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Glioblastoma (GBM) is a malignant brain tumor with no current cure and a 5 year survival rate of 5%. It is a fast growing and invasive tumor that results in universal recurrence, even after treatment. The standard of care is surgery followed by radiotherapy and chemotherapy, mainly temozolomide. While GBM affects mainly adults, it can occur at any age and there is a need for new treatments to be developed. ZFTA fusion positive ependymoma (EPN-ZFTA) is an aggressive, pediatric brain tumor also with no curative measures. EPN-ZFTA is characterized by resistance to current chemotherapies, leaving surgery and radiotherapy as the only treatment options. These tumors have a 40% recurrence rate, and a poor prognosis correlating to the younger the patient is at diagnosis. Overexpressed cancer stem cell genes and the presence of cancer stem cells have been linked causatively to higher rates of recurrence. There is a need for a therapeutic drug that both targets EPN-ZFTA tumors and can be well tolerated in young patients. CBL0137 is a small molecule drug that inhibits NF-kB signaling, decreases expression of cancer stem cell genes, and activates p53. It has been shown in other tumor types to target cancer cells while being non-toxic to normal tissue. Here we investigate the potential for CBL0137 to be used as a new therapeutic for both GBM and EPN-ZFTA.In Chapter 2, we explore how CBL0137 increases the level of DNA damage and leads to tumor cell death. Further, we show that CBL0137 increases the efficacy of radiotherapy and survival in mouse models of GBM. In Chapter 3, we investigate how CBL0137 dynamically alters the tumor microenvironment in GBM. We see an increase in DNA damage and cell death, and a decrease in stem cell proteins after CBL0137 treatment in in vivo mouse models. Lastly, in Chapter 4 we explore if EPN-ZFTA is sensitive to CBL0137. We show CBL0137 treatment decreases NF-kB target genes, decreases stem cell genes and activates p53 in EPN-ZFTA. We investigate the impact of CBL0137 on tumor cell phenotypes and viability. There was a decrease in both the stem cell phenotype and viability of EPN-ZFTA tumor cells after CBL0137 treatment. We show that CBL0137 alone and in combination with radiotherapy, increases survival in mouse models of EPN-ZFTA.This highlights the impact of CBL0137 on tumor cells and potential for this drug as a therapeutic for brain tumors. Our work shows CBL0137 treatment leads to altered gene expression, decreased DNA repair, and decreased sphere formation capabilities. Lastly, CBL0137 treatment extends survival in mouse models of both GBM and EPN-ZFTA. This research provides rationale for a new chemotherapy and treatment paradigm for two currently incurable brain tumors.

High-grade serous ovarian cancer (HGSC) and colorectal carcinomas (CRC) are highly aggressive malignancies accounting for a large number of cancer-related death worldwide. Current treatment options are limited to chemo- and radiotherapy in both malignancies and acquired resistance frequently occurred. Hence, there is an urgent clinical need to develop novel targeted therapies for these cancers. [...]