Combined Radiochemotherapy: Metalloproteinases Revisited

Besides cytotoxic DNA damage irradiation of tumor cells triggers multiple intra- and intercellular signaling processes, that are part of a multilayered, treatment-induced stress response at the unicellular and tumor pathophysiological level. These processes are intertwined with intrinsic and acquired resistance mechanisms to the toxic effects of ionizing radiation and thereby co-determine the tumor response to radiotherapy. Proteolysis of structural elements and bioactive signaling moieties represents a major class of posttranslational modifications regulating intra- and intercellular communication. Plasma membrane-located and secreted metalloproteinases comprise a family of metal-, usually zinc-, dependent endopeptidases and sheddases with a broad variety of substrates including components of the extracellular matrix, cyto- and chemokines, growth and pro-angiogenic factors. Thereby, metalloproteinases play an important role in matrix remodeling and auto- and paracrine intercellular communication regulating tumor growth, angiogenesis, immune cell infiltration, tumor cell dissemination, and subsequently the response to cancer treatment. While metalloproteinases have long been identified as promising target structures for anti-cancer agents, previous pharmaceutical approaches mostly failed due to unwanted side effects related to the structural similarities among the multiple family members. Nevertheless, targeting of metalloproteinases still represents an interesting rationale alone and in combination with other treatment modalities. Here, we will give an overview on the role of metalloproteinases in the irradiated tumor microenvironment and discuss the therapeutic potential of using more specific metalloproteinase inhibitors in combination with radiotherapy.

Present and Future of Anti-Glioblastoma Therapies: A Deep Look into Molecular Dependencies/Features

Glioblastoma (GBM) is aggressive malignant tumor residing within the central nervous system. Although the standard treatment options, consisting of surgical resection followed by combined radiochemotherapy, have long been established for patients with GBM, the prognosis is still poor. Despite recent advances in diagnosis, surgical techniques, and therapeutic approaches, the increased patient survival after such interventions is still sub-optimal. The unique characteristics of GBM, including highly infiltrative nature, hard-to-access location (mainly due to the existence of the blood brain barrier), frequent and rapid recurrence, and multiple drug resistance mechanisms, pose challenges to the development of an effective treatment. To overcome current limitations on GBM therapy and devise ideal therapeutic strategies, efforts should focus on an improved molecular understanding of GBM pathogenesis. In this review, we summarize the molecular basis for the development and progression of GBM as well as some emerging therapeutic approaches.

PATH-11. THE PROGNOSTIC ROLE OF IDH MUTATIONS IN HOMOGENEOUSLY TREATED PATIENTS WITH MALIGNANT DIFFUSE ASTROCYTOMAS

Detection of IDH mutations in patients with diffuse malignant astrocytomas resulted in substantial modifications in the WHO classification. An important observation was that patients with anaplastic astrocytomas (AA) IDH-wt had a clinical course similar to that glioblastoma (GBM) patients. The observations of the GGN and NOA-04, were based on mixed cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually only had radiotherapy or chemotherapy. This shortcoming raises the question whether AA IDH-wt patients did not behave prognostically better than GBM patients when receiving combined radiochemotherapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of IDH mutations are important if vascular proliferation or necrosis are undetectable. All patients investigated here with diagnosis of a malignant astrocytoma received combined standard radiochemotherapy independently of the histopathological diagnosis. Thus, the analysis allows to clarify whether patients with AA of IDH-wt have a prognosis similar to that of GBM patients under equivalent therapeutic conditions. We determined the IDH1/2 status by sequencing, the MGMT status by pyrosequencing. Patients with the histopathological diagnosis of an AA IDH-wt showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a glioblastoma (mOS 13 months). Instead, patients with an AA IDH-mut receiving same therapy had a mOS of 54 months. Thus, it can be concluded that in absence of IDH mutations, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and IDH mutations are examined, there is a difference between patients showing necrosis and/or vascular proliferation and those whose tumors do not. Accordingly, for patients with malignant astrocytomas with IDH mutations it can be concluded that differentiation between AA IDH-mut and GBM IDH-mut remains beneficial from a prognostic perspective.

The prognostic role of IDH mutations in homogeneously treated patients with anaplastic astrocytomas and glioblastomas

The detection of IDH mutations in patients with diffusely infiltrating malignant astrocytomas resulted in substantial modifications in the concept of WHO classification of these tumors. An important underlying observation was that patients with anaplastic astrocytomas (AA) without IDH mutation had a clinical course similar to that of patients with glioblastomas (GBM). The underlying observations of the German Glioma Network and NOA-04, however, were based on mixed patient cohorts. While most GBM patients received combined radiochemotherapy, patients with AA usually had radiotherapy or chemotherapy only. This intrinsic shortcoming of the study raised the question of whether patients with AA, IDH wildtype, WHO grade III, might have better prognosis if treated with combined radiochemotherapy than patients with GBM receiving the same combination therapy. Thus, the question remains whether the established histopathological grading criteria for malignant astrocytomas in the absence of an IDH mutation are still important if neither vascular proliferation nor necrosis are detectable. All patients in the cohort investigated here with the diagnosis of AA or GBM were subjected to a combined radiochemotherapy according to the Stupp protocol independently of the histopathological diagnosis. Thus, the analysis of these patients allows to clarify whether patients with AA, IDH wildtype, WHO grade III have a prognosis similar to that of GBM, IDH wildtype, WHO grade IV, even under equivalent therapeutic conditions. We determined the IDH1 and IDH2 status by sequencing, the MGMT status by pyrosequencing after bisulfite treatment and the EGFR status of the patients by FISH. In fact, the patients with the histopathological diagnosis of an AA IDH wild-type under similar aggressive therapy showed a comparable and therefore no better prognosis (median overall survival (mOS) 16 months) than patients with a GBM (mOS 13 months). Instead, patients with an AA and an IDH mutation receiving the same therapy had a mOS of 54 months. Thus, it can be concluded that in the absence of an IDH mutation, the established histopathological grading criteria ‘necrosis’ and ‘vascular proliferation’ actually lose their prognostic significance. If, on the other hand, patients with malignant astrocytomas and an IDH mutation are examined, there is still a difference between patients with necrosis and/or vascular proliferation and those whose tumors do not show such characteristics. Accordingly, in patients with malignant astrocytomas with IDH mutation it can be concluded that a histological differentiation between AA IDH mutated and GBM IDH mutated remains beneficial from a prognostic perspective.