Abstract 553: Antitumor efficacy of a liposomal formulation of irinotecan in preclinical gastric cancer models: Augmenting its response by antiangiogenic agents
Authors: Awasthi Niranjan , Schwarz Margaret A. , Zhang Changhua , Klinz Stephan , Meyer-Losic Florence , Beaufils Benjamin , Thiagalingam Arunthathi , Schwarz Roderich E. 
Published: September 2020

BACKGROUND: Gastric adenocarcinoma (GAC) remains the 3rd most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly a fundamental treatment for metastatic GAC that usually leads to a modest patient benefit, resulting in a 5-year survival rate of 31%. A liposomal formulation of irinotecan (nal-IRI) has shown improved pharmacokinetic and drug biodistribution compared with free irinotecan (IRI) in preclinical studies. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the therapeutic efficacy of nal-IRI in combination with nintedanib, a tyrosine kinase inhibitor targeting FGFR, PDGFR and VEGFR, and DC101, a monoclonal antibody targeting VEGFR2 in preclinical models of GAC.

METHODS: In vitro cell proliferation was evaluated in three GAC cell lines (MKN-45, KATO-III and SNU-5) by WST-1 assay. Protein expression was measured by Western blot analysis in MKN-45 cell lysates. Animal survival studies were performed using two cell lines MKN-45 and KATO-III cells in peritoneal dissemination models in NOD/SCID mice (n=5-7). Tumor growth and pharmacokinetic studies were performed in GAC cell-derived xenografts. Mechanistic evaluation included IHC and Immunoblot analysis in tumor tissues.

RESULTS: Animal survival was increased by nal-IRI (&gt;156%) and IRI (&gt;94%) therapy compared with PBS-treated controls. Importantly, nal-IRI led to a &gt;30% extension of animal survival compared with IRI. The addition of antiangiogenic agents nintedanib or DC101 led to a further improvement (range 3-40%) in animal survival caused by nal-IRI and IRI. In GAC cell-derived subcutaneous xenografts, compared to controls, nal-IRI demonstrated greater tumor growth inhibition (92%) than IRI (71%). Here, the combinations of nal-IRI or IRI with antiangiogenic agents exhibited an additive response. Ki67 staining of tumor sections revealed that nal-IRI was most effective in reducing intratumoral proliferation (by 58%), followed by IRI (39%), nintedanib (33%), and DC101 (25%). Combinations of nal-IRI or IRI with antiangiogenic agents demonstrated an additive effect in reducing tumor cell proliferation. As expected, tumor vasculature (assessed by endomucin staining) was reduced by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI showed no effect. Pharmacokinetic studies revealed that nal-IRI increased the retention, circulation time and tumor levels of IRI and its active metabolite SN-38. The addition of nintedanib or DC101 had no effect on plasma or tumor levels of IRI or SN38. In in vitro cell viability assays in mutationally different GAC cells, SN-38 had a dose-dependent growth inhibitory effect that was more pronounced than single-agent IRI. Importantly, combinations of SN-38 or IRI with antiangiogenic agents demonstrated additive effects on cell proliferation inhibition.

CONCLUSION: nal-IRI showed greater antitumor efficacy than IRI, and its antitumor effects can be enhanced by antiangiogenic agents suggesting that this combination has potential for improving clinical GAC therapy.

Citation Format: Niranjan Awasthi, Margaret A. Schwarz, Changhua Zhang, Stephan Klinz, Florence Meyer-Losic, Benjamin Beaufils, Arunthathi Thiagalingam, Roderich E. Schwarz. Antitumor efficacy of a liposomal formulation of irinotecan in preclinical gastric cancer models: Augmenting its response by antiangiogenic agents [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 553.