NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers

Purpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design: The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results: ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (~12 Units) of any normal tissue. PK/PD responses confirm that IR + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion: Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs

Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial

Importance: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. Objective: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. Design, setting, and participants: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. Interventions: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. Main outcomes and measures: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. Results: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. Conclusions and relevance: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. Trial registration: ClinicalTrials.gov Identifier: NCT01834235

Characteristics and impact of the most-cited palliative oncology studies from 1995 to 2016

Abstract Background Palliative care, as a relatively young field within medicine, has increasingly used original research to validate and standardize its practice. In particular, palliative care has been incorporated into oncology to better address end-of-life decisions and care. The goal of this study is to identify seminal studies in the field of palliative oncology while more broadly characterizing the trends across the literature. Methods The publication databases Scopus and Web of Science were queried using predefined search terms to identify palliative oncology studies published between 1995 and 2016. The 100 most-cited articles from the time periods 1995–2005 and 2006–2016 were selected and analysed for publication data and study content. Results Palliative oncology studies were found to primarily examine patients with multiple rather than single cancer types and rarely were randomized controlled trials. Early research topics of pain, symptoms, and survival studies have been replaced by the issues of access to care, healthcare utilization, and religion and spirituality. Conclusions By identifying and analyzing notable studies in palliative oncology, we found areas of research that are commonly investigated or overlooked and identified model studies that highlight the need for additional disease-specific randomized control trials to provide high quality clinical evidence in the field

Impact of diabetes mellitus on the outcome of pancreatic cancer.

Diabetes mellitus (DM) has the potential to impact the pathogenesis, treatment, and outcome of pancreatic cancer. This study evaluates the impact of DM on pancreatic cancer survival.We conducted a retrospective cohort study from the Veterans Affairs (VA) Central Cancer Registry (VACCR) for pancreatic cancer cases between 1995 and 2008. DM and no-DM cases were identified from comorbidity data. Univariate and multivariable analysis was performed. Multiple imputation method was employed to account for missing variables.Of 8,466 cases of pancreatic cancer DM status was known in 4728 cases that comprised this analysis. Males accounted for 97.7% cases, and 78% were white. Overall survival was 4.2 months in DM group and 3.6 months in the no-DM group. In multivariable analysis, DM had a HR = 0.91 (0.849-0.974). This finding persisted after accounting for missing variables using multiple imputations method with the HR in DM group of 0.93 (0.867-0.997).Our data suggest DM is associated with a reduction in risk of death in pancreatic cancer. Future studies should be directed towards examining this association, specifically impact of DM medications on cancer outcome

Baseline characteristics (n = 4728).

<p>Baseline characteristics (n = 4728).</p

Overall survival of pancreatic cancer (PC) cases according to DM status (N = 4658).

<p>Overall survival of pancreatic cancer (PC) cases according to DM status (N = 4658).</p