Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors.

High-profile studies frequently and repetitively present data on the same patients, particularly in immunotherapy studies.

BACKGROUND: Traditionally, study results have been presented as abstracts at major scientific meetings at the conclusion of the analysis. Recently, presentations of studies in progress and updates to previously presented data have been allowed at major meetings. The frequency and implications of a single study being presented multiple times, particularly in high profile oral presentations, have not been fully evaluated. METHODS: To identify studies presented multiple times, abstracts from an approximately 1-year period from international conferences for three major societies devoted largely or in part to lung cancer research were assessed (ASCO 2015, World Lung 2015, ESMO 2015 and ASCO 2016). Abstracts were selected in a two-step process. The first step was for subject matter based on keywords: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or immunotherapy. Searches differed slightly based on individual website functionality, with ASCO searched by track, World Lung by session and ESMO by individual abstract. In a second step, abstracts for which clinical outcome data was presented from a trial with an identifiable National Clinical Trial (NCT) number were selected. Immunotherapy abstracts that did not include the treatment of NSCLC or SCLC were excluded in the second step. RESULTS: A total of 851 abstracts were identified that were related to NSCLC, SCLC or immunotherapy. Of these, 357 referred to a clinical trial. In total, 110 of 357 (31%) described clinical trials that were presented multiple times (mean 2.75, range 2-7), and in 44 (12%), this occurred at the same conference. Of the 113 oral presentations, 75 (66%) presented data from clinical trials, either as posters or oral presentations. Further, 35 of the 113 (31%) oral presentations presented data from clinical trials that had generated other oral presentations. Of the 16 unique clinical trials leading to multiple oral presentations, a variety of issues led to the duplicate presentations, including different cohorts of the same trial, biomarker analysis, analysis by one study variable, or simply updated data. Moreover, 107 of the 357 (30%) clinical trial abstracts pertained to immunotherapy, including 4 of the 16 clinical trials generating multiple oral presentations. Of the 16 trials generating multiple oral presentations, 11 (69%) lead to a full-length publication by July 2017, including all of those pertaining to immunotherapy. CONCLUSIONS: There is a pattern of multiple presentations of clinical trials, particularly in oral presentations, at major meetings. In most cases, data presented in subsequent oral presentations related entirely to patients whose data was presented in the previous oral presentation.

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center.

We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288-94. ©2018 AACR.

Non-small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges.

BACKGROUND: Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated. METHODS: The authors retrospectively reviewed data generated by patients who consented to 1 or more interventional lung cancer clinical trials at the University of California-Los Angeles Jonsson Comprehensive Cancer Center between January 2013 and December 2014. Trials were considered to require a biopsy when enrollment was conditional on the procurement of tissue without intervening therapy between procurement and enrollment. RESULTS: In total, 311 patients underwent 368 screening incidents for 1 or more of 19 trials. Trials that required a new biopsy had a longer median screening duration (34 vs 14 days) than trials that did not require a biopsy (P < .001). Trials that required a biopsy had a greater screen failure rate (49.1% vs 26.5%; P < .001), which was largely driven by patients who did not undergo the required biopsy or lacked the required biomarker. Worsening performance status led to the majority of screen failures (56.5%) among biomarker-eligible patients. CONCLUSIONS: Although the scientific benefits of obtaining a new biopsy and requiring specific results for trial enrollment are clear, these requirements lead to a lengthening of the screening period, which, in some patients, is associated with clinical decline before enrollment. Implications for the interpretation of data from studies of this design should be explored. Cancer 2017;123:4800-7. © 2017 American Cancer Society.