Overcoming toxicity and resistance limitations of the anticancer drug temozolomide

McKee, Sydney Anne

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https://hdl.handle.net/2142/127439 Copy

Description

Title

Overcoming toxicity and resistance limitations of the anticancer drug temozolomide

Author(s)

McKee, Sydney Anne

Issue Date

2024-09-13

Director of Research (if dissertation) or Advisor (if thesis)

Hergenrother, Paul J.

Doctoral Committee Chair(s)

Hergenrother, Paul J.

Committee Member(s)

• Fan, Timothy M.
• Sarlah, David
• Olshansky, Lisa

Department of Study

Chemistry

Discipline

Chemistry

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• temozolomide
• glioblastoma multiforme
• anticancer
• alkylators
• targeting

Abstract

The imidaozotetrazine class – a structural amalgamation of decades’ worth of medicinal chemistry – produced the billion-dollar drug, temozolomide (TMZ), in the late 1980s. TMZ is a DNA methylating prodrug, where following hydrolytic degradation its active alkylating agent, methyl diazonium ion, can form various DNA adducts. Ultimately, the anticancer benefit of TMZ is derived from the O6-methylguanine (O6-MeG) lesion, which comprises ~5% of TMZ’s total DNA alkylation profile. TMZ has been approved since the early 2000s for glioblastoma multiforme (GBM), a grade IV astrocytoma that carries essentially a death sentence with its diagnosis. Despite improving the median survival of patients from 12.1 to 14.6 months compared to radiotherapy and surgical resection alone, TMZ still falls quite short, and no other drug has been able to oust it from GBM’s standard treatment regimen. There has also been interest to expand the scope of TMZ indication beyond brain malignancies to peripheral tumors such as lung, breast, colorectal, but clinical trials thus far have shown disappointing or inconclusive activity. The biggest obstacle currently limiting TMZ for the treatment of GBM and other cancers is the high expression of O6-methylguanine-DNA methyltransferase (MGMT), a suicide enzyme that removes TMZ’s primary cytotoxic lesion, O6-MeG. The majority of GBM patients and frequently other peripheral tumors demonstrate elevated levels of MGMT, thereby rendering TMZ intervention futile. Attempts to couple TMZ treatment with MGMT inhibitors, such as O6-benzylguanine or lomeguatrib, are thwarted due to the exacerbation of TMZ’s dose-limiting hematological toxicity. This is a consequence of the unbiased biodistribution of TMZ and MGMT inhibitors, which not only accumulate in the tumor, but bone marrow as well. To permit co-administration, TMZ dosage necessarily is reduced, resulting in no therapeutic benefit. Herein, we report multiple compounds bearing different alkyl substituents that seemingly evade MGMT removal. Indeed, these compounds are potent in cell culture irrespective of MGMT expression and demonstrate ideal in vivo properties, but efficacy in murine tumor models remains elusive. We also report the strategy to reduce TMZ’s intrinsic ability to alkylate hematopoietic stem cell DNA by altering its biodistribution, resulting in a promising new candidate that shows reduced hematological toxicity, even in conjunction with lomeguatrib, but not at the expense of in vivo efficacy. This approach lays the foundation for expanding the application of TMZ to GBM patients with high MGMT expression as well as other tumors outside of the brain.

Graduation Semester

2024-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/127439

Copyright and License Information

Copyright 2024 Sydney McKee

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