Radiotherapy is used in locally advanced pancreatic cancers where it can improve survival in combination with gemcitabine. However, prognosis is still poor in this setting where more effective therapies remain needed. MLN4924 is an investigational small molecule currently in Phase I clinical trials. MLN4924 inhibits NAE (NEDD8 Activating Enzyme), a pivotal regulator of the E3 ubiquitin ligase SCF (SKP1, Cullins, and F-box protein), that has been implicated recently in DNA repair. In this study, we provide evidence that MLN4924 can be used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924 (20–100 nM) effectively inhibited cullin neddylation and sensitized pancreatic cancer cells to ionizing radiation in vitro with a sensitivity enhancement ratio (SER) of ~1.5. Mechanistically, MLN4924 treatment stimulated an accumulation of several SCF substrates, including CDT1, WEE1 and NOXA, in parallel with an enhancement of radiation-induced DNA damage, aneuploidy, G2/M phase cell cycle arrest and apoptosis. RNAi-mediated knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy, G2/M arrest, and radiosensization, indicating a causal effect. Further, MLN4924 was an effective radiosensitizer in mouse xenograft models of human pancreatic cancer. Our findings offer proof of concept for use of MLN4924 as a novel class of radiosensitizer for the treatment of pancreatic cancer.
Chemoradiation is the treatment of choice for locally advanced head and neck squamous cell carcinoma (HNSCC). However, radioresistance, which contributes to local recurrence, remains a significant therapeutic problem. In this study, we characterized SM-164, a small second mitochondria-derived activator of caspase -mimetic compound that promotes degradation of cellular inhibitor of apoptosis-1(cIAP-1; also known as baculoviral IAP repeat-containing protein 2, BIRC2) and releases active caspases from the X-linked inhibitor of apoptosis inhibitory binding as a radiosensitizing agent in HNSCC cells. We found that SM-164 at nanomolar concentrations induced radiosensitization in some HNSCC cell lines in a manner dependent on intrinsic sensitivity to caspase activation and apoptosis induction. Blockage of caspase activation via short interfering RNA knockdown or a pan-caspase inhibitor, z-VAD-fmk, largely abrogated SM-164 radiosensitization. On the other hand, the resistant lines with a high level of Bcl-2 that blocks caspase activation and apoptosis induction became sensitive to radiation on Bcl-2 knockdown. Mechanistic studies revealed that SM-164 radiosensitization in sensitive cells was associated with NF-kB activation and TNFa secretion, followed by activation of caspase-8 and -9, leading to enhanced apoptosis. Finally, SM-164 also radiosensitized human tumor xenograft while causing minimal toxicity. Thus, SM-164 is a potent radiosensitizer via a mechanism involving caspase activation and holds promise for future clinical development as a novel class of radiosensitizer for the treatment of a subset of head and neck cancer patients. Mol Cancer Ther; 10(4); 658-69. Ó2011 AACR.
Venous thromboembolism (VTE) is an important complication of coronavirus disease 2019 (COVID-19). To date, few studies have described vascular access device use and VTE risk in this cohort. To examine the use of vascular access devices and incidence of VTE in patients hospitalized with COVID-19. We performed a retrospective, multi-center cohort study of patients hospitalized with COVID-19 who received a midline catheter, peripherally inserted central catheter (PICCs), tunneled or non-tunneled central venous catheter (CVC), hemodialysis (HD) catheter or a port during hospitalization. Mixed-effects multivariable logit models adjusting for VTE risk factors in the Caprini risk score were fit to understand the incremental risk of VTE in patients with vascular access devices vs. those that did not receive devices. Management of VTE was determined by examining anticoagulant use pre- vs. post-thrombosis. Results were expressed using odds ratios (ORs) and associated 95% confidence intervals (CI). A total of 1228 hospitalized COVID-19 patients in 40 hospitals, of which 261 (21.3%) received at least one vascular access device of interest, were included. The prevalence of acute, non-tunneled CVCs was 42.2%, acute HD catheters 18.4%, midline catheters 15.6%, PICCs 15.6%, tunneled CVCs 6.8%, and implanted ports 1.4%. The prevalence of VTE was 6.0% in the study cohort, and 10.0% among patients with vascular access devices. After adjusting for known VTE risk factors, patients that had a vascular access device placed were observed to have a four-fold greater odds of VTE than those that did not (OR 4.17, 95% CI 2.33–7.46). Patients who received multiple different catheters experienced more VTE events compared with patients that received only one type (21.5% vs. 6.1%, p < .001). Among the 26 patients with VTE, only 8 (30.8%) survived to discharge and among these, only 5 were discharged on therapeutic doses of anticoagulation. Hospitalized patients with COVID-19 that receive vascular access devices experienced higher rates of VTE than those that do not. Future studies to evaluate the nexus between COVID-19, vascular device use, and thrombosis appear are warranted.
<div>Abstract<p>Radiotherapy is used in locally advanced pancreatic cancers in which it can improve survival in combination with gemcitabine. However, prognosis is still poor in this setting in which more effective therapies remain needed. MLN4924 is an investigational small molecule currently in phase I clinical trials. MLN4924 inhibits NAE (NEDD8 Activating Enzyme), a pivotal regulator of the E3 ubiquitin ligase SCF (SKP1, Cullins, and F-box protein), that has been implicated recently in DNA damage and repair. In this study, we provide evidence that MLN4924 can be used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924 (20–100 nmol/L) effectively inhibited cullin neddylation and sensitized pancreatic cancer cells to ionizing radiation <i>in vitro</i> with a sensitivity enhancement ratio of approximately 1.5. Mechanistically, MLN4924 treatment stimulated an accumulation of several SCF substrates, including CDT1, WEE1, and NOXA, in parallel with an enhancement of radiation-induced DNA damage, aneuploidy, G<sub>2</sub>/M phase cell-cycle arrest, and apoptosis. RNAi-mediated knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy, G<sub>2</sub>/M arrest, and radiosensitization, indicating a causal effect. Furthermore, MLN4924 was an effective radiosensitizer in a mouse xenograft model of human pancreatic cancer. Our findings offer proof-of-concept for use of MLN4924 as a novel class of radiosensitizer for the treatment of pancreatic cancer. <i>Cancer Res; 72(1); 282–93. ©2011 AACR</i>.</p></div>
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