1,2:5,6-Dianhydrogalactitol (DAG) is a bifunctional DNA-targeting agent causing N7-guanine alkylation and inter-strand DNA crosslinks currently in clinical trial for treatment of glioblastoma. While preclinical studies and clinical trials have demonstrated antitumor activity of DAG in a variety of malignancies, understanding the molecular mechanisms underlying DAG-induced cytotoxicity is essential for proper clinical qualification. Using non-small cell lung cancer (NSCLC) as a model system, we show that DAG-induced cytotoxicity materializes when cells enter S phase with unrepaired N7-guanine DNA crosslinks. In S phase, DAG-mediated DNA crosslink lesions translated into replication-dependent DNA double-strand breaks (DSBs) that subsequently triggered irreversible cell cycle arrest and loss of viability. DAG-treated NSCLC cells attempt to repair the DSBs by homologous recombination (HR) and inhibition of the HR repair pathway sensitized NSCLC cells to DAG-induced DNA damage. Accordingly, our work describes a molecular mechanism behind N7-guanine crosslink-induced cytotoxicity in cancer cells and provides a rationale for using DAG analogs to treat HR-deficient tumors.

On July 24, 2020, a workshop sponsored by the National Brain Tumor Society was held on innovating brain tumor clinical trials based on lessons learned from the COVID-19 experience. Various stakeholders from the brain tumor community participated including the US Food and Drug Administration (FDA), academic and community clinicians, researchers, industry, clinical research organizations, patients and patient advocates, and representatives from the Society for Neuro-Oncology and the National Cancer Institute. This report summarizes the workshop and proposes ways to incorporate lessons learned from COVID-19 to brain tumor clinical trials including the increased use of telemedicine and decentralized trial models as opportunities for practical innovation with potential long-term impact on clinical trial design and implementation.

INTRODUCTION: Bevacizumab has been reported to be an effective treatment for symptomatic radiation necrosis and to decrease focal edema around areas of radiation necrosis. We report our preliminary results and ongoing clinical trial of bevacizumab treatment for radiation necrosis. METHODS: Thirteen patients with symptomatic radiation necrosis were treated with bevacizumab. Radiation necrosis was diagnosed according to the patients' clinical courses, magnetic resonance images, and fluoridelabeled boronophenylalanine-positron emission tomography (F-BPA-PET). Lesion/normal (L/N) ratios less than 2.0 and 2.5 on F-BPA-PET were defined as absolute and relative indications for bevacizumab treatment, respectively. The patients were treated with bevacizumab at a dose of 5 mg/ kg every 2 weeks, 6 cycles in total. RESULTS: Two patients were excluded from analysis because of adverse events. Eleven patients underwent 3 to 6 cycles of bevacizumab treatment. The median rate of the reduction in peri-lesional edema was 65.5% (range: 2.0% to 81.0%). The Karnofsky performance status (KPS) improved in 6 patients after bevacizumab treatment, and in 5 patients the status did not change. The L/N ratio on F-BPA-PET (P ¼ 0.0084) and the improvement of KPS after bevacizumab (P ¼ 0.0228) were significantly associated with the reduction rate of peri-lesional edema after bevacizumab treatment. CONCLUSION: Bevacizumab is a very effective treatment for radiation necrosis, irrespective of the original tumor histology. F-BPA-PET could be useful for diagnosing radiation necrosis and for making the decision as to whether or not to treat symptomatic radiation necrosis with bevacizumab. The clinical trial "Intra-venous administration of bevacizumab for the treatment of radiation necrosis in the brain" has been approved as Investigational Medical Care System by the Japanese Ministry of Health, Labour and Welfare. This trial has been ongoing since April, 2011.

Determination of therapeutic benefit in intracranial tumors is intimately dependent on serial assessment of radiographic images. The Response Assessment in Neuro-Oncology (RANO) criteria were established in 2010 to provide an updated framework to better characterize tumor response to contemporary treatments. Since this initial update a number of RANO criteria have provided some basic principles for the interpretation of changes on MR images; however, the details of how to operationalize RANO and other criteria for use in clinical trials are ambiguous and not standardized. In this review article designed for the neuro-oncologist or treating clinician, we outline essential steps for performing radiographic assessments by highlighting primary features of the Imaging Charter, a document that describes the clinical trial imaging methodology, and methods to ensure operationalization of the Charter into the workings of a clinical trial. Lastly, we provide recommendations for specific changes to optimize this methodology for neuro-oncology, including image registration, requirement of growing tumor for eligibility in trials of recurrent tumor, standardized image acquisition guidelines, and hybrid reader paradigms that allow for both unbiased measurements and more comprehensive interpretation.

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Mergers and acquisitions (M&A) are increasingly being included by biopharmaceutical companies within earlier stage strategies as a means of accelerating technology development and thus quickening the path to shareholder value. These drivers are generally different from those of the larger established pharmaceutical companies that are more earnings focused. The authors consider some of the drivers of and hurdles to the successful implementation of M&A from both a national and cross-border perspective. In 2000 the number of cross-border transactions increased to 41 per cent of all M&A deals; however, generally, returns from international transactions are much lower. The authors also consider the important issues of determination of the price to be paid and the use of stock as 'currency'.

This article argues for the establishment of a usability process that incorporates the study of “words” and “word phrases.” It demonstrates how semantically mapping a navigational taxonomy can help the developers of digital environments establish a more focused sense of functional meaning for the users of their digital designs.

Poor outcomes in cancer therapy due to chemo-resistance remain a significant unmet clinical problem for many solid tumors and leukemias. VAL-083 (dianhydrogalactitol) represents a structurally unique first-in-class N7-bifunctional DNA alkylating agent. VAL-083 primarily mediates guanine N7 DNA cross-links, which separates it from other DNA alkylating chemotherapeutics (e.g. temozolomide) that have their primary cytotoxicity by targeting DNA at the O6 position of guanine. As expected from its mechanism, VAL-083 overcomes resistance associated with O6-methylguanine-DNA methyltransferase (MGMT) overexpression in vitro. Furthermore, unlike other N7-acting drugs, such as cisplatin which primarily induces intrastrand crosslinks, VAL-083 mediates interstrand DNA crosslinks. When tested side-by-side in a standard syngeneic mouse fibrosarcoma model (RIF-1 cell-line in C3H mice), VAL-083 demonstrated superiority to cisplatin in tumor growth delay. For mice treated with a single injection of cisplatin of 4 mg/kg, the tumor growth delay was 1.45 days compared to untreated controls. Single IP injection of VAL-083 at a dose of 10 mg/kg delayed tumor growth by 5.6 days. Combination treatment of VAL-083 followed immediately by cisplatin produced a more than additive effect by delaying growth 8.65 days. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tissue and is effective against brain tumor cells both in vitro and in vivo, and against brain cancer stem cells in vitro. VAL-083 is currently in Phase I/II clinical trials for glioblastoma and recurrent metastatic brain tumors. Studies are underway to further characterize the efficacy of VAL-083 in various tumor cell-lines resistant to chemotherapy. Previous clinical studies showing VAL-083 activity in several tumor models, combined with the new data on MGMT-chemo-resistance and synergy with cisplatin makes VAL-083 a promising alternative for both primary and secondary brain tumors as well as cisplatin-resistant tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B252. Citation Format: Anne Steino, Jeffrey A. Bacha, William J. Garner, Sarath Kanekal, Zahid H. Siddik, Dennis M. Brown. The unique mechanism of action of VAL-083 may provide a new treatment option for some chemo-resistant cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B252.