Title: The contribution of temozolomide-associated mutagenesis to the malignant progression of grade II astrocytic gliomas
Investigator: Joseph Costello
Grantee: University of California San Francisco
After surgery to remove the bulk of their tumors, patients with brain cancer often undergo chemotherapy with temozolomide. This drug kills cells by damaging their DNA, so it should - in theory - eliminate pockets of residual cancer cells hidden in the brain and thereby reduce the threat of cancer recurrence. However, the situation changes if residual cancer cells survive temozolomide treatment. In this case, the DNA damage from temozolomide may disrupt the internal checks and balances that normally limit tumor cell growth – thus encouraging rather than opposing tumor recurrence and malignant progression.
This idea of temozolomide as a double-edged sword is particularly important for low-grade brain tumor treatment. Low-grade brain tumors are notoriously variable: some remain stable for many years, whereas others progress to aggressive malignancies quickly. If temozolomide causes DNA changes that make tumors more aggressive, then using it to treat low-grade brain tumors could make them worse instead of better.
To untangle this problem, ABC2 funded Dr. Joseph Costello (University of California San Francisco) to determine how temozolomide treatment affects low-grade gliomas. In the project funded by ABC2, Dr. Costello monitored genetic mutations in tumors from temozolomide- and non-temozolomide-treated patients over the full course of their disease. He found that DNA mutations occurred more than ten times as often in temozolomide-treated tumors, thus confirming that this drug causes tumor DNA to mutate – a lot. Even worse, many of these new mutations specifically encourage tumor growth or drug resistance.
By demonstrating that temozolomide causes genetic changes that can lead to tumor recurrence and progression, this work emphasizes the importance of judicious temozolomide use in low-grade brain cancer. It also better defines how aggressive recurrent tumors arise, thereby building a solid framework for investigating new strategies to delay or prevent cancer recurrence and malignant progression.