Exploring preventive medicine against cancer metastasis

Dr. Juan Jose Marugan of National Institutes of Health (NIH) and of National Center for Translational Science Promotion (NCATS), together with his colleagues, are committed to changing this situation. With concerted efforts from other partners, they discovered a small molecule drug called metarrestin that showed inhibition of tumor metastasis in a variety of solid tumor models. Currently, they are pushing this research compound into clinical trials, especially for the treatment of pancreatic cancer. NCATS, where Dr. Marugan works, is dedicated to solving the "pain point" in translational research and improving the efficiency of translating breakthrough research into patient-benefit therapy. 

Cancer metastasis - a complex and unclarified process

Cancer metastasis is a complex multi-step process. Initially, cancer cells become invasive, breaking through the barrier formed by epithelial tissue and invading into the blood vessels. After the blood circulation has moved to other parts of the body, they also need to leave the blood circulation and invade into the extravasation. Cancer metastasis does not occur in all tissues. Previous studies have shown that the environment of specific tissues in the human body is more conducive to the survival and colonization of metastatic cancer cells. The environment in which these metastatic cancer cells are suitable for survival is called pre-metastatic niches. Cancer cells that survived the pre-metastatic habitat may be lurking for a long time, and then stimulated by specific factors, the cancer cells expand and become metastatic colonization.

Since the first step in the metastasis of cancer cells is to become invasive, targeting cancer transfer has become one of the focuses of scientists. Studies have shown that intrinsic changes in a variety of tumor cells can lead to their invasive enhancement, including epithelial-mesenchymal transition (EMT), protease production and migration capacity.

However, due to the genetic instability of metastatic cancer cells, there may be no dominant signaling pathway controlling cancer metastasis in most cancer types. Our understanding of cancer metastasis is far from complete. Dr. Marugan said, “We know some of the mechanisms involved in the process of epithelial mesenchymal transition and the basic receptors and factors associated with this process. However, this knowledge is not sufficient to provide a panoramic view for developing targeted cancer metastasis.”

Another way to find new therapeutic molecules using phenotypic screening

Since it is not possible to develop drugs for specific molecular targets, Dr. Marugan's team decided to use phenotypic screens to identify drugs that can affect the aggressiveness of cancer cells. They found that there is a structure called a perinucleolar compartment (PNC) in highly evolved cancer cells. PNC is a subnuclear body that is attached to the nucleolus of the cell. None of the early cancer cells have PNC, but a large proportion of cancer cells in metastasis have PNC, while in metastatic cancer cells, 100% of cells have PNC.

So, Dr. Marugan's team conducted a high-throughput screening to find small molecules that could break PNC but not kill cells. They discovered that a small molecule compound, later called metarrestin, is very effective in dissolving PNC in solid tumors. So what effect does it have on cancer metastasis?

In a mouse model of cancer in mice, researchers found that if the tumor in the animal has not metastasized, metarrestin can prevent metastasis and significantly improve the survival of the animal. If metastasis has begun, metarrestin can reduce the number of metastases and extend the lifespan of animals.

In 2018, Dr. Marugan's team published a study on metarrestin at Science Translational Medicine. Further studies have found a target for metarrestin, which originally binds to a protein called eEF1A2 and controls the function of RNA polymerase 1 (Pol 1). Pol 1 is essential for the synthesis of ribosomal RNA. Therefore, in cancer cells, eEF1A2 can help improve the biosynthesis of ribosomes, which is important for the rapid proliferation, division and evolution of cells. Metarrestin blocks the production of new ribosomes in highly evolved cancer cells by blocking eEF1A2. 

Specially targeting for the treatment of pancreatic cancer 

Dr. Marugan said that the current preclinical trials on metarrestin have been completed and the IND application will be submitted to the FDA. The emergence of this drug candidate is the result of collaboration among multiple research institutions. The original idea of using PNC for phenotypic screening came from Professor Sui Huang of Northwestern University. Kansas University's Specialized Chemistry Center helped with medical chemistry research. The National Translational Science Promotion Center conducted preclinical development work, including GMP expansion, toxicology research and formulation. They will also work with the National Cancer Institute (NCI) on Phase 1 and Phase 2 clinical trials.

The National Institutes of Health (NIH) has patented metarrestin, and Dr. Marugan plans to push this research into phase 2 clinical trials and then work with pharmaceutical companies to obtain FDA approval.

Although metarrestin has produced excellent results in animal models of metastatic prostate cancer and breast cancer, Dr. Marugan said that they will mainly develop metarrestin for pancreatic cancer. Pancreatic cancer is the most terrible cancer because of high mortality. 90% of patients cannot survive for one year after diagnosis. What’ worse, for pancreatic cancer, there is almost no treatment option.

At the same time, Dr. Marugan is also exploring metarrestin-based combination therapies and early diagnosis of pancreatic cancer biomarkers in an effort to treat it more effectively at an earlier stage of cancer.