Therapeutic Implications

The marked chemotherapy and radiation resistance of gliomas has focused attention on the means by which signaling aberrations underlying gliomagenesis contribute to resistance to cell death. In this regard, the PI3-kinase pathway is recognized for supporting cellular proliferation and survival, thereby promoting both malignant transformation and resistance to therapy.

Several lines of investigation identify PI3-kinase as a regulator of cellular responses to ionizing radiation. Biochemical inhibitors of PI3-kinase, LY294002, and wortmannin, enhance the anti-neoplastic effects of radiation [64-66], and recent data indicate that PKB/ Akt mediates LY294002-mediated radiosensitization [82]. Ionizing radiation has been shown to activate PKB/Akt and p70S6K in epithelial tumors in vitro, however this has not been shown to be the case in malignant glioma cell lines (Nakamura and Haas-Kogan, unpublished data).

In addition to direct effects on tumor cells, PKB/ Akt mediates responses of vascular endothelium to ionizing radiation [67]. PI3-kinase inhibition may provide a means of targeting elements in the tumor microenvironment such as vascular endothelium [68]. Thus, PI3-kinase inhibition may have anti-neoplastic effects through direct tumor killing as well as through disruption of the supportive microenvironmental components such as vascularization [69].

The importance of PKB/Akt function in survival after cytotoxic therapy is highlighted by the evidence that mutant receptor tyrosine kinases such as EGFRvIII exert cytoprotective effects through PI3-kinase [70] (Fig. 13.2). However, the effectiveness of EGFR tyrosine kinase inhibitors may be compromised by compensatory signaling through PTEN loss and/or PKB/Akt activation [71,72]. Combinations of signaling inhibitors, based on growing insights into glioma genetic pathogenesis, may help circumvent these escape mechanisms. Although such combinations may appear redundant, the ability of dysregulated PI3-kinase signaling to rescue cells from cytotoxic therapies may be one molecular explanation for the modest clinical efficacy of signaling inhibitors [73].

Redundant activation of PI3-kinase from alternate growth factor receptors may also provide a means of rescuing malignant gliomas from EGFR inhibition. For example, insulin-like growth factor receptor-I (IGFR-I) has been shown to maintain PI3-kinase signaling in the face of AG1478, the EGFR inhibitor and in fact co-suppression of IGFR-I and EGFR produced greater cytotoxicity compared to individual receptor inhibition [74]. These data further confirm that therapeutic signaling inhibition will be delivered as polychemotherapy, and increasing recognition of the molecular basis of resistance will improve our ability to intelligently incorporate signaling inhibitors into multimodality therapy. The same complexity and cross talk of signaling cascades contributing to drug resistance may also protect tumors from alternate mechanisms of cell death. EGFR inhibitors AG1478 and PD153035 can protect malignant gliomas from hypoxia-induced cell death [75].

Signaling through mTOR represents another potential target for molecular-based therapeutics. Phase I studies of CCI-779, an ester of rapamycin that inhibits mTOR, are ongoing for malignant gliomas [76]. mTOR and its downstream effector eIF4E may be particularly important targets because recent data indicate that they mediate resistance to therapy and treatment with rapamycin sensitizes lymphomas to chemotherapy [77]. Furthermore, tumors with activated PKB/Akt display particular sensitivity to mTOR inhibition [78]. In glioma, mTOR inhibition may have multiple inhibitory effects. Rapamycin radiosensitizes U87 in vivo [79], a finding that suggests improved efficacy when combining mTOR inhibition with radiotherapy. Recent data also indicate that mTOR inhibition alone using the rapamycin derivative RAD001 reduces glioma invasiveness and VEGF secretion [80].

Recent data suggest the possibility of targeting eIF4E as a strategy. Kentsis, et al. described the suppression of eIF4E-mediated transformation by the guanosine ribonucleoside analog ribavirin [81].

Increasing recognition of the redundancy of inputs into the PI3-kinase pathway and the cross talk between signaling pathways emphasizes the need to rationally coordinate signaling inhibitors for maximal efficacy. In vitro and in vivo data defining compensatory mechanisms after single-agent signaling inhibition should be used to offer more appropriate combinatorial therapy.

FIGURE 13.2 Schema of some signaling inhibitors currently in clinical trials. A variety of mechanisms are available to suppress aberrant signaling through growth factor receptors and the PI3-kinase pathway. STI-571, ZD1839, and OSI-774 inhibit tyrosine kinase activity, while R115777 is a farnesyl transferase inhibitor suppressing the necessary post-translational processing of Ras, and CCI-779, a rapamycin analog, inhibits mTOR. See Plate 13.2 in Color Plate Section.

FIGURE 13.2 Schema of some signaling inhibitors currently in clinical trials. A variety of mechanisms are available to suppress aberrant signaling through growth factor receptors and the PI3-kinase pathway. STI-571, ZD1839, and OSI-774 inhibit tyrosine kinase activity, while R115777 is a farnesyl transferase inhibitor suppressing the necessary post-translational processing of Ras, and CCI-779, a rapamycin analog, inhibits mTOR. See Plate 13.2 in Color Plate Section.

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PLATE 13.1 (Fig. 13.1)
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