Ross Carruthers

Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer

Aim  Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour‐free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment.

An efficient targeted radiotherapy/gene therapy strategy utilising human telomerase promoters and radioastatine and harnessing radiation-mediated bystander effects

Targeted radiotherapy achieves malignant cell‐specific concentration of radiation dosage by tumour‐affinic molecules conjugated to radioactive atoms. Combining gene therapy with targeted radiotherapy is attractive because the associated cross‐fire irradiation of the latter induces biological bystander effects upon neighbouring cells overcoming low gene transfer efficiency.

Selective inhibition of parallel DNA damage response pathways optimizes radiosensitization of glioblastoma stem-like cells

Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2-M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2-M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC.

Abrogation of radioresistance in glioblastoma stem-like cells by inhibition of ATM kinase

Resistance to radiotherapy in glioblastoma (GBM) is an important clinical problem and several authors have attributed this to a subpopulation of GBM cancer stem cells (CSCs) which may be responsible for tumour recurrence following treatment. It is hypothesised that GBM CSCs exhibit upregulated DNA damage responses and are resistant to radiation but the current literature is conflicting. We investigated radioresistance of primary GBM cells grown in stem cell conditions (CSC) compared to paired differentiated tumour cell populations and explored the radiosensitising effects of the ATM inhibitor KU‐55933.

Accelerated hypo-fractionated radiotherapy for non small cell lung cancer: results from 4 UK centres.

BACKGROUND AND PURPOSE A variety of radiotherapy fractionations are used as potentially curative treatments for non-small cell lung cancer. In the UK, 55 Gy in 20 fractions over 4 weeks (55/20) is the most commonly used fractionation schedule, though it has not been validated in randomized phase III trials. This audit pooled together existing data from 4 UK centres to produce the largest published series for this schedule. MATERIALS AND METHODS 4 UK centres contributed data (Cambridge, Cardiff, Glasgow and Sheffield). Case notes and radiotherapy records of radically treated patients between 1999 and 2007 were retrospectively reviewed. Basic patient demographics, tumour characteristics, radiotherapy and survival data were collected and analysed. RESULTS 609 patients were identified of whom 98% received the prescribed dose of 55/20. The median age was 71.3 years, 62% were male. 90% had histologically confirmed NSCLC, 49% had stage I disease. 27% had received chemotherapy (concurrent or sequential) with their radiotherapy. The median overall survival from time of diagnosis was 24.0 months and 2 year overall survival was 50%. CONCLUSION These data show respectable results for patients treated with accelerated hypo-fractionated radiotherapy for NSCLC with outcomes comparable to those reported for similar schedules and represent the largest published series to date for 55/20 regime.

Cauda equina lymphoma – a rare presentation of primary central nervous system lymphoma: case report and literature review

The spinal cord is an extremely rare site for primary central nervous system (CNS) lymphoma (< 1%). Very few cases of primary cauda equina (including conus) lymphoma were previously reported. We report such a case, and with literature review, discuss their clinical features, operative and histopathological findings. Although rare, with an increasing incidence of CNS lymphoma, they should be considered in the differential diagnosis of intradural lesions. Furthermore, with intraoperative smear to establish diagnosis, extensive surgery can be avoided. The controversial role of glucocorticoids in the management of these patients is also discussed.

The potential of PARP inhibitors in neuro-oncology

DNA damaging agents have an integral role in the treatment of brain tumors. Recent advances in our understanding of how cancer cells repair DNA damage have made it possible to consider modification of the DNA damage response as a way in which resistance to radiotherapy and chemotherapy might be overcome. PARP inhibitors are potent but nontoxic drugs that inhibit repair of DNA single-strand breaks and increase the cytotoxic effects of radiotherapy and alkylating chemotherapy agents, including temozolomide. PARP inhibitors have potential applications in neuro-oncology because there is increasing evidence that their radio- and chemo-sensitizing effects are tumor specific. This review explores the mechanisms of action of PARP inhibitors and describes their putative mechanisms of radio- and chemo-sensitization in the context of CNS oncology. The authors go on to review their development in recent clinical trials, with a focus on glioblastoma.

Combination of PARP Inhibitors with Clinical Radiotherapy

Radiosensitisation of solid tumours by manipulation of the DNA damage response offers an opportunity to increase the effectiveness of radiotherapy in terms of enhanced local tumour control, better alleviation of symptoms and improved cure rates. PARP inhibitors are the best characterised DNA damage response inhibitors and possess many qualities that predict clinical utility as radiosensitisers. Pre-clinical data indicate that PARP inhibitors will provide tumour specific radiosensitisation and may be effective radiosensitisers of hypoxic tumour cells and cancer stem cells. They have minimal systemic toxicity as single agents and if combined with modern radiotherapy technology are likely to have acceptable ‘in-field’ toxicity. As such, they represent ideal candidate radiosensitisers for development in clinical trials. Significant challenges and opportunities exist in designing appropriate clinical trials that will assess toxicity and benefit from these agents in a rigorous manner. This chapter reviews the clinical rationale for the use of PARP inhibitors as radiosensitisers and summarises their current clinical development.

Real world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer

To investigate the uptake, safety and efficacy of docetaxel chemotherapy in hormone‐naïve metastatic prostate cancer (mPC) in the first year of use outside of a clinical trial.

Hidden in plain sight: promising therapeutic targets for glioblastoma lurk within DNA damage response pathways

In Dr. Herst’s excellent “Perspective”, the author reflects on recent attempts to improve outcomes for patients with glioblastoma (GBM) by combining conventional cytotoxic agents (radiation therapy and temozolomide) with molecular targeted agents. We agree with her conclusion that targeting epidermal growth factor receptor (EGFR) signalling and angiogenesis has been unsuccessful to date, despite the apparently sound scientific rationale and promising pre-clinical data. We found her argument that components of the DNA damage response (DDR) represent more promising therapeutic targets to be very persuasive, and value the opportunity to respond to some of the key points.