Scientists are constantly seeking genetic alterations in cancer cells that they might be able to target for therapeutic purposes. Loss-of-function mutations in tumor suppressor genes are crucial in the development of cancer, but they are extremely hard to target.
More than 40 years ago, researchers identified one such mutation—a deletion in the methylthioadenosine phosphorylase (MTAP) gene. This deletion occurs in 10 to 15 percent of all human cancers, including many with limited treatment options such as non-small cell lung cancer, mesothelioma, glioblastoma, and pancreatic cancer. Low MTAP expression has been linked to poor prognosis—shorter overall survival and progression-free survival—tumor recurrence, and a higher risk of metastatic disease.
Studies have shown that loss of MTAP increases the cells’ dependency on a compensating enzyme, PRMT5. A new clinical trial has been launched to see if a selective PRMT5 inhibitor could be used successfully to exploit the vulnerabilities in MTAP-deleted tumors and kill cancer cells.
What Is PRMT5?
PRMT5 is an essential gene required for cell survival, thus a potential cancer therapeutic target.
PRMT5 stimulates cell proliferation and growth through the repression of 227 tumor suppressor and cell cycle regulatory genes. Multiple studies have demonstrated that loss of PRMT5 activity induces cellular stress, which leads to activation of the p53 tumor suppressor gene.
However, PRMT5 inhibitors kill normal cells—particularly those in the bone marrow—as effectively as cancer cells. The resulting toxicity means the dose of non-synthetic lethal PRMT5 inhibitors needed to kill cancer cells is difficult to deliver without causing unacceptable bone marrow suppression.
Using a Different Approach
Synthetic lethality is a method of inducing cell death in tumors that have a critical gene deletion by inhibiting a different protein or gene that is very important to the tumor cells. The drug used in this study, TNG908, is a selective PRMT5 inhibitor, which targets cancer cells with the MTAP deletion while sparing normal cells.
This trial uses synthetic lethality through a drug that inhibits PRMT5 for tumors with MTAP deletion, thus causing a detrimental effect on the tumor cells. Because cells with the MTAP deletion have a reduced amount of PRMT5, patients with MTAP-deleted tumors can be given a lower dose of the drug, reducing the possibility of side effects.
Participating in the Study
The trial is available for patients with advanced or metastatic solid tumors known to have an MTAP deletion. Participants will be given TNG908 in increasing doses to determine the dose safety and best dosing schedule. Researchers will monitor the effectiveness of the drug for up to 16 weeks.
We encourage you to consult your physicians for clinical trials that may be right for you. The website ClinicalTrials.gov provides more details about this trial as well as many others. You can visit the EmergingMed Trial Finder for a list of all active pancreatic cancer clinical trials.