Michael Siedow

Molecular Advances of Brain Tumors in Radiation Oncology

Glioblastoma, grade IV malignant glioma based on the World Health Organization classification, is the most common primary brain tumor in adults. The average survival time of less than 1 year has not improved notably over the last 3 decades. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, whereas the value of chemotherapy has been marginal and controversial. The dismal prognosis of glioblastoma patients is largely caused by the striking radioresistance of these tumors. A better understanding of the molecular mechanisms that underlie the malignant phenotype of glioblastomas and plausible mechanisms of radiation resistance can provide new possibilities in terms of targeted therapeutic strategies. Despite the genetic heterogeneity of malignant gliomas, common aberrations in the signaling elements of the growth and survival pathways are found. New treatments have emerged to target molecules in these signaling pathways with the goal to increase specific efficacy and minimize toxicity. Monoclonal antibodies and low molecular-weight kinase inhibitors are the most common classes of agents in targeted cancer treatment. This review introduces these new targeted therapies in the context of current treatment options for patients with glioblastoma. It is hoped that this combined approach will overcome the current limitations in the treatment of patients with glioblastoma and result in a better prognosis for these patients.

Inhibition of p21-activated kinase 6 (PAK6) increases radiosensitivity of prostate cancer cells.

p21‐activated kinase 6 (PAK6) is a serine/threonine kinase belonging to the p21‐activated kinase (PAK) family. We investigated the role of PAK6 in radiation‐induced cell death in human prostate cancer cells.

Survivin Is a Potential Mediator of Prostate Cancer Metastasis

PURPOSE We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer. METHODS AND MATERIALS A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5-127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34→Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated. RESULTS Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. CONCLUSIONS This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.

Technological Advances in Radiation Oncology for Central Nervous System Tumors

Advances in computer software technology have led to enormous progress that has enabled increasing levels of complexity to be incorporated into radiotherapy treatment planning systems. Because of these changes, the delivery of radiotherapy evolved from therapy designed primarily on plain 2-dimensional X-ray images and hand calculations to therapy based on 3-dimensional images incorporating increasingly complex computer algorithms in the planning process. In addition, challenges in treatment planning and radiation delivery, such as problems with setup error and organ movement, have begun to be systematically addressed, ushering in an era of so-called 4-dimensional radiotherapy. This review article discusses how these advances have changed the way in which many common neoplasms of the central nervous system are being treated at present.

Antiangiogenic therapy for patients with recurrent and newly diagnosed malignant gliomas.

Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression-free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas.

Abstract 1077: Galectin-1 is implicated in G1/S-checkpoint control following irradiation - possible explanation of Galectin-1 mediated radioresistance

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Purpose: The purpose of the conducted study was to examine a possible therapeutic relevance of Galectin 1 (Gal-1), a beta-galactoside binding protein. Gal-1 is overexpressed in high grade gliomas and leads to increased radioresistance in glioma cell culture models. Inhibition of Gal-1 increases radiosensitivity and thus is a potential therapeutic target for radiation sensitization. P53 has been shown to negatively regulate Gal-1, hence radiosensitivity could possibly be cell cycle mediated. Experimental Design: We used flow cytometry based cell cycle analysis to investigate cell cycle distribution of LN 229 glioma cells following irradiation. LN229 control cell lines and shRNA mediated Gal-1 knockdown LN 229 cell line were exposed to 6 Gy of irradiation and cell cycle analysis was performed. Furthermore Western blot analysis was carried out, probing for multiple proteins implicated in cell proliferation. The phosphorylation status of a variety of phosphorylation sites of p53, Chk1/2 and AKT were examined. Additionally p53-Gal-1 double-knockdown cell lines were created and clonogenic survival assays as well as AnnexinV apoptosis assays were conducted to analyze the influence on radiation sensitivity. Results: The results of the flow cytometry based cell cycle analysis show significant differences between the LN 229 control cell line and the Gal-1 knockdown cell line after irradiation. 24 h after irradiation 77 % of the control line cells are in G1 whereas only 60 % of the Gal-1 knockdown cells are in G1. Previous data has identified differences in the phosphorylation status of Akt in control vs. Gal-1 knockdown glioma cell lines. Phosphorylation of Akt is induced after irradiation. Western blot analysis indicates a reduction of phosphorylated Chk1/2 in Gal1 knockdown cell lines after irradiation. The phosphorylation state of the p53 phosphorylation site, correlating with Chk1/2 activity, exhibit anticipated results. P53-Gal-1 double-knockdown cell lines demonstrate significantly reduced clonogenic survival compared to control cell lines. Conclusions: The finding that less Gal-1 knockdown cells are in G1 phase after irradiation and that there is a reduction in phosphorylated Chk1/2 leads to the conclusion that Gal-1 knockdown abrogates G1 arrest through a Chk1/2 mediated pathway. That means in reverse that Gal-1 can mediate cell cycle arrest, thus potentially can explain Gal-1 mediated radioresistance. Further analysis of Chk1/2 independent phosphorylation sites of p53 is going to be conducted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1077.