Blocking protein quality control to counter hereditary cancers

Inhibitors of molecular chaperones and the ubiquitin‐proteasome system have already been clinically implemented to counter certain cancers, including multiple myeloma and mantle cell lymphoma. The efficacy of this treatment relies on genomic alterations in cancer cells causing a proteostatic imbalance, which makes them more dependent on protein quality control (PQC) mechanisms than normal cells. Accordingly, blocking PQC, e.g. by proteasome inhibitors, may cause a lethal proteotoxic crisis in cancer cells, while leaving normal cells unaffected. Evidence, however, suggests that the PQC system operates by following a better‐safe‐than‐sorry principle and is thus prone to target proteins that are only slightly structurally perturbed, but still functional. Accordingly, implementing PQC inhibitors may also, through an entirely different mechanism, hold potential for other cancers. Several inherited cancer susceptibility syndromes, such as Lynch syndrome and von Hippel‐Lindau disease, are caused by missense mutations in tumor suppressor genes, and in some cases, the resulting amino acid substitutions in the encoded proteins cause the cellular PQC system to target them for degradation, although they may still retain function. As a consequence of this over‐meticulous PQC mechanism, the cell may end up with an insufficient amount of the abnormal, but functional, protein, which in turn leads to a loss‐of‐function phenotype and manifestation of the disease. Increasing the amounts of such proteins by stabilizing with chemical chaperones, or by targeting molecular chaperones or the ubiquitin‐proteasome system, may thus avert or delay the disease onset. Here, we review the potential of targeting the PQC system in hereditary cancer susceptibility syndromes.     

HOPX is methylated and exerts tumour‐suppressive function through Ras‐induced senescence in human lung cancer

HOPX acts as a tumour suppressor in various cancers. However, the regulation of HOPX in human lung cancer as well as the mechanism underlying its tumour‐suppressive function has not yet been well elucidated. Here we investigated the epigenetic regulation and molecular mechanism by which HOPX exerts growth inhibitory effects. We found that HOPX was down‐regulated in 12 out of 13 lung cancer cell lines and in 69 out of 120 primary lung tumours at mRNA and protein levels. Patients with lung adenocarcinoma (ADC) exhibited significantly more positive staining of HOPX protein compared with lung squamous cell carcinoma (SCC) (p =0.036). Again in ADC, patients with higher HOPX expression had a significantly longer disease‐free survival (p =0.001). Methylation analysis showed that down‐regulation of HOPX was associated with DNA methylation (p =0.011). To analyse the function of HOPX in lung cancer cells, stable transfection with an expression vector of HOPX was performed. It turned out that HOPX inhibited tumour cell proliferation rate, migration, and invasion, and, more interestingly, forced expression of HOPX enhanced cellular senescence via activation of oncogenic Ras and the downstream MAPK pathway, which in turn led to decreased MDM2 and increased p21. On the contrary, knockdown of HOPX by siRNA resulted in reduced Ras activity, inactivation of the MAPK pathway, and decreased p21 levels, accompanied by reduced cellular senescence. Additionally, the HOPX‐induced senescence pathway was also active in human bronchial epithelial cells. Taken together, our data suggest that down‐regulation of HOPX was related to DNA methylation and that HOPX exerts tumour‐suppressive activity by oncogenic Ras‐induced cellular senescence in lung cancer cells. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Planned FDG PET-CT Scan in Follow-Up Detects Disease Progression in Patients With Locally Advanced NSCLC Receiving Curative Chemoradiotherapy Earlier Than Standard CT

The role of positron emission tomography-computed tomography (PET-CT) in surveillance of patients with nonsmall cell lung cancer (NSCLC) treated with curatively intended chemoradiotherapy remains controversial. However, conventional chest X-ray and computed tomography (CT) are of limited value in discriminating postradiotherapy changes from tumor relapse. The aim of this study was to evaluate the clinical value of PET-CT scan in the follow-up for patients with locally advanced (LA) NSCLC receiving concomitant chemoradiotherapy (CCRT).Between 2009 and 2013, eligible patients with stages IIB–IIIB NSCLC were enrolled in the clinical trial NARLAL and treated in Odense University Hospital (OUH). All patients had a PET-CT scan scheduled 9 months (PET-CT9) after the start of the radiation treatment in addition to standard follow-up (group A). Patients who presented with same clinical stage of NSCLC and received similar treatment, but outside protocol in OUH during this period were selected as control group (group B). Patients in group B were followed in a conventional way without PET-CT9. All patients were treated with induction chemotherapy followed by CCRT.Group A included 37 and group B 55 patients. The median follow-up was 16 months. Sixty-six (72%) patients were diagnosed with progression after treatment. At the time of tumor progression, patients in group A had better performance status (PS) than those in group B (P = 0.02). Because of death (2 patients), poor PS (3) or retreatment of relapse (9), only 23 patients had PET-CT9 in group A. Eleven (48%) patients were firstly diagnosed with progression by PET-CT9 without any clinical symptoms of progression. The median progression-free survival (PFS) was 8.8 months in group A and 12.5 months in group B (P = 0.04). Hazard function PFS showed that patients in group A had higher risk of relapse than in group B.Additional FDG PET-CT scan at 9 months in surveillance increases probability of early detection of disease progression in advanced NSCLC patients treated with curatively intended CCRT.     

Semi-Quantitative Calculations of Primary Tumor Metabolic Activity Using F-18 FDG PET/CT as a Predictor of Survival in 92 Patients With High-Grade Bone or Soft Tissue Sarcoma

To assess the prognostic value of primary tumor metabolic activity in patients with high-grade bone sarcomas (BS) or soft tissue sarcomas (STS) using F-18 FDG PET/CT.A single-site, retrospective study including 92 patients with high-grade BS or STS. Pretreatment F-18 FDG PET/CT scan was performed. Clinical data were registered. Accuracy of maximum standardized uptake value of primary tumor (SUV_max) and tumor-to-background (T/B) uptake ratio as prognostic variables and identification of cut-off values to group patients were determined. Kaplan–Meier survival estimates and log-rank test were used to compare survival distributions. Prognostic variables were assessed using Cox proportional hazards regression analysis.Forty-one of 92 patients died during follow-up (45%). Average survival was 6.5 years (95% CI 5.8–7.3 years) and probability of 5-year survival was 52%. Accuracy of SUV_max and T/B uptake ratio as prognostic variables in all patients and during subgroup analysis of patients with STS was significant. No significant results for AUCs were registered in patients with BS. Surgery was independently prognostic for survival throughout multivariate regression analysis of all patients (P = 0.001, HR 3.84) and subgroup analysis (BS: P = 0.02, HR 11.62; STS: P = 0.005, HR 4.13). SUV_max was significant as prognostic variable in all patients (P = 0.02, HR 3.66) and in patients with STS (P = 0.007, HR 3.75). No significant results were demonstrated for T/B uptake ratio.Estimation of primary tumor metabolic activity with pretherapeutic SUV_max using F-18 FDG PET/CT demonstrates independent properties beyond histologic grading for prediction of survival in patients with high-grade STS, but not with high-grade BS.     

Constant post-irradiation repopulation rates and linear relationship between cellular blood response and number of transplanted bone marrow cells in inbred mice.

Graded doses of syngeneic bone marrow cells were transplanted into lethally irradiated mice. Repopulation curves of peripheral blood granulocytes and platelets were apparently exponential and parallel after doses larger than 5 X 10(5) cells. The blood platelet Td was reduced from 111 h to 53-57 h, and granulocyte Td from 57 to 40 h in transplanted groups. The mean blood cell counts were reproducible enough to be used as a biological assay of the amount of bone marrow cells transplanted. Linear relationship between increment of blood cells up to day 16 and number of bone marrow cells transplanted on day 1 was demonstrated (1,200 granulocytes and 14,300 platelets/mul blood per 10(5) bone marrow cells). The linearity suggested a mean Td less than 22.5 h of proliferating bone marrow cells, and allowed a rough estimation of mouse bone marrow stem cell radiosensitivity (Do 76 rad).     

Mortality in cancer patients previously diagnosed with herpes zoster in the hospital setting: a nationwide cohort study

Background:

Herpes zoster (HZ) is associated with underlying immunodeficiency and may thereby predict mortality of subsequent cancer.

Methods:

By using Danish nationwide medical databases, we identified all cancer patients with a prior hospital-based HZ diagnosis during 1982–2011 (n=2754) and a matched cancer cohort without prior HZ (n=26 243). We computed adjusted mortality rate ratios (aMRRs) associating prior HZ with mortality following cancer.

Results:

Prior HZ was associated with decreased mortality within the year after cancer diagnosis (aMRR 0.87; 95% confidence interval (CI): 0.81–0.93), but not thereafter (aMRR 1.07; 95% CI: 0.99–1.15). However, prior HZ predicted increased mortality throughout the entire follow-up among patients aged <60 years (aMRR 1.39; 95% CI: 1.15–1.68) and those with disseminated HZ (aMRR 1.18; 95% CI: 1.01–1.37). The increased mortality rates were observed primarily for haematological and immune-related cancers.

Conclusions:

Overall, HZ was not a predictor of increased mortality following subsequent cancer.     

Combining clinicopathological predictors and molecular biomarkers in the oncogenic K-RAS/Ki67/HIF-1α pathway to predict survival in resectable pancreatic cancer

Background:

The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS hyperactivation is virtually universal in pancreatic cancer, that confers drug resistance, drives aggressive tumorigenesis and rapid metastasis. Pancreatic tumours are often marked by hypovascularity, increased hypoxia and ineffective drug delivery. Thus, biomarker discovery and developing innovative means of countervailing oncogenic K-RAS activation are urgently needed.

Methods:

Tumour specimens from 147 pancreatic cancer patients were analysed by immunohistochemical (IHC) staining and tissue microarray (TMA). Statistical correlations between selected biomarkers and clinicopathological predictors were examined to predict survival.

Results:

We find that heightened hypoxia response predicts poor clinical outcome in resectable pancreatic cancer. SIAH is a tumour-specific biomarker. The combination of five biomarkers (EGFR, phospho-ERK, SIAH, Ki67 and HIF-1α) and four clinicopathological predictors (tumour size, pathological grade, margin and lymph node status) predict patient survival post surgery in pancreatic cancer.

Conclusions:

Combining five biomarkers in the K-RAS/Ki67/HIF-1α pathways with four clinicopathological predictors may assist to better predict survival in resectable pancreatic cancer.