Developing new Temozolomide analogs to improve brain tumor patient survival
SIGNIFICANCE
Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults. Despite the advances in understanding the molecular mechanism underlying GBM tumorigenesis, most of the current targeted therapies are still ineffective and temozolomide (TMZ) has remained the cornerstone of GBM treatment.
Treatment with radiation and TMZ followed by adjuvant TMZ shows significant improvement in GBM patient survival, but ultimately all tumors recur and median survival is only 12-15 months.
There is an absolute need for alternative chemotherapeutic options in the clinic.
What we know about temozolomide
Unfortunately, over 50% of GBM patients treated with TMZ do not respond to the therapy due to intrinsic resistance, and those that do respond eventually develop acquired resistance.
Unrepressed expression of the DNA repair enzyme MGMT is the primary known driver of intrinsic resistance to TMZ. Small sub-populations of TMZ-resistant glioma stem cells will cause tumor recurrence with their high capacity for self-renewal and tumor initiation.
In addition to resistance mechanisms, overcoming the dose limiting myelosuppressive toxicity of TMZ while maintaining its efficacy remains a major challenge. Hence, the development of a new chemical class of TMZ analogs with improved brain-to-plasma ratios and a broader therapeutic window is desperately needed.
Initial progress of temozolomide
To overcome existing clinical barriers with TMZ, our lab has designed and synthesized a series of novel TMZ analogs. These analogs were structurally characterized, evaluated, and then ranked according to their efficacy and brain permeability.
During this process we identified VMY-TP9 as an initial lead compound (renamed TP-9). Our lead compound showed promising inhibitory activity in cell lines with high MGMT expression, and elevated drug levels in the brain of an orthotopic GBM model, with an improved safety profile over TMZ while maintaining similar anti-tumor efficacy.
Proposed project
We propose to optimize our TP9 analog to further improve brain permeability and potential efficacy, and understand the signaling pathway for their activity in MGMT-positive and TMZ-resistant GBM models.
Research impact
Completion of this study to optimize novel TMZ analogs will address clinical limitations of TMZ and establish a therapeutic avenue for a particularly vulnerable proportion of GBM patients to improve overall survival.
INNOVATION
Critical barriers to improving response and survival of patients with GBM include tumor heterogeneity, drug resistance, the blood brain barrier, and inadequate response to standard therapies. Our proposed research presents a leading-edge strategy to develop a new chemical class of TMZ analogs that can overcome the clinical limitations of TMZ.
There are three main technical aspects of this proposal that are highly innovative and will generate improved treatment options.
Methodological and technical innovation
- Our TP9 analog has a better calculated central nervous system (CNS) multiparameter optimization (MPO) score and log BB than TMZ. Our in vivo brain permeability data also suggests that TP9 has a greater brain-to-plasma ratio in both intravenous and oral administration routes, compared to TMZ.
- Our TP9 analog demonstrated superior cell killing in unmethylated MGMT (MGMT Positive) cell lines and a greater DNA damage effect compared to TMZ.
- In an initial orthotopic GBM animal model study, our lead TP9 was well tolerated (little effect on body weight) and showed a slightly better neutrophil count (bone marrow toxicity) in mice at the tested dose compared to TMZ, while showing similar tumor growth inhibition.
Introduces an alternative therapeutic option for treating glioblastoma
The initial findings of our TP9 analog encourage us to optimize this class of compounds for IND-enabling preclinical studies. Our long-term goal is to create a TMZ analog for the treatment of GBM. The proposed research is innovative as we will identify lead TP9 analogs that overcome the clinical limitations of TMZ and develop a novel alternative chemotherapeutic option to significantly improve patient survival and alleviate the healthcare burden associated with primary and recurrent GBM.
Last updated: May 6th, 2021