Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer

Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.

Prognostic Value of Tumour Size in Colon Cancer – Smaller is Better?

Background: The prognostic value of tumour size in colon cancer remains controversial. This study aimed to reveal the correlation between tumour size and prognosis of colon cancer.Methods: A total of 498 patients with colon cancer were included in this study. The correlation of tumour size with prognosis, mismatch repair status and other clinicopathological characteristics as well as tumour microenvironment was analysed.Results: For stage IIA microsatellite stable (MSS) colon cancer, tumours sized <3.5 cm and ≥5 cm were associated with a poorer disease free survival (DFS) compared with tumours sized between 3.5 and 5 cm (p=0.002). Small tumour size (HR=5.098, p=0.001) and large tumour size (HR=2.749, p=0.029) were found to be independent prognostic factors for stage IIA MSS colon cancer. Moreover, high expression of transgelin (TAGLN), a marker of cancer-associated fibroblasts (CAFs), was found to be an independent prognostic factor for poorer DFS (HR=9.651, p=0.009), which was also associated with smaller tumour size (p=0.027).Conclusion: Small (<3.5 cm) and large (≥5 cm) tumour sizes are associated with decreased DFS in stage IIA MSS colon cancer. Enrichment of TAGLN+ CAFs is associated with decreased DFS and small tumour size.

A mathematical investigation of different growth rates in simultaneous tumors at two distant sites

Experimental data demonstrates that simultaneous injection of cancer cells at two distinct sites often results in one large and one small tumour. Unbalanced tumour-stimulating inflammation is hypothesized to be the cause of this growth rate separation, causing one tumour to grow faster than the other. Here, a mathematical model for immune recruitment and competition between two cancer sites is developed to explore the role of tumour-promoting inflammation in the observed growth rate separation. Due to the experimental set-up, immune predation may be neglected, focusing the model on tumour-promoting immune actions. A new mathematical model with localized immune recruitment and competition between the two cancer sites is developed using a multi-compartment ODE system. A simulated annealing algorithm is used to fit the model to control data (one tumour burden). Stability and parameter sensitivity analyses are used to explore the mathematical model and parameter space. Next, the two-tumour scenario is predicted by testing parameter values tied to possible biological mechanisms of action. The model predicts that indeed inflammation may be a contributor to growth rate separation observed in simultaneous tumour growth, if one site is pre-inflamed compared to the other.

A mathematical investigation of different growth rates in simultaneous tumors at two distant sites

Experimental data demonstrates that simultaneous injection of cancer cells at two distinct sites often results in one large and one small tumour. Unbalanced tumour-stimulating inflammation is hypothesized to be the cause of this growth rate separation, causing one tumour to grow faster than the other. Here, a mathematical model for immune recruitment and competition between two cancer sites is developed to explore the role of tumour-promoting inflammation in the observed growth rate separation. Due to the experimental set-up, immune predation may be neglected, focusing the model on tumour-promoting immune actions. A new mathematical model with localized immune recruitment and competition between the two cancer sites is developed using a multi-compartment ODE system. A simulated annealing algorithm is used to fit the model to control data (one tumour burden). Stability and parameter sensitivity analyses are used to explore the mathematical model and parameter space. Next, the two-tumour scenario is predicted by testing parameter values tied to possible biological mechanisms of action. The model predicts that indeed inflammation may be a contributor to growth rate separation observed in simultaneous tumour growth, if one site is pre-inflamed compared to the other.

Rapid EGFR evaluation from used H&E, IHC and FISH diagnostic slides with the Idylla platform

AimsDiagnostic tumour samples are mandatory for morphologic and molecular diagnosis of non-small cell lung cancer (NSCLC) to establish the best therapeutic approach. In the presence of small tumour tissue sample, the pathologist needs to make responsible choices to achieve a correct diagnosis and save material for subsequent molecular evaluations. Nevertheless, in some instances, the diagnostic process can lead to tissue depletion. The automated Idylla epidermal growth factor receptor (EGFR) mutation test has been developed to rapidly process formalin-fixed paraffin-embedded (FFPE) pathologic material, without previous DNA extraction. This study aimed to test whether this platform is suitable for the reuse of H&E, immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) diagnostic slides.MethodsA training set of 19 FFPE tissues with known EGFR status was revaluated on H&E slides. Fourteen of them were also tested using IHC and FISH treated specimens. An additional series of 25 H&E, IHC or FISH slides of NSCLC cases tested for EGFR mutation at an external institution was blindly assessed as a validation cohort.ResultsCombining the two sets, 32 of 32 classical ex19dels and p.L858R were correctly identified. Three uncommon mutations (p.G719X, p.L861Q and ex20ins) were also detected. Four discrepancies were related to rare ex19del/ins not included in the Idylla list of detectable mutations. Two p.T790M variants were missed on one FFPE and two H&E slides but were detected using IHC and FISH sections from the same FFPE blocks.ConclusionsThe Idylla EGFR mutation test is highly reliable using differently treated tumour specimens and should be validated in larger studies.

Small choroidal melanoma: outcomes following apical height dose brachytherapy

AimTo assess the outcomes of small choroidal melanoma following iodine-125 episcleral brachytherapy (apical height dose of 85 Gy).MethodsPatients with small choroidal melanoma that underwent iodine-125 episcleral brachytherapy between January 2004 and December 2017 were reviewed. Inclusion criterion for this study was the COMS small tumour size (tumour apical height of 1.0–2.5 mm and largest basal diameter (LBD) <16.0 mm). Patients that received any form of prior therapy or adjuvant transpupillary thermotherapy were excluded. Outcome measures were visual acuity (VA), recurrence, ocular survival and metastasis at 3 years. Kaplan-Meier estimation was calculated for VA, recurrence, ocular survival and survival outcome (overall and metastasis-free survival rate) at 3 years.Results161 cases of choroidal melanoma were included in this study, with the mean (SD) age of 59.6 (14.1) years, and 93 (58%) were males. The mean (SD) apical height for the tumours were 2.1 (0.4) mm and mean (SD) LBD was 8.3 (2.2) mm. The mean (SD, median) follow-up was 40.7 months (37.1, 25 months). The VA was 20/50 or better in 69%. Only one recurrence event (1%) and one enucleation event (1%) were observed. Overall survival was 97%, and no metastatic events were observed at 3 years.ConclusionSmall choroidal melanomas treated with iodine-125 episcleral brachytherapy have excellent outcomes. The majority (69%) of patients retained VA of 20/50 or better with very high local control and ocular survival rate (99.3%) with the absence of metastasis (100%).

Merkel cell polyomavirus small tumour antigen activates the p38 MAPK pathway to enhance cellular motility

Merkel cell carcinoma (MCC) is an aggressive skin cancer with high rates of recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is associated with the majority of MCC cases. MCPyV-induced tumourigenesis is largely dependent on the expression of the small tumour antigen (ST). Recent findings implicate MCPyV ST expression in the highly metastatic nature of MCC by promoting cell motility and migration, through differential expression of cellular proteins that lead to microtubule destabilisation, filopodium formation and breakdown of cell–cell junctions. However, the molecular mechanisms which dysregulate these cellular processes are yet to be fully elucidated. Here, we demonstrate that MCPyV ST expression activates p38 MAPK signalling to drive cell migration and motility. Notably, MCPyV ST-mediated p38 MAPK signalling occurs through MKK4, as opposed to the canonical MKK3/6 signalling pathway. In addition, our results indicate that an interaction between MCPyV ST and the cellular phospatase subunit PP4C is essential for its effect on p38 MAPK signalling. These results provide novel opportunities for the treatment of metastatic MCC given the intense interest in p38 MAPK inhibitors as therapeutic agents.

Mathematically modelling inflammation as a promoter of tumour growth

Inflammation is now known to play a significant role in tumour growth and progression. It is also difficult to adequately quantify systemic inflammation and the resulting localized effects in cancer. Here, we use experimental data to infer the possible contributions of inflammation in a mouse model of cancer. The model is validated by predicting tumour growth under anti-inflammatory treatments, and combination cancer therapies are explored. We then extend the model to consider simultaneous tumour implants at two distinct sites, which experimentally was shown to result in one large and one small tumour. We use this model to examine the role inflammation may play in the growth rate separation. Finally, we use this predictive two-tumour model to explore implications of inflammation on metastases, surgical removal of the primary and adjuvant anti-inflammatory treatments. This work suggests that improved tumour control can be obtained by targeting both the cancer and host, through anti-inflammatory treatments, including reduced metastatic burden post-surgical removal of primary tumours.