Goellner, Eva
(2011)
Demonstrating functional crosstalk between DNA base excision repair and cellular bioenergetics: A strategy for the treatment of chemotherapy resistant glioblastoma.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
DNA damaging agents are commonly used in the clinic for the treatment of cancer. In particular, the DNA alkylating agent, temozolomide, is the primary chemotherapeutic option for the treatment of glioblastoma, a particularly aggressive form of brain cancer. Temozolomide produces three main DNA lesions: O6-methylguanine, N7-methylguanine and N3-methyladenine. Most of the clinical toxicity is a result of the O6-methylguanine lesion, which activates the mismatch repair pathway and results in apoptosis. The N7 methylguanine and N3-methyladenine lesions are effectively repaired by the base excision repair pathway (BER) and hence the toxicity of these lesions is minimal. Resistance to O6-methylguanine mediated cell death is prevalent, particularly in recurrent glioblastomas, at which point treatment options are
limited. We have previously shown that targeting of the BER pathway through genetic means or small molecules (resulting in BER failure) can produce tumor cell death independent of the O6-methylguanine lesion. This dissertation addresses the critical questions of the mechanisms by which BER failure results in tumor cell death and investigates new combinational therapy
options to enhance tumor cell death by BER failure. Cell death after BER failure results from accumulation of repair intermediates and hyperactivation of PARP1. I have shown PARP1 hyperactivation results in cellular loss of NAD+ and ATP. In particular, nuclear PARP activation results in a severe block to glycolysis and a defect in mitochondrial respiratory capacity. These metabolic defects result in subcellular ATP loss from the mitochondria as well as from the nuclear and cytosolic compartments. This suggests that targeting both BER and cellular energetic pathways would enhance N7-methylguanine and N3-methyladenine mediated toxicity. To this end I have shown that dual targeting of BER (inhibition by methoxyamine) and NAD+ biosynthesis (inhibition by FK866) in combination with TMZ results in enhanced tumor cell
death and is capable of overcoming resistance to the O6-methylguanine lesion. This opens the possibility for further pre-clinical testing using xenograft models, as well as, potential synthetic lethal interactions for the treatment of glioblastomas deficient in an alternate arm of NAD+ biosynthesis.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
9 December 2011 |
| Date Type: |
Publication |
| Defense Date: |
29 July 2011 |
| Approval Date: |
9 December 2011 |
| Submission Date: |
1 December 2011 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
160 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Glioblastoma, DNA damage, Base excision repair, Bioenergetics, Cancer, Temozolomide |
| Date Deposited: |
09 Dec 2011 17:24 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10635 |
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