Innovative compounds paired with state-of-the-art techniques may lead the way to a more effective means of killing cancer cells.
Glutamine is an amino acid that is abundantly found in our bodies, especially in blood and bone tissue. Its main role is to sustain the synthesis of proteins in cells.
Unfortunately, though, glutamine is also a key nutrient for many types of cancerous tumors, which tend to "consume" more of this amino acid because their cells divide more rapidly.
This is why research has been investigating the possibility of blocking cancer cells' access to glutamine as a new therapeutic approach in cancer treatment.
Charles Manning and several other researchers from the Vanderbilt Center for Molecular Probes at Vanderbilt University in Nashville, TN, have now managed, in a breakthrough move, to stop the growth of a cancer tumor.
To do so, they used an experimental compound called V-9302 to block the uptake, or absorption, of glutamine by cancer cells. The researchers' findings were published this week in the journal Nature Medicine.
"Cancer cells exhibit unique metabolic demands that distinguish them biologically from otherwise healthy cells. The metabolic specificity of cancer cells affords us rich opportunities to parlay chemistry, radiochemistry, and molecular imaging to discover new cancer diagnostics as well as potential therapies."
New compound inhibits glutamine carrier
The researchers explain that glutamine is carried through the body and "fed" to cancer cells via the amino acid transporter ASCT2, a type of protein.
"Elevated ASCT2 levels have been linked to poor survival in many human cancers, including lung, breast, and colon," the researchers note in their introduction.
However, studies that have managed to silence the gene that encodes ASCT2 — gene SLC1A5 —have succeeded in diminishing the growth of cancer tumors.
Spurred by this knowledge, Manning and colleagues set out to design an especially strong ASCT2 inhibitor, the compound V-9302. The researchers tested the compound on cancer cells grown in mice, as well as using cancer cell lines developed in the laboratory, in vitro.
The amino acid transporter inhibitor managed to diminish the growth of cancer cells and impair their ability to spread by "boosting" the cancer cells' oxidative stress, leading to their eventual death.
"These results not only illustrate the promising nature of the lead compound V-9302 but also support the concept that antagonizing [disrupting] glutamine metabolism at the transporter level represents a potentially viable approach in precision cancer medicine," the researchers conclude in their paper.
Innovations in PET imaging on the horizon
At the same time, the authors note that in order to treat patients with tumors that rely on glutamine to grow and spread, in the future, "this novel class of inhibitors will require validated biomarkers."
This means that the researchers will need to develop a way in which they will be able to tell how effectively the inhibitor is acting on the protein, or how little of the glutamine reaches the cancer cells eventually. This is because the production of ACST2 and its activity are likely to be different for each individual.
To address this problem, Manning and team suggest using positron emission tomography (PET) tracers that will spot cancerous tumors by detecting any increases in the glutamine metabolism rate, which will be higher compared with that of normal, healthy cells in the body.
The Vanderbilt Center for Molecular Probes is now hosting five clinical trials designed to test the effectiveness of 18F-FSPG, a new radiopharmaceutical — that is, a radioactive drug used in PET scans — in tracing various types of cancer tumors, including lung, liver, ovary and colon cancer ones.
Manning and team are also conducting tests on 11C-Glutamine, a metabolic tracer for glutamine. Additionally, the researchers can use a molecular tracer to confirm whether the protein inhibitor actually reaches its target.
"Wouldn't it be provocative," Manning asks, "if we could make a PET imaging tracer based on a certain drug that could help us predict which tumors will accumulate the drug and therefore be clinically vulnerable to it?"
"This is the very essence of 'visualized' precision cancer medicine," he enthuses.