Development of a brain penetrant prodrug that inhibits guanine nucleotide synthesis for the treatment of glioblastoma
Active Project Grant Awarded Last action
- Award ID
- F30CA301968
- Recipient
-
The University Of Texas Southwestern Medical Center UEI YZJ6DKPM4W63
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $94,468
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- Dallas, TX 75390, USA
Award details come from USAspending.gov.
Description
- Abstract
- The treatment for glioblastoma (GBM), the most common malignant brain tumor, has not changed in nearly two decades. 90% of patients progress on the standard of care (radiation therapy combined with temozolomide) and often become resistant to all treatment options. Emerging studies on the mechanisms of resistance indicate that purine synthesis is critical in promoting tumorigenesis of glioma-initiating cells and may be a potential target in GBM. Inosine monophosphate dehydrogenase (IMPDH), the rate limiting enzyme in guanylate biosynthesis, is upregulated in GBM and provides high levels of guanine nucleotides that allow the tumor cells to overcome DNA damage induced by radiation. Mycophenolate mofetil (MMF), an FDA-approved immunosuppressant that inhibits IMPDH, synergizes with radiation in GBM mouse models and is currently tested in phase I clinical trial. Since the 1960S, MMF has been investigated in multiple clinical trials for cancer treatment, but has not been approved for any cancer, likely due to its dose-limiting toxicities. Compound 21 is a small molecule that exhibits efficacy in a neural cancer similar to GBM. In a CO-first author publication, I discovered that compound 21 and its analogs are nicotinamide-like prodrugs activated by NAD salvage pathway enzymes (nampt and NMNAT1) into cytotoxic metabolite derivatives of NAD. These unnatural derivatives inhibit the NAD dependent enzyme IMPDH by competitively blocking NAD binding. Through medicinal chemistry, we developed an orally bioavailable, brain penetrant analog compound 9 (C9). C9 exhibits on-target cytotoxicity in patient-derived GBM cells. To maximize the therapeutic index, IT is critical to develop biomarkers to identify drug-sensitive tumors. In colorectal cancer cells, C9 cytotoxicity directly correlates with NMNAT1 protein levels. RNA sequencing analysis in fifteen glioma cell lines reveals a spectrum of nmnat RNA levels, some higher than that of normal human astrocytes. We anticipate C9 to have wider therapeutic index than MMF, since C9 cytotoxicity requires both upregulated NAD metabolism and IMPDH dependence, a unique feature of GBM but not normal tissues. Further, 9-ad's negative charge allows its levels to remain steady in the brain for an extended period, which would maximize target tissue penetration and require less frequent dosing, thus increasing its tolerability. This proposal will integrate DR. Deepak nijhawan's (SPONSOR) expertise in small molecule target identification and DR. Samuel mcbrayer's (CO- SPONSOR) expertise in metabolic reprogramming in gliomas. In aim 1, I will determine the tolerability and efficacy of C9 directly compared to MMF. Based on the established clinical rationale of targeting IMPDH with MMF, I will examine whether C9 also synergizes with radiation therapy to increase the DNA damage response in tumor tissues. In aim 2, I will determine whether high nmnat expression is a potential biomarker for GBM sensitivity to C9. The completion of these aims will provide the foundation for future clinical testing of C9 for the treatment of GBM and renew our understanding of the therapeutic potential of prodrugs activated by tumor-specific metabolic pathways.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $47,234 | |
| Amendment | $47,234 | |
| Original award | $0 |
Quick answers
Who received award F30CA301968?
F30CA301968 was awarded to The University Of Texas Southwestern Medical Center by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F30CA301968 worth?
$94,468 has been obligated on F30CA301968.
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