Diverse temporal and spatial mechanisms work, partially through Stanniocalcin-1, V-ATPase and senescence, to activate the extracellular ATP-mediated drug resistance in human cancer cells.

Introduction: Resistance to drug therapies is associated with a large majority of cancer-related deaths. ATP-binding cassette (ABC) transporter-mediated drug efflux, epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), glutathione (GSH), senescence, and vacuole-type ATPase (V-ATPase) all contribute to the resistance. We recently showed that extracellular ATP (eATP) induces and regulates EMT, CSC formation, and ABC transporters in human cancer cells and tumors. eATP also consistently upregulates Stanniocalcin-1 (STC1), a gene that significantly contributes to EMT, CSC formation, and tumor growth. We also found that eATP enhances drug resistance in cancer cells through eATP internalization mediated by macropinocytosis, leading to an elevation of intracellular ATP (iATP) levels, induction of EMT, and CSC formation. However, these factors have never been systematically investigated in the context of eATP-induced drug resistance. Methods: In this study, we hypothesized that eATP increases drug resistance via inducing ABC efflux, EMT, CSCs, STC1, and their accompanied processes such as GSH reducing activity, senescence, and V-ATPase. RNA sequencing, metabolomics, gene knockdown and knockout, and functional assays were performed to investigate these pathways and processes. Results and discussion: Our study results showed that, in multiple human cancer lines, eATP induced genes involved in drug resistance, elevated ABC transporters' efflux activity of anticancer drugs; generated transcriptomic and metabolic profiles representing a drug resistant state; upregulated activities of GSH, senescence, and V-ATPase to promote drug resistance. Collectively, these newly found players shed light on the mechanisms of eATP-induced as well as STC1- and V-ATPase-mediated drug resistance and offer potential novel targets for combating drug resistance in cancers.

Interobserver variability in target volume delineation for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer.

OBJECTIVES: Quantify target volume delineation uncertainty for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer. Define optimal imaging sequences for target delineation. METHODS: Six experienced radiation oncologists delineated clinical target volumes (CTVs) on CT and 2D and 3D-MRI in three patients with rectal cancer, using consensus contouring guidelines. Tumour GTV (GTVp) was also contoured on MRI acquired week 0 and 3 of radiotherapy. A STAPLE contour was created and volume and interobserver variability metrics were analysed. RESULTS: There were statistically significant differences in volume between observers for CT and 2D-MRI-defined CTVs (p < 0.05). There was no significant difference between observers on 3D-MRI. Significant differences in volume were seen between observers for both 2D and 3D-MRI-defined GTVp at weeks 0 and 3 (p < 0.05). Good interobserver agreement (IOA) was seen for CTVs delineated on all imaging modalities with best IOA on 3D-MRI; median Conformity index (CI) 0.74 for CT, 0.75 for 2D-MRI and 0.77 for 3D-MRI. IOA of MRI-defined GTVp week 0 was better compared to CT; CI 0.58 for CT, 0.62 for 2D-MRI and 0.7 for 3D-MRI. MRI-defined GTVp IOA week three was worse compared to week 0. CONCLUSION: Delineation on MRI results in smaller volumes and better IOA week 0 compared to CT. 3D-MRI provides the best IOA in CTV and GTVp. MRI-defined GTVp on images acquired week 3 showed worse IOA compared to week 0. This highlights the need for consensus guidelines in GTVp delineation on MRI during treatment course in the context of dose escalation MRI-guided rectal boost studies. ADVANCES IN KNOWLEDGE: Optimal MRI sequences for CT/MRI simulation and MRI-guided adaptive radiotherapy in rectal cancer have been defined.

Considerations for the treatment of pancreatic cancer during the COVID-19 pandemic: the UK consensus position.

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.

Comparison of the dose escalation potential for two hypofractionated radiotherapy regimens for locally advanced pancreatic cancer.

OBJECTIVES: To determine the potential for dose escalation to a biological equivalent dose BED10 ≅ 100 Gy in hypofractionated radiotherapy for locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ten unselected LAPC patients were retrospectively included in the study. Two fractionation regimens were compared (5 and 15 fractions). The aim was to cover 95% of the Planning Target Volume (PTV) with a BED10 = 54 Gy (base dose = 33 Gy in 5 fractions, 42.5 Gy in 15 fractions) whilst respecting organs-at-risk (OAR) constraints. Once the highest PTV coverage was achieved dose escalation to a BED10 ≅ 100 Gy (escalated dose = 50 Gy in 5 fractions, 67.5 Gy in 15 fractions) was attempted, limiting the PTV maximum dose to 130% of the escalated dose. RESULTS: In 5 fractions, 95% PTV coverage by both base and escalated doses could be achieved for one patient with PTV more than 1 cm away from OAR. 95% and 90% PTV coverage by the base dose was achieved in one and two patients respectively. In all other patients, coverage even by the base dose had to be compromised to comply with OAR constraints. In 15 fractions, 95% PTV coverage by the base dose was feasible for all patients except one. Dose escalation allowed improvement in target coverage by the base dose in both fractionation regimen whilst covering a sub-volume of the PTV with a BED10 ≅ 100 Gy. Both fractionation schemes were equivalent in terms of dose escalation potential. CONCLUSION: LAPC patients with OAR close to the PTV are generally not eligible for hypofractionation with dose escalation. However, this planning study shows that it is possible to cover PTV sub-volumes with a BED10 ≅ 100 Gy in addition to delivering a BED10 = 54 Gy to 90-95% of the PTV as commonly prescribed to this population. Combined with an adaptive approach, this may maximize PTV coverage by a high BED on days with favourable anatomy.