Factors affecting the radiation response in glioblastoma.

Glioblastoma (GBM) is a highly invasive primary brain tumor in adults with a 5-year survival rate of less than 10%. Conventional radiotherapy with photons, along with concurrent and adjuvant temozolomide, is the mainstay for treatment of GBM although no significant improvement in survival rates has been observed over the last 20 years. Inherent factors such as tumor hypoxia, radioresistant GBM stem cells, and upregulated DNA damage response mechanisms are well established as contributing to treatment resistance and tumor recurrence. While it is understandable that efforts have focused on targeting these factors to overcome this phenotype, there have also been striking advances in precision radiotherapy techniques, including proton beam therapy and carbon ion radiotherapy (CIRT). These enable higher doses of radiation to be delivered precisely to the tumor, while minimizing doses to surrounding normal tissues and organs at risk. These alternative radiotherapy techniques also benefit from increased biological effectiveness, particularly in the case of CIRT. Although not researched extensively to date, combining these new radiation modalities with radio-enhancing agents may be particularly effective in improving outcomes for patients with GBM

In vitro radiosensitization of breast cancer with hypoxia-activated prodrugs

KP167 is a novel hypoxia-activated prodrug (HAP), targeting cancer cells via DNA intercalating and alkylating properties. The single agent and radiosensitizing efficacy of KP167 and its parental comparator, AQ4N, were evaluated in 2D and 3D cultures of luminal and triple negative breast cancer (TNBC) cell lines and compared against DNA damage repair inhibitors. 2D normoxic treatment with the DNA repair inhibitors, Olaparib or KU-55933 caused, as expected, substantial radiosensitization (sensitiser enhancement ratio, SER0.01 of 1.60-3.42). KP167 induced greater radiosensitization in TNBC (SER0.01 2.53 in MDAMB-231, 2.28 in MDAMB-468, 4.55 in MDAMB-436) and luminal spheroids (SER0.01 1.46 in MCF-7 and 1.76 in T47D cells) compared with AQ4N. Significant radiosensitization was also obtained using KP167 and AQ4N in 2D normoxia. Although hypoxia induced radioresistance, radiosensitization by KP167 was still greater under 2D hypoxia, yielding SER0.01 of 1.56-2.37 compared with AQ4N SER0.01 of 1.13-1.94. Such data show KP167 as a promising single agent and potent radiosensitiser of both normoxic and hypoxic breast cancer cells, with greater efficacy in TNBCs

CYP2S1 and CYP2W1 expression is associated with patient survival in breast cancer

The cytochrome P450 family of enzymes metabolise a wide range of compounds and play important roles in breast cancer pathogenesis due to their involvement in estrogen metabolism and the production of carcinogenic metabolites during this process. The orphan CYPs, CYP2S1, and CYP2W1 are reportedly upregulated in breast cancer. However, their expression and association with clinicopathological and survival parameters have not been previously assessed in a large cohort of breast cancers. Protein expression of CYP2S1 and CYP2W1 was assessed in early-stage invasive breast cancers (n = 1,426) using immunohistochemistry and correlated with various clinicopathological parameters and survival. mRNA expression of CYP2S1 and CYP2W1 was also assessed in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Low nuclear and cytoplasmic CYP2S1 was significantly associated with high-grade tumours (p ≤ 0.009), intermediate Nottingham prognostic index (NPI) group (p ≤ 0.025), high mitotic frequency (p ≤ 0.002), human epidermal growth factor receptor 2 (HER2)-negative disease (p ≤ 0.011), and ductal carcinoma (p ≤ 0.022). Cytoplasmic CYP2S1 was additionally associated with patients ≥50 years (p < 0.001), estrogen receptor (ER)-positive tumours (p = 0.011), and high nuclear pleomorphism (p = 0.003). Low cytoplasmic CYP2W1 was significantly associated with patients ≥50 years (p = 0.002), HER2-negative disease (p = 0.003), intermediate NPI (p = 0.013), and mitosis (p = 0.009). Low cytoplasmic CYP2S1 was significantly associated with adverse breast cancer specific survival (p = 0.034), which remained so in multivariate analysis (hazard ratio [HR]: 0.639; 95% confidence interval [CI]: 0.483-0.846; p = 0.002). Low nuclear CYP2W1 was significantly associated with adverse breast cancer specific survival (p = 0.012), with significance also maintained in multivariate analysis (HR: 0.677; 95% CI: 0.510-0.898; p = 0.007). No associations with survival were observed in the METABRIC cohort. CYP2S1 and CYP2W1 are associated with patient survival in breast cancer and may be important prognostic biomarkers

A retrospective analysis of ezrin protein and mRNA expression in breast cancer: Ezrin expression is associated with patient survival and survival of patients with receptor‐positive disease

Introduction: The cytoskeletal protein ezrin is upregulated in many cancer types and is strongly associated with poor patient outcome. While the clinical and prognostic value of ezrin has been previously evaluated in breast cancer, most studies to date have been conducted in smaller cohorts (less than 500 cases) or have focused on specific disease characteristics. The current study is the largest of its kind to evaluate ezrin both at the protein and mRNA levels in early‐stage breast cancer patients using the Nottingham (n = 1094) and METABRIC (n = 1980) cohorts, respectively. Results: High expression of ezrin was significantly associated with larger tumour size (p = 0.027), higher tumour grade (p < 0.001), worse Nottingham Prognostic Index prognostic group (p = 0.011) and HER2‐positive status (p = 0.001). High ezrin expression was significantly associated with adverse survival of breast cancer patients (p < 0.001) and remained associated with survival in multivariate Cox‐regression analysis (p = 0.018, hazard ratio (HR) = 1.343, 95% confidence interval (CI) = 1.051–1.716) when potentially confounding factors were included. High ezrin expression was significantly associated with adverse survival of patients whose tumours were categorised as receptor (oestrogen receptor (ER), progesterone receptor (PgR) or HER2) positive (p < 0.001) in comparison to those categorised as triple‐negative breast cancer (p = 0.889). High expression of ezrin mRNA (VIL2) in the METABRIC cohort was also significantly associated with adverse survival of breast cancer patients (p < 0.001). Conclusion: Retrospective analyses show that ezrin is an independent prognostic marker, with higher expression associated with shortened survival in receptor‐positive (ER, PgR or HER2) patients. Ezrin expression is associated with more aggressive disease and may have clinical utility as a biomarker of patient prognosis in early‐stage breast cancer

High BMP7 expression is associated with poor prognosis in ovarian cancer

Bone Morphogenetic Protein 7 (BMP7) is an extracellular signalling protein that belongs to the transforming growth factor‐β (TGF‐ β) superfamily. Previous transcriptomic data suggested that BMP7 expression may be disrupted in ovarian carcinoma and may play an important role in the aggressiveness of the disease. However, the protein expression in patient tumours has not been well studied. The current study aimed to assess BMP7 protein expression in a large cohort of ovarian carcinoma patient tumour samples to establish its associations with different clinical endpoints. Ovarian carcinoma tissue samples from 575 patients who underwent surgery for different subtypes of ovarian cancer were used. BMP7 protein expression was analysed by immunohistochemistry using tissue microarray and full face tumour sections. High BMP7 expression is associated with aggressive ovarian cancer clinicopathological variables including advanced FIGO stage, high grade, residual disease and poor overall survival. Elevated cytoplasmic and nuclear BMP7 expression was significantly associated with advanced FIGO stage, high tumour grade, presence of residual tumours and high‐grade serous carcinomas (p = 0.001, 0.005, 0.004, <0.001 and p < 0.001, <0.001, 0.002, 0.001 respectively). Increased cytoplasmic and nuclear BMP7 expression was also significantly associated with an adverse overall survival (p = 0.001 and 0.046 respectively). The study highlights the potential of BMP7 as a prognostic tool and as a potential novel target for ovarian cancer therapies to limit disease progression