The novel PI3K-δ inhibitor TGR-1202 enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest

Locatelli, Silvia L.; Careddu, Giuseppa; Inghirami, Giorgio; Castagna, Luca; Sportelli, Peter; Santoro, Armando; Carlo‐Stella, Carmelo

doi:10.1038/leu.2016.224

Cited by 14 publications

(8 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, recent data in solid tumors show that PI3Kg signaling regulates the switch between macrophage polarization and that selectively targeting the g isoform of PI3K in TAMs inhibited their immunosuppressive phenotype resulting in tumor regression (16,17). Our previous finding on the antilymphoma efficacy of the PI3Kd inhibitor TGR-1202 also highlighted the potential of targeting the d isoform of PI3K in Hodgkin lymphoma (13). Thus, our current work confirmed and expanded these observations by using a dual PI3Kd/g inhibitor.…”

Section: Discussionsupporting

confidence: 83%

“…The d isoform of PI3K is highly expressed in tissues of hematopoietic origin and is involved in the activation, proliferation, survival, homing, and retention of B-cells in lymphoid tissues (10). Idelalisib is the first PI3Kd inhibitor to be approved for follicular lymphoma and chronic lymphocytic leukemia (11,12), and we previously reported that PI3Kd isoform inhibition results in direct Hodgkin lymphoma cell killing (13). The PI3Kg isoform, although highly expressed in leukocytes, may play a more crucial role in the immune system than that in oncogenesis (10).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Locatelli

Careddu

Serio

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the d and g isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kd/g inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Experimental Design: Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. Results: In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kd/g-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%-76%). Conclusions: Our results support PI3Kd/g inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Locatelli

Careddu

Serio

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Recent evidences revealing that germinal center B-cells (GCB cells) are the cellular origin of HRS cells [294], and the facts that PRMT5 is upregulated by B-cell receptor signaling and forms a positive-feedback loop with PI3K/AKT in both activated B cell-like (ABC) and GCB cells of diffuse large B cell lymphoma (DLBCL) [297] suggest that PI3K/AKT may promote lymphomagenesis of GCB cells in HL, which is a remarkable coincidence with the other evidences that the PI3K/AKT pathway plays a pathogenetic role in HL [298,299]. Thus, novel therapeutic options targeted PI3K/AKT pathway promote apoptosis or cell death, as well as regulate tumor microenvironment (TME) of HL cells in preclinical studies [300][301][302], and patients may get beneficial strategy in clinical trials of PI3K/AKT inhibitors (Tables 2 and 3).…”

Section: Description Of the Pi3k/akt Pathway In The Hemato-immune Sysmentioning

confidence: 91%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

View full text Add to dashboard Cite

Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

show abstract

“…INPP5, a PI3K inhibitor, is silenced in HL cells, 56 PI3K activation has been implicated in the development of resistance to brentuximab vedotin, while inhibition of PI3K by TGR-1202 increases the efficacy of the drug by promoting mitotic arrest. 57 STAT proteins are activated in RS and Hodgkin cells. 58 and are essential for their survival and proliferation.…”

Section: Mechanisms Involved In the Development Of Refractory And Relmentioning

confidence: 99%

Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin’s lymphoma with an emphasis on targeted therapies and transplantation strategies

Karantanos

Politikos

Boussiotis

2017

BLCTT

View full text Add to dashboard Cite

Hodgkin’s lymphoma (HL) is highly curable with first-line therapy. However, a minority of patients present with refractory disease or experience relapse after completion of frontline treatment. These patients are treated with salvage chemotherapy followed by autologous stem cell transplantation (ASCT), which remains the standard of care with curative potential for refractory or relapsed HL. Nevertheless, a significant percentage of such patients will progress after ASCT, and allogeneic hematopoietic stem cell transplantation remains the only curative approach in that setting. Recent advances in the pathophysiology of refractory or relapsed HL have provided the rationale for the development of novel targeted therapies with potent anti-HL activity and favorable toxicity profile, in contrast to cytotoxic chemotherapy. Brentuximab vedotin and programmed cell death-1-based immunotherapy have proven efficacy in the management of refractory or relapsed HL, whereas several other agents have shown promise in early clinical trials. Several of these agents are being incorporated with transplantation strategies in order to improve the outcomes of refractory or relapsed HL. In this review we summarize the current knowledge regarding the mechanisms responsible for the development of refractory/relapsed HL and the outcomes with current treatment strategies, with an emphasis on targeted therapies and hematopoietic stem cell transplantation.

show abstract

The novel PI3K-δ inhibitor TGR-1202 enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest

Cited by 14 publications

References 14 publications

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin’s lymphoma with an emphasis on targeted therapies and transplantation strategies

Contact Info

Product

Resources

About

The novel PI3K-δ inhibitor TGR-1202 enhances Brentuximab Vedotin-induced Hodgkin lymphoma cell death via mitotic arrest

Cited by 14 publications

References 14 publications

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin&rsquo;s lymphoma with an emphasis on targeted therapies and transplantation strategies

Contact Info

Product

Resources

About

Advances in the pathophysiology and treatment of relapsed/refractory Hodgkin’s lymphoma with an emphasis on targeted therapies and transplantation strategies