Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy

Abstract

Gastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared to IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.

Enhancing gastric cancer conventional chemotherapy effects by triple angiokinase inhibitor nintedanib in preclinical models

“…Peritoneal metastasis is the most frequent form of metastasis in advanced GAC, and it is associated with poor prognosis ( 37 , 38 ). We established two peritoneal dissemination xenograft models using human MKN-45 cells and KATO-III cells that closely resemble the clinical GAC progression pattern ( 39 ). Nintedanib exhibited noticeable improvement in animal survival in these two models, which was much higher in KATO-III xenografts compared with MKN-45 xenografts.…”

“…Consistent with our findings, a meta-analysis of randomized controlled trials showed significantly improved survival and anti-tumor activity with the combination of multitarget antiangiogenic agents and taxane-containing chemotherapy in advanced NSCLC ( 42 ). Further, the combination of irinotecan with multitarget antiangiogenic drugs has been shown to have a synergistic antitumor response in gastric cancer and colorectal cancer models ( 39 , 43 ).…”

Nab-Paclitaxel in the Treatment of Gastrointestinal Cancers—Improvements in Clinical Efficacy and Safety

“…The median OS of GAC patients receiving secondline therapy ranges from 3.6 to 10.9 months [112,129,130]. In GAC preclinical models, Awasthi et al recently demonstrated that nab-paclitaxel and liposomal irinotecan (nal-IRI) have higher anti-tumor efficacy than their solvent-based formulations [131][132][133][134][135]. Due to the low response rates of current standard therapies, and the development of chemoresistance and toxicity [136], several clinical studies evaluated nab-paclitaxel in GAC (Table 2).…”