期刊
BMC CANCER
卷 22, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12885-022-09272-2
关键词
Cancer stroma; Tumour microenvironment; Cancer-associated fibroblasts; Cancer-restraining CAFs; Meflin; ISLR; AM80; Tamibarotene; MIKE-1
类别
资金
- Japan Agency for Medical Research and Development (AMED) [JP21lk0201142, JP21cm0106704]
- Nagoya University Hospital
- Japanese government
Cancer-associated fibroblasts (CAFs) are an important component of the tumor microenvironment. Recent studies have identified a subset of CAFs, called cancer-restraining CAFs (rCAFs), which can suppress cancer progression. This study aims to investigate the efficacy of a combination of the synthetic retinoid AM80 and chemotherapy drugs gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer.
Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancerrestraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into a-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. Methods: The phase I part is a 3 +3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma.
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