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An experimental cancer drug tested in animal studies shows promise in restoring the immune system’s ability to fight tumors. Glasshouse Images/Getty Images
  • Researchers from the University of Texas at Austin have discovered a novel drug that enhances the ability of immune cells to combat cancer.
  • In experiments involving mice with melanoma, bladder cancer, leukemia, and colon cancer, the drug hindered tumor growth, prolonged life, and amplified immunotherapy results.
  • The discovery targets the troublesome 9p21 DNA segment deletion, prevalent in many cancers, that empowers tumors to grow unrestrained and evade immune responses.
  • With promising results in animal studies, the drug, PEG-MTAP, could amplify immunotherapy treatments and is poised for further testing and potential human clinical trials.

New research published in Cancer Cell has the potential to revolutionize cancer therapies.

Many cancers exhibit a deletion in the DNA segment known as 9p21. This deletion occurs in about 15% of all human cancers. It is particularly prevalent in cancers such as melanoma, bladder, mesothelioma, and some brain cancers.

Researchers have long recognized that the presence of the 9p21 deletion often leads to poorer patient outcomes and a decreased response to immunotherapies, treatments aimed at enhancing the body’s innate immune reaction to cancer cells.

The deletion aids cancer cells in evading detection and destruction by the immune system. This is partly because it triggers the cancer cells to release a harmful compound named methylthioadenosine (MTA).

This compound not only disrupts the regular operations of immune cells but also diminishes the effectiveness of immunotherapies.

In animal studies, this new drug reduces the levels of MTA to their usual state, rejuvenating the immune system.

A noticeable increase in T cells surrounding the tumor can be observed, and these cells are aggressive.

T cells play a crucial role in the immune system, acting like a special forces unit that can identify and target tumor cells. They release enzymes that break down and destroy the tumor from within.

Deleting the 9p21 segment results in the absence of crucial genes in cancer cells.

This deletion eradicates a set of genes responsible for producing cell cycle regulators, which are proteins that maintain the controlled growth and division of healthy cells.

Without these genes, cells can proliferate without restraint, turning them malignant.

Additionally, a maintenance gene that creates an enzyme to neutralize the toxic MTA is also removed.

The researchers suggest that this particular loss empowers cancer cells with an enhanced ability: to suppress the immune system.

“For a once normal cell to become an altered, cancerous cell it must develop the ability to grow uncontrollably and at the same time it must find a way to keep the immune system from eradicating it,” said Dr. Everett Stone, Ph.D., a research associate professor in the Department of Molecular Biosciences and associate professor of oncology at Dell Medical School, lead author of the study.

“One very common way cancers grow uncontrollably is to lose a gene called CDKN2A that normally prevents runaway growth,” Dr. Stone explained.

“What was curious was that a nearby gene called MTAP is almost always lost at the same time as CDKN2A which early on was described as a loss of an “innocent bystander” gene. In other words the function of MTAP did not initially appear to have a role that would help promote cancer growth. Instead, we discovered that the loss of MTAP causes the cancer cell to release a potent immune cell inhibitor (MTA) into its environment and thus keep anti-tumor immune cells from eradicating malignant cells.”

– Dr. Everett Stone

“This new perspective now explains why melanoma and bladder cancer patients with loss of MTAP do not respond well to immunotherapies, which otherwise works well in these cancers,” Dr. Stone said.

Dr. Przemyslaw Twardowski, medical oncologist and Professor of Medical Oncology and Director of Clinical Research at Saint John’s Cancer Institute at Providence Saint John’s Health Center, not involved in this research, spoke to MNT, saying, “this is very important work shedding new light on one of the potential mechanisms of resistance to immune therapy.”

Dr. Wael Harb, board certified hematologist and medical oncologist at Memorial Care Cancer Institute at Orange Coast Medical Center in Fountain Valley and Saddleback Medical Center in Laguna Hills, CA, also not involved in the study, said, “This is an intriguing study that explores a novel approach to overcoming immunotherapy resistance in certain cancers.”

“The authors identified that depletion of the metabolite methylthioadenosine (MTA) can help restore T cell function and anti-tumor immunity in cancers with MTAP deficiency. This is an important finding given that MTAP deficiency is common in certain cancers and associated with poor responses to immunotherapy.”

– Dr. Wael Harb

“Realizing that loss of the MTAP gene in cancer is a signal that the immune system will have a difficult time in attacking the tumor, we created a therapeutic that wipes out the immune toxic molecule MTA released by the tumor, which restores proper immune function in killing cancer cells,” Dr. Stone said.

“One potential implication for patients is that if their cancer has lost the MTAP gene certain immunotherapies may not be as effective and for the time being conventional chemotherapies may be more effective. From a public health perspective getting the new drug (PEG-MTAP) into the clinic has the potential to provide a much needed life-extending therapy that can boost the immune system’s ability to take control of the cancer.”

– Dr. Everett Stone

Dr. Twardowski agreed, saying, “the implications of this work are profound because it may significantly expand the population of patients who may benefit from immunotherapy.”

“Immunotherapy has been transformational for the treatment of many malignancies however benefit still applies to minority of patents and some cancers are intrinsically resistant to immunotherapy. Understanding the mechanisms of resistance and reversing it would be extremely valuable.”

– Dr. Przemyslaw Twardowski

“However[,] the road between this important observation and its application to patients is still long and uncertain because sometimes even spectacular laboratory observations don’t translate into the same benefit in human organism,” Dr. Twardowski pointed out.

“The key implication is that targeting MTA metabolism could potentially open up new immunotherapy treatment options for patients with MTAP-deficient cancers,” Dr. Harb explained.

“However, more research is still needed to validate these findings and determine if modulating MTA levels is a viable therapeutic strategy. Phase I/II clinical trials will be an important next step to evaluate safety and preliminary efficacy of this approach.”

– Dr. Wael Harb

“Overall, this study provides early but promising evidence that metabolite-targeted therapies could expand the benefits of immunotherapy to more cancer patients,” Dr. Harb said.

“If validated, it suggests new treatment combinations focused on the metabolic state of tumors could make immunotherapies effective for cancers currently resistant to these treatments.”

Dr. Harb concluded, “However, it is still early days and considerable work remains to translate these findings into patient benefit.”