promoted tumor-associated macrophage (TAM) intratumor infiltrations, which resulted from spleen and circulating monocytic myeloid-derived suppressor cell mobilization. Neuropeptide Y (NPY) released from NE-treated Myc-CaP cells promotes macrophage trafficking and IL6 releasing, which activates STAT3 signaling pathway in prostate cancer cells. Clinical specimens from patients with prostate cancer with higher score of depression revealed higher CD68(+) TAM infiltration and stronger NPY and IL6 expression. Conclusions: Depression promotes myeloid cell infiltration and increases IL6 levels by a sympathetic-NPY signal. Sympathetic-NPY inhibition may be a promising strategy for patients with prostate cancer with high score of psychologic depression.

IF:8.91

EGFR/Notch Antagonists Enhance the Response to Inhibitors of the PI3K-Akt Pathway by Decreasing Tumor-Initiating Cell Frequency

期刊: CLINICAL CANCER RESEARCH, 2019; 25 (9)

Purpose: Both EGFR and PI3K-Akt signaling pathways have been used as therapeutically actionable targets, but resistance is frequently reported. In this report, we show that enrichment of the cancer stem cell (CSC) subsets and dysregulation of Notch signaling underlie the challenges to therapy and describe the development of bispecific antibodies targeting both HER and Notch signaling. Experimental Design: We utilized cell-based models to study Notch signaling in drug-induced CSC expansion. Both cancer cell line models and patient-derived xenograft tumors were used to evaluate the antitumor effects of bispecific antibodies. Cell assays, flow cytometry, qPCR, and in vivo serial transplantation assays were employed to investigate the mechanisms of action and pharmacodynamic readouts. Results: We found that EGFR/Notch targeting bispecific antibodies exhibited a notable antistem cell effect in both in vitro and in vivo assays. Bispecific antibodies delayed the occurrence of acquired resistance to EGFR inhibitors in triple-negative breast cancer cell line-based models and showed efficacy in patient-derived xenografts. Moreover, the EGFR/Notch bispecific antibody PTG12 in combination with GDC-0941 exerted a stronger antitumor effect than the combined therapy of PI3K inhibitor with EGFR inhibitors or tarextumab in a broad spectrum of epithelial tumors. Mechanistically, bispecific antibody treatment inhibits the stem cell-like sub-population, reduces tumor-initiating cell frequency, and downregulates the mesenchymal gene expression. Conclusions: These findings suggest that the coblockade of EGFR and Notch signaling has the potential to increase the response to PI3K inhibition, and PTG12 may gain clinical efficacy when combined with PI3K blockage in cancer treatment.

IF:8.91

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