PF-4136309

Colorectal cancer (CRC) is the most common digestive neoplasms worldwide, metastasis and recurrence still account for the leading cause for the high mortality rate, but the exact mechanisms remain unclear. More and more evidence has indicated that the deregulation of GOLM1 plays a crucial role in cancer progression. Here, we reported a novel role of GOLM1 in promoting CRC metastasis. In this study, the expression of GOLM1 was detected in human CRC cohort. The function of GOLM1 in CRC metastasis was analyzed by in vivo cecum orthotopic model. We found that the expression of GOLM1 was significantly increased in CRC tissues than adjacent nontumor. Overexpression GOLM1 can promote CRC immune escape and metastasis by recruiting of myeloid-derived suppressor cells (MDSCs) at the same time. PF-04136309, a small molecule and specific inhibitor of CCR2 can largely suppressed GOLM1-mediated CRC metastasis. These results suggest that GOLM1 can promote CRC metastasis and is a prognostic biomarker in human CRC.

Background In pancreatic ductal adenocarcinoma (PDAC), the chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-C motif) receptor 2 (CCR2) axis plays a key role in immunosuppressive properties of the tumor microenvironment, patient prognosis, and chemoresistance. This phase Ib study assessed the effects of the orally administered CCR2 inhibitor PF-04136309 in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic PDAC. Methods Patients received PF-04136309 twice daily (BID) continuously plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) administered on days 1, 8, and 15 of each 28-day cycle. The primary objectives were to evaluate safety and tolerability, characterize dose-limiting toxicities (DLTs), and determine the recommended phase II dose (RP2D) of PF-04136309. Results In all, 21 patients received PF-04136309 at a starting dose of 500 mg or 750 mg BID. The RP2D was identified to be 500 mg BID. Of 17 patients treated at the 500 mg BID starting dose, three (17.6%) experienced a total of four DLTs, including grade 3 dysesthesia, diarrhea, and hypokalemia and one event of grade 4 hypoxia. Relative to the small number of patients (n = 21), a high incidence (24%) of pulmonary toxicity was observed in this study. The objective response rate for 21 patients was 23.8% (95% confidence interval: 8.2–47.2%). Levels of CD14 + CCR2+ inflammatory monocytes (IM) decreased in the peripheral blood, but did not accumulate in the bone marrow. Conclusions PF-04136309 in combination with nab-paclitaxel plus gemcitabine had a safety profile that raises concern for synergistic pulmonary toxicity and did not show an efficacy signal above nab-paclitaxel and gemcitabine. ClinicalTrials.gov identifier: NCT02732938.