Biomedical Sciences and Engineering MS Thesis Defense by Tolga Lokumcu

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KOÇ UNIVERSITY

GRADUATE SCHOOL OF SCIENCES & ENGINEERING

BIOMEDICAL SCIENCES AND ENGINEERING

MS THESIS DEFENSE BY TOLGA LOKUMCU

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Title: Assessing the function of chromatin modifying enzymes in medulloblastoma

Speaker: Tolga LOKUMCU

Time: July 24, 2017, 11:00

Place: ENG 208

Koç University

Rumeli Feneri Yolu

Sariyer, Istanbul

Thesis Committee Members:

Asst. Prof. Tuğba Bağcı-Önder (Advisor, Koç University)

Asst. Prof. Tamer Önder (Koç University)

Assoc. Prof. Tolga Emre (Boğaziçi University)

Abstract:

Medulloblastoma is the most common pediatric brain cancer and it consists of four main molecular subgroups, which are Wingless (WNT), Sonic Hedgehog (SHH), Group 3 and Group 4. These subgroups have different transcriptional, cytogenetic and mutational spectra, meaning that targeted therapies are necessary for efficient treatment of medulloblastoma. Current therapy protocols for medulloblastoma include surgical resection, craniospinal irradiation and chemotherapy. Although current treatments result in high overall survival, many survivors experience intellectual and neurological disorders.

Genomic studies revealed that many chromatin modifying enzymes (CMEs) are recurrently mutated and/or differentially expressed in medulloblastomas. However, the roles of epigenetic modifiers in the initiation and progression of medulloblastoma are ill-defined. To this end, we mainly focused on epigenetics of medulloblastoma to develop new and more effective therapeutic options. For this purpose, we investigated the role of chromatin modifying enzymes (CMEs) in medulloblastoma by utilizing a chemical library targeting different CMEs. Through these screens, we identified potential inhibitors that induced cell death in medulloblastoma cells.

Although most of medulloblastoma tumors respond to chemotherapy well, there are still many medulloblastoma patients who do not respond to standard of care chemotherapy. Since Vincristine is one of the major chemotherapeutics used in different treatment protocols, we established a Vincristine-resistant medulloblastoma cell line by dose-escalation method and examined the functions of CMEs in drug resistance. We discovered that combined treatment of certain epigenetic inhibitors and Vincristine could be a promising approach to overcome Vincristine resistance in medulloblastoma.