Muhammad Furqan

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

Germline mutations predisposing to non-small cell lung cancer

Lung cancer in multiple first degree relatives had previously been attributed to smoking and to inherited enzymes associated with increased activation of carcinogens in smoke. There was not clear agreement on the significance of the testing methods for lung cancer susceptibility. More recent studies have identified germline mutations associated with lung cancer even in the absence of smoking and other mutations with plausible explanations for their association with lung cancer caused by smoking. At this time, the clinical significance of the various germline mutations for screening and the implications for therapy are not certain. This review summarizes the currently identified germline mutations associated with lung cancer, but this growing area of research will very likely identify further significant mutations as well.

Erratum: O2 ⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate (Cancer Cell (2017) 32 (2)(268) (S1535610817300624) (10.1016/j.ccell.2017.02.018))

Joshua D. Schoenfeld1, Zita A. Sibenaller1, Kranti A. Mapuskar1, Brett A. Wagner1, Kimberly L. Cramer-Morales1, Muhammad Furqan2, Sonia Sandhu2, Thomas L. Carlisle2, Mark C. Smith1, Taher Abu Hejleh2, Daniel J. Berg2, Jun Zhang2, John Keech3, Kalpaj R. Parekh3, Sudershan Bhatia1, Varun Monga2, Kellie L. Bodeker1, Logan Ahmann1, Sandy Vollstedt1, Heather Brown1, Erin P. Shanahan Kauffman2, Mary E. Schall2, Ray J. Hohl2, Gerald H. Clamon2, Jeremy D. Greenlee4, Matthew A. Howard4, Michael K. Shultz5, Brian J. Smith6, Dennis P. Riley7, Frederick E. Domann1, Joseph J. Cullen3, Garry R. Buettner1, John M. Buatti1, Douglas R. Spitz1,*,#, and Bryan G. Allen1,* 1Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, 52242, USA

Mitochondrial Superoxide Increases Age-Associated Susceptibility of Human Dermal Fibroblasts to Radiation and Chemotherapy

Elderly cancer patients treated with ionizing radiation (IR) or chemotherapy experience more frequent and greater normal tissue toxicity relative to younger patients. The current study demonstrates that exponentially growing fibroblasts from elderly (old) male donor subjects (70, 72, and 78 years) are significantly more sensitive to clonogenic killing mediated by platinum-based chemotherapy and IR (∼70%-80% killing) relative to young fibroblasts (5 months and 1 year; ∼10%-20% killing) and adult fibroblasts (20 years old; ∼10%-30% killing). Old fibroblasts also displayed significantly increased (2-4-fold) steady-state levels of O2•-, O2 consumption, and mitochondrial membrane potential as well as significantly decreased (40%-50%) electron transport chain (ETC) complex I, II, IV, V, and aconitase (70%) activities, decreased ATP levels, and significantly altered mitochondrial structure. Following adenoviral-mediated overexpression of SOD2 activity (5-7-fold), mitochondrial ETC activity and aconitase activity were restored, demonstrating a role for mitochondrial O2•- in these effects. Old fibroblasts also demonstrated elevated levels of endogenous DNA damage that were increased following treatment with IR and chemotherapy. Most importantly, treatment with the small-molecule, superoxide dismutase mimetic (GC4419; 0.25 μmol/L) significantly mitigated the increased sensitivity of old fibroblasts to IR and chemotherapy and partially restored mitochondrial function without affecting IR or chemotherapy-induced cancer cell killing. These results support the hypothesis that age-associated increased O2•- and resulting DNA damage mediate the increased susceptibility of old fibroblasts to IR and chemotherapy that can be mitigated by GC4419. Cancer Res; 77(18); 5054-67. ©2017 AACR.

Lobar versus sub-lobar surgery for pulmonary typical carcinoid, a population-based analysis

Background The optimal surgery for resectable pulmonary typical carcinoid (TC), e.g., lobar resection (L-R) vs. sub-lobar resection (SL-R), is controversial. This is further explored in this population-based study. Methods The Surveillance, Epidemiology, and End Results (SEER) Program was used to select patients ≥66 years old, and diagnosed between 2000 and 2012 with pulmonary TC. A similar cohort was developed using the SEER-Medicare database (diagnosed from 2000-2007) to identify chemotherapy (CTX) use and co-morbidity. Five-year survival was calculated using univariate and multivariate analysis. Results A total of 1,506 and 512 patients were identified from SEER and SEER-Medicare, respectively. In the SEER cohort, 49%, 29% and 21% received L-R, SL-R, and no surgery (NS), respectively. Those who received NS were older (P<0.001), had a higher stage (P<0.001), greater comorbidity (P<0.001), and were more likely to receive radiotherapy (XRT) (P<0.001) and CTX (P<0.001). Relative survival was nearly 100% for those who received L-R or SL-R as opposed to 72% for those who received NS (P<0.001). Cox models showed no survival difference for L-R vs. SL-R (HR 1.1, P=0.663), but worse survival for those who received NS vs. L-R or SL-R (HR 3.6, P<0.001). XRT in NS cohort was associated with increased risk of death (HR 2.3, P=0.017). Conclusions SL-R was better than NS, and similar to L-R in terms of survival. SL-R should be considered over NS if L-R is unfeasible. Role of adjuvant CTX and XRT is unclear as these did not improve survival in this study.

Screening Patients with Esophageal Cancer to Determine Eligibility for Adjuvant Treatment Trials

Background: The tolerability of adjuvant chemotherapy in esophageal cancer is unclear. Patients and Methods: This was a phase II trial of adjuvant paclitaxel in patients with esophageal cancer after trimodality treatment. Patients with residual viable tumor after resection were eligible for study inclusion. Treatment was 80 mg/m2 paclitaxel intravenously on days 1, 8, and 15 every 28 days for total of two cycles. The primary objective was to determine whether 75% or more of the patients would tolerate 240 mg/m2 or more of paclitaxel, which corresponded to 50% or more of the total planned dose. Results: Eleven out of the 12 enrolled patients (92%, 95% confidence interval (CI)=62-100%) were able to complete at least 50% of the planned paclitaxel dose. Median progression-free survival was 7 months (95% CI=2-28 months). Median overall survival was 28 months (95% CI=12-36 months). Only one patient experienced a grade 4 adverse event. Conclusion: Screening patients with esophageal cancer after trimodality treatment might improve completion of adjuvant trials.

Once Daily High-dose Radiation (≥60 Gy) Treatment in Limited Stage Small Cell Lung Cancer

BACKGROUND To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. METHODS We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). RESULTS 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. CONCLUSIONS In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.