Pharmacodynamic Biomarker-Guided Metabolic Collapse of IDH-Mutant Glioma

This project intends to pioneer a new strategy for evaluating the health of cancer cells within the live brain. Glioma is the most common type of brain cancer. These cancers remain incurable, despite decades of effort. One of the key vulnerabilities of glioma is their dependency on Nicotinamide adenine dinucleotide (NAD), which serves as the currency of energy within cells. Due to the many abnormalities within cancer cells, their requirement for NAD to remain alive is higher. The way that glioma cells generate NAD is also different than normal cells. A new class of medications to treat cancer targets their ability to generate NAD by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), a requirement for most cancer cells to generate NAD. Therefore, if cancer cells do not have functional NAMPT, they quickly run out of energy. Importantly, however, cancer cells are notoriously adaptable. Although they normally require NAMPT, if given some warning they can reprogram themselves to devise other ways of generating NAD. As such, if NAMPT inhibition is going to be effective, it must be blocked completely and quickly for cancer cells to reliably die.

Because NAD is the currency of energy for all cells, blocking NAMPT can be toxic for healthy cells. Healthy cells have an alternate way of generating NAD, using vitamin B3 (nicotinic acid); however, there is usually insufficient vitamin B3 available to prevent toxicity. Therefore, healthy cells can be supported through NAMPT inhibition by providing additional nicotinic acid. It is imperative for both safety and efficacy that levels of these chemicals in the cancer are just right. However, each cancer responds slightly differently.

Traditionally, experimental drug therapies are given to many people and the long-term results (e.g., survival), compared to those who did not get the therapy. If patients with the therapy live longer, the drug is considered a success. For brain cancer, this approach has not been very effective. The last time a new drug was found to increase survival for aggressive glioma was in 2005. We propose that by measuring the impact of therapies within the tumor itself, we can find out how well the therapy is working and what needs to be done to improve its impact. In this project, we will use NAMPT inhibitors as a prototype therapy that requires this 'biomarker' guided approach to succeed quickly.

We are developing a technique to use within the human brain, called 'microperfusion.' This allows us to sample levels of chemicals within the tumor continuously over time. It has been shown that NAMPT inhibitors can succeed or fail within 3 days. By measuring NAD and other biomarkers in the tumor over a 3-day period, we propose to confirm whether or not the drug is having an effect within the tumor and whether or not the effect is sufficient to kill the cancer cell. Moreover, we have evidence that we can understand from these biomarkers how the cancer cell is developing resistance to survive. Critically, by measuring these same chemicals in 'normal' brain, we can confirm that toxicity is being avoided.

In this project, we will use a model of glioma that is highly sensitive to NAMPT inhibition. This glioma has a mutation in a gene called IDH1, which is mutated in the majority of gliomas in young adults. We will also use a model of glioma that is resistant to NAMPT inhibition. We will determine whether or not it is possible to detect and optimize the efficacy and safety of NAMPT inhibition in these gliomas.

If this strategy of obtaining feedback from the tumor is found to be helpful and practical, we believe that it can transform the current approach to new drug therapies for glioma. Our long-term goal is that patients with glioma can undergo not just neurosurgery to remove their tumor, but informative testing that will identify the best therapy for their cancer before they leave the hospital. Many clinical trials fail because drugs are given to cancers that don't respond. We want to eliminate this practice and ensure to the best of our ability that patients are consistently given drugs that can work. This is the first step toward a new paradigm of treating cancer based upon data and staying ahead of the tumor when it tries to develop resistance. All of the technology necessary to do this work is available. If effective, we anticipate to begin using this strategy with human patients to accelerate therapeutic discovery within 3-5 years.