3 results on '"GELARDI, Teresa"'
Search Results
2. A Novel Toll-Like Receptor 9 Agonist Cooperates with Trastuzumab in Trastuzumab-Resistant Breast Tumors through Multiple Mechanisms of Action
- Author
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Ekambar R. Kandimalla, Sudhir Agrawal, Teresa Gelardi, Giampaolo Tortora, Vincenzo Damiano, Rosa Caputo, Luigi Racioppi, Corrado Garbi, Roberto Bianco, Sonia Garofalo, G. Merola, Roberta De Rosa, Damiano, Vincenzo, Bianco, Roberto, Garofalo, Sonia, Rosa, Roberta, R., Caputo, Gelardi, Teresa, G., Merola, Racioppi, Luigi, Garbi, Corrado, and Tortora, Giampaolo
- Subjects
endocrine system ,Cancer Research ,Receptor, ErbB-2 ,Oligonucleotides ,Angiogenesis Inhibitors ,Breast Neoplasms ,Pharmacology ,Antibodies, Monoclonal, Humanized ,resistance ,TLR9 ,Mice ,Breast cancer ,Trastuzumab ,HER2 ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Neoplasm Metastasis ,skin and connective tissue diseases ,neoplasms ,trastuzumab ,Mice, Inbred BALB C ,Tumor microenvironment ,biology ,business.industry ,Antibodies, Monoclonal ,Cancer ,Middle Aged ,TLR-9 ,medicine.disease ,TRASTUZUMAB RESISTANCE ,Oncology ,Mechanism of action ,Drug Resistance, Neoplasm ,Toll-Like Receptor 9 ,Cancer cell ,biology.protein ,Female ,Endothelium, Vascular ,medicine.symptom ,Signal transduction ,business ,Neoplasm Transplantation ,medicine.drug - Abstract
Purpose: Resistance to anti-HER2 monoclonal antibody trastuzumab is a relevant issue in breast cancer patients. Among the mechanisms implicated in trastuzumab resistance, increasing evidence supports a role of tumor microenvironment. We previously found that a novel toll-like receptor 9 agonist, referred to as immune modulatory oligonucleotide (IMO) and currently under clinical investigation, acts through epidermal growth factor receptor (EGFR) and shows direct antiangiogenic effects by cooperating with anti-EGFR or anti-VEGF drugs, thus interfering with cancer cells and microenvironment.Experimental Design: In this study, we used KPL-4 and JIMT-1 trastuzumab-resistant breast cancer cells to evaluate the combination IMO plus trastuzumab as a therapeutic option for trastuzumab-resistant breast cancers.Results: IMO inhibits KPL-4 and JIMT-1 xenografts growth and potentiates trastuzumab antitumor effect, with complete suppression of tumor growth, potent enhancement of trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity, and strong inhibition of EGFR/HER2-related signaling. In KPL-4 xenografts, IMO alone interferes with HER signal transduction, whereas trastuzumab is ineffective. IMO induces an HER-dependent signal inhibition also in vitro by modulating a functional interaction between toll-like receptor 9 and HER receptors occurring at membrane level. Finally, IMO plus trastuzumab produces a cooperative antiangiogenic effect related to suppression of endothelial HER-related signaling.Conclusions: We showed a cooperative effect of IMO plus trastuzumab in trastuzumab-resistant breast cancers due to IMO direct antitumor and antiangiogenic activity and antibody-dependent cell-mediated cytotoxicity enhancement. Moreover, we provided first evidence of a toll-like receptor 9/HER interaction at membrane level as novel mechanism of action. Altogether, we propose IMO plus trastuzumab as an effective strategy in trastuzumab-resistant breast cancers. (Clin Cancer Res 2009;15(22):692130)
- Published
- 2009
3. Toll-like receptor 9 agonist IMO cooperates with cetuximab in K-ras mutant colorectal and pancreatic cancers
- Author
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Roberta De Rosa, Giampaolo Tortora, Davide Melisi, Vincenzo Damiano, Roberto Bianco, Sonia Garofalo, Federica Di Nicolantonio, Alberto Bardelli, Sudhir Agrawal, Aldo Scarpa, Teresa Gelardi, Rosa, Roberta, Melisi, D, Damiano, Vincenzo, Bianco, Roberto, Garofalo, S, Gelardi, Teresa, Agrawal, S, Di Nicolantonio, F, Scarpa, A, Bardelli, A, and Tortora, G.
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Cancer Research ,Colorectal cancer ,pancreatic cancer ,Nude ,Drug Resistance ,Oligonucleotides ,Cetuximab ,Pharmacology ,drug therapy/genetics ,Mice ,Random Allocation ,0302 clinical medicine ,Monoclonal ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Epidermal growth factor receptor ,administration /&/ dosage ,ras ,EGFR inhibitors ,0303 health sciences ,Tumor ,biology ,Antibodies, Monoclonal ,TLR-9 ,cetuximab ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,medicine.drug ,endocrine system ,EGFR ,Mice, Nude ,Antibodies, Monoclonal, Humanized ,K-ra ,Antibodies ,Cell Line ,03 medical and health sciences ,Pancreatic cancer ,Cell Line, Tumor ,Animals ,Humans ,MAPK ,Toll-Like Receptor 9 ,neoplasms ,030304 developmental biology ,business.industry ,Cancer ,Animals, Antibodies ,administration /&/ dosage, Antineoplastic Combined Chemotherapy Protocols ,therapeutic use, Cell Line ,Tumor, Colorectal Neoplasms ,drug therapy/genetics, Drug Resistance ,Neoplasm ,drug effects, Genes ,ras, Humans, Mice, Mice ,Nude, Mutation, Oligonucleotides ,therapeutic use, Pancreatic Neoplasms ,drug therapy/genetics, Random Allocation, Toll-Like Receptor 9 ,agonists, Xenograft Model Antitumor Assays ,medicine.disease ,Xenograft Model Antitumor Assays ,digestive system diseases ,Pancreatic Neoplasms ,Genes, ras ,Genes ,Drug Resistance, Neoplasm ,therapeutic use ,drug effects ,Cancer cell ,Mutation ,biology.protein ,agonists ,business - Abstract
Purpose: K-Ras somatic mutations are a strong predictive biomarker for resistance to epidermal growth factor receptor (EGFR) inhibitors in patients with colorectal and pancreatic cancer. We previously showed that the novel Toll-like receptor 9 (TLR9) agonist immunomodulatory oligonucleotide (IMO) has a strong in vivo activity in colorectal cancer models by interfering with EGFR-related signaling and synergizing with the anti-EGFR monoclonal antibody cetuximab. Experimental Design: In the present study, we investigated, both in vitro and in vivo, the antitumor effect of IMO alone or in combination with cetuximab in subcutaneous colon and orthotopic pancreatic cancer models harboring K-Ras mutations and resistance to EGFR inhibitors. Results: We showed that IMO was able to significantly restore the sensitivity of K-Ras mutant cancer cells to cetuximab, producing a marked inhibition of cell survival and a complete suppression of mitogen—activated protein kinase phosphorylation, when used in combination with cetuximab. IMO interfered with EGFR-dependent signaling, modulating the functional interaction between TLR9 and EGFR. In vivo, IMO plus cetuximab combination caused a potent and long-lasting cooperative antitumor activity in LS174T colorectal cancer and in orthotopic AsPC1 pancreatic cancer. The capability of IMO to restore cetuximab sensitivity was further confirmed by using K-Ras mutant colorectal cancer cell models obtained through homologous recombination technology. Conclusions: We showed that IMO markedly inhibits growth of K-Ras mutant colon and pancreatic cancers in vitro and in nude mice and cooperates with cetuximab via multiple mechanisms of action. Therefore, we propose IMO plus cetuximab as a therapeutic strategy for K-Ras wild-type as well for K-Ras mutant, cetuximab-resistant colorectal and pancreatic cancers. Clin Cancer Res; 17(20); 6531–41. ©2011 AACR.
- Published
- 2011
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