Nereus Pharmaceuticals was a pharmaceutical company focused on the development of natural products from marine microbial and other natural sources into small molecule human therapeutics. The major disease area addressed by Nereus is cancer. Nereus was purchased by Triphase Research and Development in 2012.
8054 Background: Plinabulin (N) inhibits tumor growth by targeting both angiogenesis and tumor vasculature as well as directly by inducing apoptosis via the Ras-JNK pathway. This trial compared the combination of N and docetaxel (DN) to docetaxel alone (D). Methods: Patients (pts) with advanced NSCLC previously treated with standard chemotherapy (ChRx) were randomized between D (75 mg/m2 IV) on Day 1 plus N 30 mg/m2 IV on Days 1 and 8 in 21-day cycles (DN) vs D (75 mg/m2 ) (30 Cohort). Pts with Stage IIIB/IV NSCLC and 1 or 2 prior ChRx were eligible. Prior D or vascular disrupting agent (VDA) were not allowed. A 2nd dose cohort (DN 20 mg/m2) of pts with 1 prior ChRx (20 Cohort) was enrolled. The primary end point was overall survival (OS). Results: 172 pts were randomized into 2 dosing cohorts with 163 treated: 30 Cohort (50 DN; 55 D) and 20 Cohort (40 DN; 18 D). For 30 Cohort, OS (months (M)), 90% confidence interval [90% CI]) was 8.7 (6.6, 12.6) for DN and 7.5 (6.3, 10.5) for D; response rate was 14.0% for DN and 14.5% for D; and duration of response (M, 90% CI) for DN was 12.7 (4.0, 13.9) and 1.5 (1.1, 3.1) for D (p=0.049). Results appeared better for the DN 30 Cohort vs 20 Cohort. Post hoc subset analysis identified pts with large, lung tumors (>3 cm) and 1 prior ChRx as having better survival with DN. OS (M, 95% CI) for this subset was 11.5 (7.1, 15.1) DN vs 7.8 (4.1, 17.4) D. The most common adverse events were nausea, fatigue, diarrhea, constipation, and anorexia. There were fewer dose reductions of D among DN pts (10%) vs D pts (18.2%). There was a lower incidence of neutropenia in patients in the DN 30 Cohort compared to D (8.0% vs 36.4%, p<0.001) and the DN 20 Cohort compared with its companion D (7.5% vs 22.2%). A post hoc analysis showed that the DN 30 Cohort (n=50) had a significantly lower incidence of ≥ Grade 3 neutropenia vs the pooled D (n=73) at 8.0% vs 27.4%, respectively (p=0.010). Conclusions: Pts with large, lung tumors (>3 cm) and 1 prior ChRx may be more likely to have an increased survival with DN as compared to D. This finding is consistent with the mechanism of action of a VDA with anti-angiogenesis and apoptotic properties. A Phase 3 trial in pts with large, lung tumors is planned. Clinical trial information: NCT00630110.
AbstractThe key steps are stereoselective epoxidation of the alkene (I) and subsequent regio‐ and stereoselective oxirane ring‐opening.
Resistance to drug treatments underlies the high lethality of pancreatic ductal adenocarcinoma. Along with others, we have recently identified that proteasome inhibition is a promising therapeutic option in this highly refractory disease. The pleiotropic effects of proteasome inhibition include the activation of apoptotic signaling pathways and also antiapoptotic signaling pathways such as EGFR, AKT and the MAP kinases that reduce the apoptotic potential of this class of drug. In this study, we sought to determine the mechanism behind the activation of EGFR in response to proteasome inhibition in pancreatic cancer cells. We found that the second-generation proteasome inhibitor NPI-0052 induced the mRNA transcription of several EGFR family ligands (EGF, HB-EGF and epiregulin), however only increases in HB-EGF were detected at the protein level. Using both pharmacological inhibitors and lentiviral-mediated shRNA knockdown of EGFR ligand expression, we discovered that ligand cleavage by MMP/ADAMs and HB-EGF expression is required for activation of EGFR in response to proteasome inhibition. Furthermore, we discover that induction of HB-EGF is dependent on reactive oxygen species and p38-MAPK signaling but not ERK and that the transcription factor SP-1 is involved in NPI-0052-induced HB-EGF transcription. Together, these results indicate that stress signaling leading to induction of HB-EGF expression and increases in MMP/ADAM-dependent HB-EGF cleavage are responsible for proteasome inhibitor-induced activation of EGFR in pancreatic cancer cells.
Our previous study showed that the novel proteasome inhibitor NPI-0052 induces apoptosis in multiple myeloma (MM) cells resistant to conventional and bortezomib (Velcade™, Takeda, Boston, MA, USA) therapies. In vivo studies using human MM-xenografts demonstrated that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for an ongoing phase-1 clinical trial of NPI-0052 in relapsed/refractory MM patients. Here we performed pharmacodynamic (PD) studies of NPI-0052 using human MM xenograft murine model. Our results showed that NPI-0052: (i) rapidly left the vascular compartment in an active form after intravenous (i.v.) administration, (ii) inhibited 20S proteasome chymotrypsin-like (CT-L, β5), trypsin-like (T-L, β2), and caspase-like (C-L, β1) activities in extra-vascular tumours, packed whole blood (PWB), lung, liver, spleen, and kidney, but not brain and (iii) triggered a more sustained (>24 h) proteasome inhibition in tumours and PWB than in other organs (<24 h). Tissue distribution analysis of radiolabeled compound ( 3 H-NPI-0052) in mice demonstrated that NPI-0052 left the vascular space and entered organs as the parent compound. Importantly, treatment of MM.1S-bearing mice with NPI-0052 showed reduced tumour growth without significant toxicity, which was associated with prolonged inhibition of proteasome activity in tumours and PWB but not normal tissues.
Metastasis is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics and invasive properties by tumor cells, a process known as epithelial to mesenchymal transition (EMT). Snail expression, through nuclear factor (NF)-κB activation, is an EMT determinant. The proteasome inhibitor, NPI-0052, induces the metastasis tumor suppressor/immune surveillance cancer gene, Raf kinase inhibitor protein (RKIP), via NF-κB inhibition. We hypothesized that NPI-0052 may inhibit Snail expression and, consequently, the metastatic phenotype in DU-145 prostate cancer cells. Cell treatment with NPI-0052 induced E-cadherin and inhibited Snail expression and both tumor cell invasion and migration. Inhibition of Snail inversely correlated with the induction of RKIP. The underlying mechanism of NPI-0052-induced inhibition of the metastatic phenotype was corroborated by: (1) treatment with Snail siRNA in DU-145 inhibited EMT and, in contrast, overexpression of Snail in the nonmetastatic LNCaP cells induced EMT, (2) NPI-0052-induced repression of Snail via inhibition of NF-κB was corroborated by the specific NF-κB inhibitor DHMEQ and (3) RKIP overexpression mimicked NPI-0052 in the inhibition of Snail and EMT. These findings demonstrate, for the first time, the role of NPI-0052 in the regulation of EMT via inhibition of NF-κB and Snail and induction of RKIP.
