Cancer: New drug may fight treatment resistance

Treatment resistance is a huge problem in cancer therapy and a major barrier to improving survival for many patients. Scientists have discovered that a solution might lie in a new drug that tackles cancer cells differently.

In the study paper, now published in the journal Molecular Cancer Therapeutics, they report how the experimental drug showed promising results in animal models of both breast and colorectal cancer.

The drug targets a molecule that helps cancer cells to read instructions in their DNA. In fact, targeting this function has received attention lately as a new approach to treating cancer.

"Treatment-resistant tumors represent a significant threat for patients," says study author Charles Coombes, who is a professor of medical oncology at Imperial College London in the United Kingdom, "as once a cancer stops responding to treatments there is increasingly little clinicians can do."

The new drug, called ICEC0942, has been licenced to a private company. They have developed it further and entered it into a phase I clinical trial that started treating people in November 2017.

The trial will assess the safety and effectiveness of the drug in humans. It is likely to be several years before it is approved for clinical use, however.

Cancer and drug resistance

Cancer is a group of diseases that have one thing in common: they arise because abnormal cells in the body grow out of control and spread.

The human body contains trillions of cells that will normally follow an "orderly process," in which damaged and aged cells die and are replaced by new ones.

In cancer, however, as cells become increasingly abnormal, the orderly process is disrupted, and cells that should die continue to survive, divide, and produce more abnormal cells, eventually giving rise to tumors.

There are more than 100 different types of cancer, which are traditionally named after the tissue that they started growing in — for instance, breast cancer, lung cancer, prostate cancer, and pancreatic cancer.

Drug resistance is a well-known problem in the treatment of cancer, and it affects nearly every type of therapy, apart from surgery.

Many patients have drug-resistant cancers. This can happen right from the start of treatment, or because their cancer acquires resistance as treatment ensues. In addition, some people might be resistant to one drug and sensitive to others, while others may have multi-drug resistance.

Cancer cells and tumors have many mechanisms for promoting or enabling drug resistance and there is a growing need to find new ways to defeat them.

Transcription inhibition as a new approach

The drug at the center of the new study targets the way that cancer cells read their DNA. For a cell to thrive, it needs to keep reading its DNA, which contains instructions on how make proteins and regulate vital functions that keep cells alive.

The process of reading DNA is called transcription and involves copying instructions in the relevant section of DNA into a molecule called messenger RNA, which carries them from the nucleus into the body of the cell where it makes proteins.

In their study paper, the researchers refer to recent work that suggests that some types of cancer may be "especially sensitive to transcription inhibition," and that "targeting the transcriptional machinery" may offer a new approach to treatment.

The new drug that they tested targets a molecule called cyclin-dependent kinase 7 (CDK7), which helps to steer cells through the stages of growth, DNA copying, and cell division.

CDK7 also kick-starts the process of transcription and helps to control other transcription factors, including estrogen receptor (ER)-α, which is a "key protein in breast cancer."

'Substantial anti-tumor effects'

When they ran some tests in the laboratory, the researchers found that "a wide range of cancer types are sensitive to CDK7 inhibition."

They also found that the drug had "substantial anti-tumor effects" in animals with breast and colorectal tumors that grew from implanted human cancer cells.

Finally, when they combined the drug with tamoxifen, it completely stopped the growth of ER-positive tumors in the animals.

The researchers conclude that their findings show that blocking CDK7 offers a new way to treat cancer — especially ER-positive breast cancer.

In particular, the results suggest that ICEC0942 is a good candidate drug, either on its own or combined with hormone therapies, for the treatment of breast cancer.

The study authors note that the new drug could also be effective against other cancers — such as small-cell lung cancer and acute leukemia — that "display characteristics of transcription factor addiction."

"Drugs such as these could help to shift the balance back in favor of the patients, potentially providing a new option to patients for who[m] existing treatments no longer work."

Prof. Charles Coombes