Modulation of autophagy, specifically its inhibition, stands to transform the capacity to effectively treat a broad range of cancers. However, the clinical efficacy of autophagy inhibitors has been ...inconsistent. To delineate clinical and epidemiological features associated with autophagy inhibition and a positive oncological clinical response, a retrospective analysis of patients is conducted treated with hydroxychloroquine, a known autophagy inhibitor. A direct correlation between smoking status and inhibition of autophagy with hydroxychloroquine is identified. Recognizing that smoking is associated with elevated circulating levels of carbon monoxide (CO), it is hypothesized that supplemental CO can amplify autophagy inhibition. A novel, gas‐entrapping material containing CO in a pre‐clinical model is applied and demonstrated that CO can dramatically increase the cytotoxicity of autophagy inhibitors and significantly inhibit the growth of tumors when used in combination. These data support the notion that safe, therapeutic levels of CO can markedly enhance the efficacy of autophagy inhibitors, opening a promising new frontier in the quest to improve cancer therapies.
Carbon monoxide potently induces autophagy in cancer cells through increased autophagosome formation. It is demonstrated that the combination of orally administered carbon monoxide biofoams generates a robust anti‐cancer effect when combined with autophagy inhibitors in vitro and in vivo. This finding is bolstered by actively smoking cancer patients, which is a state of elevated carbon monoxide levels, who received autophagy inhibitors in clinical trials.
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.
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•High-dose ascorbate sensitizes NSCLC and GBM cells to radio-chemotherapy•O2⋅− and H2O2 increase labile iron causing cancer cell-selective ascorbate toxicity•Therapeutic levels of ascorbate are achievable and well tolerated in GBM and NSCLC•Cancer cell oxidative metabolism can be targeted with ascorbate for cancer therapy
Schoenfeld et al. show that cancer cells are selectively sensitive to ascorbate due to their altered redox-active iron metabolism. They present preclinical and clinical data demonstrating the feasibility, tolerability, and potential efficacy of pharmacological ascorbate for treating glioblastoma and non-small cell lung cancer.
Adenoid cystic cancers (ACC) in the head and neck are rare yet present a clinical dilemma. Although 5 year survivals are excellent, their have a propensity for late recurrences. Most of these cancers ...are initially treated with surgery followed by radiation. When recurrences happen, treatment options are limited both by the morbidity and low efficacy of re-irradiation and repeated surgical resection. Reported response rates to chemotherapy are low and targeted therapies may be one option. We, therefore, investigated signaling pathways that may be active in adenoid cystic cancers. Tissues from the last 9 ACC patients resected at the University of Iowa were immunohistochemically stained with antibodies for EGFR, phosphorylated (P) Akt, and P-MAPK in order to molecularly characterize these tumors. An ACC cell line (ACC3) was also characterized by Western blot. We found that seven of the 9 tumor samples had strong expression of P-Akt and 5/9 had P-MAPK. None of them had EGFR expression. In the ACC3 cell line, similar data was found in that there was P-Akt and P-MAPK but no EGFR expression. We tested the HIV protease inhibitor nelfinavir (NFV) which has been shown to inhibit Akt signaling to see its effect on ACC3 cells. Both P-Akt and P-MAPK were inhibited with NFV in ACC3 cells and this resulted in growth inhibition and clonogenic death. In patients where re-irradiation or further surgery is not an option, a trial of NFV may be warranted.
Patient accrual is essential for the success of oncology clinical trials. Recruitment for trials involving the development of quantitative imaging biomarkers may face different challenges than ...treatment trials. This study surveyed investigators and study personnel for evaluating accrual performance and perceived barriers to accrual and for soliciting solutions to these accrual challenges that are specific to quantitative imaging-based trials. Responses for 25 prospective studies were received from 12 sites. The median percent annual accrual attained was 94.5% (range, 3%-350%). The most commonly selected barrier to recruitment (n = 11/25, 44%) was that "patients decline participation," followed by "too few eligible patients" (n = 10/25, 40%). In a forced choice for the single greatest recruitment challenge, "too few eligible patients" was the most common response (n = 8/25, 32%). Quantitative analysis and qualitative responses suggested that interactions among institutional, physician, and patient factors contributed to accrual success and challenges. Multidisciplinary collaboration in trial design and execution is essential to accrual success, with attention paid to ensuring and communicating potential trial benefits to enrolled and future patients.
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 H
O
; 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 O
and H
O
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 H
O
. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.
Abstract Background Response evaluation criteria in solid tumors (RECIST) is the accepted method for determining tumor progression. However, RECIST may not estimate disease burden accurately because ...the axial plane often does not produce the actual longest diameter. Volumetric measurements may be an alternative to better determine tumor size. Our aim was to compare volumetric measurements with RECIST in pancreatic ductal adenocarcinomas (PDA) and hepatocellular carcinomas (HCC). Methods RECIST and volumetric measurements were determined in 9 patients with metastatic PDA and 17 patients with HCC who subsequently underwent liver transplantation. Gross pathologic measurements after hepatectomy also were analyzed for volumes. Results Three-dimensional diameter in volumetric analysis was 38% and 36% higher than RECIST diameter in PDA and HCC, respectively ( P < .01). However, RECIST yielded 78% and 23% larger estimated tumor volumes than volumetric analysis in PDA and HCC, respectively ( P < .01). Gross pathologic volume in HCC showed a linear correlation with both volumetric analysis ( r = .95; P < .01) and RECIST ( r = .96; P < .01) but RECIST significantly overestimated gross pathologic volume by an average of 28% ( P < .01) whereas volumetric analysis was similar to gross pathologic volume ( P = .56). In categorizing treatment response in PDA, RECIST and volumetric analysis were in moderate agreement (κ = .49). Conclusions RECIST significantly may overestimate tumor burden compared with volumetric measurements in both PDA and HCC. Volumetric analysis may be the preferred method to detect tumor progression.
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