Article

PDGFR blockade is a rational and effective therapy for NPM-ALK-driven lymphomas.

1] Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria. [2].
Nature medicine (Impact Factor: 28.05). 10/2012; DOI: 10.1038/nm.2966
Source: PubMed

ABSTRACT Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK-triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-ALK(+) ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

0 Followers
 · 
386 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.
    PLoS ONE 11/2014; 9(11):e112148. DOI:10.1371/journal.pone.0112148 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many epithelial-mesenchymal transition (EMT)-promoting transcription factors have been implicated in tumorigenesis and metastasis, as well as chemoresistance of cancer. However, the underlying mechanisms mediating these processes are unclear. Here we report that Foxq1, a forkhead box-containing transcription factor and EMT-inducing gene, promotes stemness traits and chemoresistance in mammary epithelial cells. Using an expression profiling assay, we identified Twist1, Zeb2, and PDGFRα and β as Foxq1 downstream targets. We further show that PDGFRα and β can be directly regulated by Foxq1 or indirectly regulated through the Foxq1/Twist1 axis. Knockdown of both PDGFRα and β results in more significant effects on reversing Foxq1-promoted oncogenesis in vitro and in vivo than knockdown of either PDGFRα or β alone. In addition, PDGFRβ is a more potent mediator of Foxq1-promoted stemness traits than PDGFRα. Finally, pharmacological inhibition or gene silencing of PDGFRs sensitizes mammary epithelial cells to chemotherapeutic agents in vitro and in vivo. These findings collectively implicate PDGFRs as critical mediators of breast cancer oncogenesis and chemoresistance driven by Foxq1, with potential implications for developing novel therapeutic combinations to treat breast cancer.
    Cancer Research 12/2014; Cancer Res; Published OnlineFirst December 10, 2014;(3). DOI:10.1158/0008-5472.CAN-13-3029 · 9.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Rearrangements involving the Anaplastic Lymphoma Kinase (ALK) gene are defining events in several tumors, including Anaplastic Large Cell Lymphoma (ALCL) and Non-Small Cell Lung Carcinoma (NSCLC). In such cancers, the oncogenic activity of ALK stimulates signaling pathways that induce cell transformation and promote tumor growth. In search for common pathways activated by oncogenic ALK across different tumors types, we found that hypoxia pathways were significantly enriched in ALK-rearranged ALCL and NSCLC, as compared to other types of T cell lymphoma or EGFR and K-RAS mutated NSCLC, respectively. Consistently, in both ALCL and NSCLC we found that under hypoxic conditions ALK directly regulated the abundance of Hypoxia-Inducible Factors (HIFs), which are key players of the hypoxia response in normal tissues and cancers. In ALCL, the upregulation of HIF-1α and HIF-2α in hypoxic conditions required ALK activity and its downstream signaling proteins Stat3 and C/EBPβ. In vivo, ALK regulated VEGFA production and tumor angiogenesis in ALCL and NSCLC, and the treatment with the anti-VEGFA antibody bevacizumab strongly impaired ALCL growth in mouse xenografts. Finally, HIF-2α, but not HIF-1α, was required for ALCL growth in vivo whereas the growth and metastasis potential of ALK-rearranged NSCLC required both HIF-1α and HIF-2α. In conclusion, we uncovered an ALK specific regulation of the hypoxia response across different ALK positive tumor types, and propose HIFs as a powerful specific therapeutic target in ALK-rearranged ALCL and NSCLC.
    Cancer Research 09/2014; 74(21). DOI:10.1158/0008-5472.CAN-14-0268 · 9.28 Impact Factor

Full-text

Download
89 Downloads
Available from
May 22, 2014

Daniela Laimer