Project description:Netrin-1 is up-regulated in a large fraction of human cancers as a pro-tumoralmechanism. Therefore, a phase I trial assessing netrin-1 blockade using an anti- netrin-1 monoclonal antibody (NP137) in patients with advanced solid cancer is ongoing. We analyzed here the potential implication of netrin-1 in endometrial carcinoma. We show that netrin-1 is up-regulated in the vast majority of human endometrial carcinomas, and demonstrate that NP137 treatment is effective in reducing tumor progression in preclinical mouse models of endometrial carcinoma. We report here a confirmed objective response in a patient with endometrial carcinoma (EC) treated in monotherapy with NP137. A 51.16% reduction of target lesions at 6 weeks and up to 54.65% reduction during the next 6 months of NP137 treatment was observed for a 74 years old woman. To evaluate the mechanism of action of the anti-netrin-1 mAb, we performed gene profiling of mouse PTENf/f endometrial tumors treated with NP137 and observed that, in addition to cell death induction, NP137 induced a reversion of the Epithelial-to-Mesenchymal Transition (EMT). Of interest, by analyzing 13 pre/post paired biopsies of the patients with endometrial carcinoma treated in the NP137 trial, we confirmed a significant reduction of EMT in tumors. We thus performed pre/post NP137 treatment biopsy- based single cell RNA sequencing in a patient with endometrial carcinoma, and showed a net decrease of neoplastic cells and a reversion of EMT markers in the remaining tumor cells, with associated change in the tumor microenvironment. Given the importance of EMT in resistance to the current standard of care including chemotherapy or immune-checkpoint inhibitors, we showed in a PTENf/f endometrial cancer mouse model that combining NP137 with carboplatin paclitaxel outperformed carboplatin paclitaxel alone. Our results thus identify for the first time, in preclinical models and in patients, netrin-1 blockade as a clinical strategy triggering both tumor debulking and reversion of EMT, thus potentially alleviating resistance to standard treatments.

Project description:Focal adhesion kinase (FAK) is frequently amplified and acts as an immune modulator across cancer types. However, evidence illustrates that targeting FAK is most effective in combination therapy rather than in monotherapy. Here, we demonstrated that the FAK inhibitor, IN10018, and pegylated liposome doxorubicin (PLD) exerted effective antitumor activity preclinically and clinically (clinical trial ID: CTR20200913). The clinical study is a phase Ib trial which includes dose confirmation and expansion sections. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. As of the data cutoff date (30 November 2022), a total of 61 platinum-resistant ovarian cancer (PROC) patients were enrolled and no IN10018-related grade 4 or 5 adverse effects (AEs) were reported. The ORR was 46.3% (95% confidence interval (CI): 32.6%, 60.4%) and the DCR was 83.3% (95% CI: 70.7%, 92.1%). The median PFS was 7.26 months (95% CI: 5.16 - 8.02 months), and the median duration of response (DoR) was 6.93 months (95% CI: 4.17 - 9.13 months). The primary and secondary endpoints were met. The median OS was not reached, and still maturing. Notably, the regimen exhibited response latency and long-lasting effects in the clinical trial, outcomes frequently observed in immunotherapy. Our preclinical study revealed that the 2-drug combination can maximize the immunogenic cell death (ICD) of cancer cells, boosting the maturation of dendritic cells (DCs) and stimulating CD8 T cells to strengthen the antitumor effects. At present, immune checkpoint blockade (ICB) is widely considered to exert long-term treatment benefits by activating antitumor immunity. However, many cancer patients show poor clinical responses to ICB due in part to the lack of immunogenic niche. Our work confirmed that IN10018 in combination with PLD can prime the tumor microenvironment, supplementing it with sufficient tumor-infiltrating lymphocytes (TILs) to activate antitumor immunity. Correspondingly, animal studies validated that the antitumor effects of ICB can be significantly enhanced by this doublet regimen. The preclinical results warrant further clinical exploration for the triplet regimen with IN10018, PLD, and ICB.

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Netrin-1 blockade alleviates resistance to first line chemotherapy in locally advanced pancreatic cancer

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