Breakthrough cancer treatment uses DNA defects to fight drug-resistant tumors

It might be a key to curing the most aggressive type of brain cancer.
Mert Erdemir
MR imaging of glioblastoma
MR imaging of glioblastomaTonpor Kasa/iStock
  • The novel strategy could pave the way for new glioma therapies and set a new method for developing medications that take advantage of specific DNA repair defects to fight drug-resistant tumors.
  • Glioblastoma is known as the most aggressive type of brain cancer.
  • TMZ analogs create a dynamic primary DNA lesion that can be repaired in healthy cells with working MGMT-mediated DNA repair mechanisms.

A cure for deadly brain tumors is an immediate need for humanity. Though many developments and studies are being conducted on cancers, there are still many deadly types of cancer, and glioblastoma is only one of them, according to research.

Scientists from Yale University have developed a new class of glioma drugs that employs tumors lacking the DNA repair enzyme MGMT and selectively kills tumor cells without the risk of resistance. The novel strategy could pave the way for new glioma therapies and set a new method for developing medications that take advantage of specific DNA repair defects to fight drug-resistant tumors.

"We have discovered a way to modify cancer DNA in a manner that is irreparable to cancer cells, with minimal negative impacts to healthy cells," told Dr. Ranjit Bindra, M.D, Ph.D., to IE. He further stated that they're targeting key DNA repair defects in cancer cells that are seen in glioblastomas. "As reported in the Science publication, our new class of molecules was found to be exquisitely active and selective against cancer cells that lack expression of a key DNA repair protein called MGMT (O6-methylguanine methyl transferase). Approximately half of all glioblastomas and up to 80% of gliomas lack MGMT, making them a perfect target."

Is glioblastoma fatal?

A glioma is a type of tumor that begins in glial cells, which normally support nerves and help the central nervous system function. Glioblastoma occurs in the brain and spinal cord, and it’s known as the most aggressive type of brain cancer.

Glioblastoma is the most common form of malignant brain tumor. It's so fast-growing and aggressive that only one in 20 patients can survive for five years following their diagnosis. Unfortunately, patient survival time is about 14 months on average, even after surgery, radiation treatment, and traditional chemotherapy.

The current treatment of the disease includes a combination of radiotherapy and the chemotherapy drug temozolomide (TMZ). But the problem is that drug resistance can be seen in many patients, so an easier treatment method for glioblastoma is needed.

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Breakthrough cancer treatment uses DNA defects to fight drug-resistant tumors
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Lack of the DNA repair protein MGMT is common in glioblastoma and glioma tumors, and this deficiency may contribute to the development of treatment resistance in these tumor types. Kingson Lin and his colleagues offer a novel therapeutic method that uses the absence of MGMT to selectively target and kill glioblastoma tumor cells.

A mechanism-based design approach

Lind and his team used a mechanism-based design approach to develop TMZ analogs, which create a dynamic primary DNA lesion that can be repaired in healthy cells with working MGMT-mediated DNA repair mechanisms. However, cancer cells lacking MGMT expression cannot repair the harm. The original lesions in these cells gradually progress, generating an increasing number of harmful secondary DNA lesions that lead to the selective destruction of MGMT-deficient tumor cells.

How will this approach contribute to the eradication of such a deadly cancer type, though? "Our new therapeutic molecules are orally delivered and are similar in structure to current drugs being tested in humans, but Modifi Bio’s molecules are critically different because they are able to overcome key resistance mechanisms in cancers," Dr. Bindra answers. The team is now filing an Investigative New Drug application with the U.S. Food and Drug Administration (FDA), which will allow them to start clinical trials on humans. "We will need to conduct these studies for the FDA review process," he concludes.

Using a mouse model of TMZ-resistant human GBM, the scientists discovered that drug-induced selective tumor-cell death had an acceptable toxicity profile both in vitro and in vivo.

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