Elicit differential stress responses in normal-and cancer cells to chemotherapy drugs in vitro ; and that short-term starvation can protect mice and potentially humans from the side-effects of high-dose chemotherapy. In addition to the fact that malignant cells are unresponsive to starvation-induced cellular protection, our recent study has shown that 15 out of the 17 murine and human cancer cell lines tested were sensitized to chemotherapeutic drugs Doxorubicin and/or Cyclophosphamide under starvation mimicking conditions in vitro. In mice, STS in combination with DXR or CP resulted in enhanced treatment efficacy of a variety of malignancies, including murine breast cancer and melanoma, as well as human neuroblastoma, breast- and ovarian cancer. Here we tested the hypothesis that short-term starvation can augment the efficacy of TMZ and radiotherapy, the standard treatments for glioma in the MK-0683 aggressive subcutaneous and intracranial murine models of GBM. The multimodal treatment of GBM, based on surgical removal of the tumor followed by chemotherapy and radiotherapy, has improved the survival of GBM patients. However, the frequency of recurrence and rapid progression in adults emphasizes the need for a major enhancement of the therapy to achieve long-term survival without relying exclusively on the uncertain and very long and expensive drug development process. In addition, chemotherapy often causes severe toxic side effects and might even fail due to the development of drug resistance as glioma, and GBM in particular, are among the most inherent chemotherapy- resistant tumors. The aim of this study was to investigate whether fasting, which could be rapidly, inexpensively and widely integrated into existing cancer treatments by clinicians, can improve the efficacy of chemo-and radiotherapies in treating mouse models of aggressive GBM. The intracranial inoculation of C57BL/6 mice with GL26luc cells showed a fast tumor progression that led to severe signs of illness such as backhunching, reduced grooming and hypo-activity, possibly due to increasing intracranial pressure. One cycle of TMZ treatment at day 7 and 8 after tumor inoculation, or a 48 hour STS alone, lengthened the median survival from 14 to 15 days, although this effect was not statistically significant. By contrast, the combination of STS and TMZ delayed the onset of mortality but significantly extended median survival to 16 days. Remarkably, one animal in the STS+TMZ group achieved long-term survival. These results indicate that the combination of starvation with TMZ, the standard chemotherapy drug for the treatment of malignant glioma, has the potential to extend survival, at least in a portion of the subjects treated. EPHB receptors interact with the Ephrin family of ligands. Upon interaction with their Ephrin ligands, EPH receptors modulate a variety of biological activities, including cell-cell interaction and cell migration. Loss of the kinase-dead EPHB6 is associated with advanced tumor stages and cancer progression. Several publications report on high EPHB6 expression being a favorable prognostic marker in neuroblastoma. In addition, mRNA expression of EPHB6 was decreased in metastatic melanoma and in invasive breast cancer cell lines with metastatic potential. Functionally, EPHB6 suppresses invasiveness, growth rate and colony-forming efficiency of cultured breast cancer cells, regulates cell adhesion and affects migration. Previously, we identified several human RTKs whose expression level correlated with the development of metastasis in earlystage NSCLC.