Abstract 3289: Microenvironment modulation and enhancement of cytotoxic therapy by the heparanase inhibitor Roneparstat against human B-non Hodgkin lymphomas

Abstract Background: The standard chemotherapy treatment for Non-Hodgkin lymphoma (NHL) consists in the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Because of the relevant treatment-related toxicity and the minor therapeutic effectiveness of CHOP therapy variants, the development of novel therapeutic approaches represents an urgent clinical need. Despite treatment with the anti-CD20 monoclonal antibody Rituximab and CHOP has led to favourable results for CD20+ lymphoma, many patients experienced drug resistance. Based on studies indicating that the malignant behaviour of tumors depends on the interactions between tumor and its microenvironment, we tested…

HSPH1 inhibition downregulates Bcl-6 and c-Myc and hampers the growth of human aggressive B-cell non-Hodgkin lymphoma

We have shown that human B-cell non-Hodgkin lymphomas (B-NHLs) express heat shock protein (HSP)H1/105 in function of their aggressiveness. Here, we now clarify its role as a functional B-NHL target by testing the hypothesis that it promotes the stabilization of key lymphoma oncoproteins. HSPH1 silencing in 4 models of aggressive B-NHLs was paralleled by Bcl-6 and c-Myc downregulation. In vitro and in vivo analysis of HSPH1-silenced Namalwa cells showed that this effect was associated with a significant growth delay and the loss of tumorigenicity when 10(4) cells were injected into mice. Interestingly, we found that HSPH1 physically interacts with c-Myc and Bcl-6 in both Namalwa cells and pr…

A novel CXCR4 antagonist counteracts paradoxical generation of cisplatin-induced pro-metastatic niches in lung cancer.

Platinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite experimental evidence of its potential to induce long-term detrimental effects, including the promotion of pro-metastatic microenvironments. In this study, we investigated the interconnected pathways underlying the promotion of cisplatin-induced metastases. In tumor-free mice, cisplatin treatment resulted in an expansion in the bone marrow of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IMs) and an increase in lung levels of stromal SDF-1, the CXCR4 ligand. In experimental lung metastasis assays, cisplatin-induced IMs promoted the extravasation of tumor cells and the expansion of CD133+CXCR…

Anti-tumor activity of CpG-ODN aerosol in mouse lung metastases

Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-γ and IL-1β and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD4+ cells in lung and was more efficacious tha…

Pleiotropic antitumor effects of the pan-HDAC inhibitor ITF2357 against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas

Histone deacetylases (HDAC) extensively contribute to the c-Myc oncogenic program, pointing to their inhibition as an effective strategy against c-Myc-overexpressing cancers. We, thus, studied the therapeutic activity of the new-generation pan-HDAC inhibitor ITF2357 (Givinostat®) against c-Myc-overexpressing human B-cell non-Hodgkin lymphomas (B-NHLs). ITF2357 anti-proliferative and pro-apoptotic effects were analyzed in B-NHL cell lines with c-Myc translocations (Namalwa, Raji and DOHH-2), stabilizing mutations (Raji) or post-transcriptional alterations (SU-DHL-4) in relationship to c-Myc modulation. ITF2357 significantly delayed the in vitro growth of all B-NHL cell lines by inducing G1 c…

Serological identification of HSP105 as a novel non-Hodgkin lymphoma therapeutic target.

Abstract We reported that the clinical efficacy of dendritic cell–based vaccination is strongly associated with immunologic responses in relapsed B-cell non-Hodgkin lymphoma (B-NHL) patients. We have now investigated whether postvaccination antibodies from responders recognize novel shared NHL-restricted antigens. Immunohistochemistry and flow cytometry showed that they cross-react with allogeneic B-NHLs at significantly higher levels than their matched prevaccination samples or nonresponders' antibodies. Western blot analysis of DOHH-2 lymphoma proteome revealed a sharp band migrating at approximately 100 to 110 kDa only with postvaccine repertoires from responders. Mass spectrometry ident…

PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells

Triple negative breast cancer (TNBC) is a very aggressive subgroup of breast carcinoma, still lacking specific markers for an effective targeted therapy and with a poorer prognosis compared to other breast cancer subtypes. In this study we investigated the possibility that TNBC cells contribute to the establishment of tumor vascular network by the process known as vasculogenic mimicry, through endothelial cell differentiation. Vascular-like functional properties of breast cancer cell lines were investigated in vitro by tube formation assay and in vivo by confocal microscopy, immunofluorescence or immunohistochemistry on frozen tumor sections. TNBCs express endothelial markers and acquire th…

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

Abstract Background To explore the activity of pazopanib in solitary fibrous tumour (SFT). Patients and methods In a preclinical study, we compared the activity of pazopanib, sorafenib, sunitinib, regorafenib, axitinib and bevacizumab in a dedifferentiated-SFT (DSFT) xenotransplanted into Severe Combined Immunodeficiency (SCID) mice. Antiangiogenics were administered at their reported optimal doses when mean tumour volume (TV) was 80 mm3. Drug activity was assessed as TV inhibition percentage (TVI%). From May 2012, six consecutive patients with advanced SFT received pazopanib, on a national name-based programme. In one case sunitinib was administered after pazopanib failure. Results In the …

Poly(I:C) and CpG-ODN combined aerosolization to treat lung metastases and counter the immunosuppressive microenvironment.

The immunostimulatory ability of synthetic oligonucleotides containing CpG motifs (CpG-ODN), agonists of Toll-like receptor 9 (TLR9), can be harnessed to promote antitumor immunity by their application at the tumor site to stimulate local activation of innate immunity; however, particularly in the lung, tumor-associated immunosuppression can subvert such antitumor innate immune responses. To locally maintain continuous activation of innate subpopulations while inhibiting immunosuppressive cells, we evaluated aerosol delivery CpG-ODN combined with Poly(I:C), a TLR3 agonist able to convert tumor-supporting macrophages to tumoricidal effectors, in the treatment of B16 melanoma lung metastases …

Microenvironment modulation and enhancement of antilymphoma therapy by the heparanase inhibitor roneparstat

SDF-1/CXCR4 inhibition prevents paradoxical generation of cisplatin-induced pro-metastatic niches

AbstractPlatinum-based chemotherapy remains widely used in advanced non-small cell lung cancer (NSCLC) despite its ineffectiveness in long-term control of metastasis.Here, we uncover the interconnected pathways subtending cisplatin-induced metastasis promotion.We report that cisplatin treatment of tumor-free mice results in bone-marrow expansion of CCR2+CXCR4+Ly6Chigh inflammatory monocytes (IM) concomitantly with increased levels in the lungs of stromal SDF-1, the CXCR4 ligand. In experimental metastasis assays, cisplatin-induced IM favor tumor cells extravasation and expansion of CD133+CXCR4+ metastasis initiating cells (MICs), facilitating lung metastasis formation. At the primary tumor,…