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The Epigenetic Regulation of Chemotherapy Resistance in Melanoma

Tawbi, Hussein Abdul-Hassan (2011) The Epigenetic Regulation of Chemotherapy Resistance in Melanoma. Doctoral Dissertation, University of Pittsburgh.

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    Abstract

    Melanoma is rapidly increasing in incidence throughout the world. Early stages are curable with surgical approaches with excellent prognosis. However, a substantial proportion of patients progress to metastatic disease with survival rates of less than 5% making melanoma the culprit for over 65% of all skin-cancer related deaths. Novel agents targeting the immune system and the signaling pathways of melanoma are generating new promise, but chemotherapy remains an important therapeutic alternative, despite low response rates. The resistance of melanoma to chemotherapy is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. In this dissertation, we first identified the epigenetic silencing of the DNA mismatch repair (MMR) gene MLH1 as a determinant of response and survival for melanoma patients treated with alkylator-based chemotherapy (dacarbazine/ temozolomide). We then determined the safe dosage of the epigenetic agent decitabine that can be administered in combination with temozolomide. The safety, tolerability and efficacy of the combination of decitabine and temozolomide were evaluated in a Phase II population. We finally determined the pharmacokinetic and pharmacodynamic effects of treatment with the combination of decitabine and temozolomide in the blood and tumor tissues of metastatic melanoma patients.


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    Item Type: University of Pittsburgh ETD
    Creators/Authors:
    CreatorsEmailORCID
    Tawbi, Hussein Abdul-Hassantawbih@upmc.edu
    ETD Committee:
    ETD Committee TypeCommittee MemberEmailORCID
    Committee ChairKirkwood, John MKirkwoodJM@upmc.edu
    Committee MemberUnruh, Mark Lunruh@pitt.edu
    Committee MemberDavidson, Nancy Edavidsonne@upmc.edu
    Committee MemberBranch, Robert Arab13@pitt.edu
    Committee MemberDay, Roger Sday01@pitt.edu
    Title: The Epigenetic Regulation of Chemotherapy Resistance in Melanoma
    Status: Unpublished
    Abstract: Melanoma is rapidly increasing in incidence throughout the world. Early stages are curable with surgical approaches with excellent prognosis. However, a substantial proportion of patients progress to metastatic disease with survival rates of less than 5% making melanoma the culprit for over 65% of all skin-cancer related deaths. Novel agents targeting the immune system and the signaling pathways of melanoma are generating new promise, but chemotherapy remains an important therapeutic alternative, despite low response rates. The resistance of melanoma to chemotherapy is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. In this dissertation, we first identified the epigenetic silencing of the DNA mismatch repair (MMR) gene MLH1 as a determinant of response and survival for melanoma patients treated with alkylator-based chemotherapy (dacarbazine/ temozolomide). We then determined the safe dosage of the epigenetic agent decitabine that can be administered in combination with temozolomide. The safety, tolerability and efficacy of the combination of decitabine and temozolomide were evaluated in a Phase II population. We finally determined the pharmacokinetic and pharmacodynamic effects of treatment with the combination of decitabine and temozolomide in the blood and tumor tissues of metastatic melanoma patients.
    Date: 16 May 2011
    Date Type: Completion
    Defense Date: 19 April 2011
    Approval Date: 16 May 2011
    Submission Date: 21 April 2011
    Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
    Patent pending: No
    Institution: University of Pittsburgh
    Thesis Type: Doctoral Dissertation
    Refereed: Yes
    Degree: PhD - Doctor of Philosophy
    URN: etd-04212011-142508
    Uncontrolled Keywords: Chemotherapy Resistance; DNA Repair; Epigenetics; Melanoma; Pharmacogenomics; Phase I/II Clinical Trials; Translational Research
    Schools and Programs: School of Medicine > Clinical and Translational Science
    Date Deposited: 10 Nov 2011 14:40
    Last Modified: 29 May 2012 15:51
    Other ID: http://etd.library.pitt.edu/ETD/available/etd-04212011-142508/, etd-04212011-142508

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