Potential molecular targets for diagnosis and therapy of malignant gliomas

Abstract

Aivokasvaimet ovat lisääntyvästä lääketieteellisestä tiedosta ja tekniikasta huolimatta vaikeasti hoidettava kasvainryhmä. Eritoten pahanlaatuiset glioomat ovat haastavia hoitaville lääkäreille ja tutkijoille. Vaikka syöpähoidot ovat kehittyneet monien muiden kiinteiden kasvainten osalta viime vuosikymmenien aikana merkittävästi, ovat glioomat yhä yksi huonoennusteisimmistä kasvaintyypeistä. Tästä huolimatta edistysaskeliakin on tehty. Tutkijat ovat onnistuneet saamaan uutta tietoa, jota käytetään diagnostisoinnissa ja ennusteen arvioinnissa. Myös uusia hoitomenetelmiä on kehitetty. Kipeästi tarvittavat läpimurrot aivokasvainten hoidossa perustuvat toivottavasti näihin tutkimuksiin.

Tässä väitöskirjassa esitellään uusia tuloksia kliinisen molekyylibiologian ja patologian tutkimussaralta. Kirjassa käydään läpi antioksidatiivisten entsyymien esiintymistä pahanlaatuisissa astrosytoomissa ja oligodendroglioomissa, esitellään uusi lupaava täsmähoitoihin soveltuva kohdemolekyyli hiilihappo anhydraasi IX oligodendroglioomissa ja esitellään tehokas tapa epidermaalisen kasvutekijäreseptorin geenin amplifikaation todentamiseen astrosytoomissa.

Malignant gliomas are a challenging entity of tumors. The treatment of gliomas has not proceeded dramatically inspite of advances in the treatment of many other solid tumors. However, research has revealed new approaches for the diagnosis and prognosis and introduced new treatment options. These cornerstones are a basis for breakthroughs in glioma treatment in the future.

In this thesis, new results from molecular biological and clinicopathological topics are introduced: the significance of several antioxidative enzymes in malignant gliomas, a potential therapeutic target molecule, carbonic anhydrase IX, in oligodendrogliomas and an effective way for analyzing gene amplification of epidermal growth factor receptor (EGFR) in astrocytomas.

In study I, the role of antioxidative enzymes manganese superoxide dismutase (MnSOD), thioredoxin (Trx), thioredoxin reductase (TrxR), gamma glutamyl cysteinyl synthetase catalytic unit (GLCL-C) and gamma glutamyl cysteinyl synthetase regulatory unit (GLCL-R) was studied in a series of oligodendroglial tumors. All of the studied antioxidative enzymes (AOEs) except for Trx showed expression in the majority of the tumor samples. However, when tumor cells expressed Trx, it was associated with higher tumor grade, increased proliferation index, increased apoptosis and decreased survival. MnSOD positive tumors were associated with decreasing survival, too. Based on this study it is concluded that at least Trx and MnSOD analysis could be usable in certain cases when more information is needed for prognosis. Antioxidative enzymes are likely to have a role in tumorigenesis, since their enzymatic target, free radicals, are one pathway in the initiation of cancer.

In study II, chromogenic in situ hybridization (CISH) was introduced as a useful diagnostic tool for EGFR amplifications in astrocytomas. EGFR amplification is one of the most common genetic lesions in grade IV astrocytomas, glioblastoma multiformes (GBMs). EGFR analysis is sometimes needed to distinguish primary and secondary GBMs from each other, since EGFR amplification is more characteristic for primary GBMs. EGFR amplification has also been associated with poor prognosis. In this study, a significant association between grade III astrocytomas with EGFR amplification and poor outcome was found, while grade IV astrocytomas did not have such a correlation. However, EGF receptor is a potential target molecule for targeted therapies. In conclusion CISH-analysis was found to be reliable, affordable and easy to put in practice in pathology laboratories.

In study III, carbonic anhydrase (CA) IX was studied in oligodendrogliomas. The majority of the tumor samples had positive expression for CA IX. Furthermore, the proliferation index (MIB-1) was decreased among CA IX positive tumors. Patients with CA IX positive tumors were also associated with decreased survival. CA IX is an attractive molecule for targeted therapies based on its many favorable characteristics. There are multiple studies ongoing for the use of CA targeted inhibitors and CA IX may prove to be usable in the treatment of gliomas, too.

In study IV, peroxiredoxins (Prx) I-VI were studied in a series of astrocytomas. The majority of tumor samples showed expression for Prx I and II, and even more often in recurrent tumors. Higher tumor grade was associated with decreased Prx I or Prx II expression. In a similar manner, Prx I and Prx II positive tumors were associated with decreased apoptotic activity. Patients with these Prx I and Prx II tumors were also considerably younger and had better prognosis than others. Prxs seemed to have a different profile in gliomas than in normal brain tissue and they certainly represent interesting targets for further studies to evaluate their clinical value.