It kills 90 percent of cancer patients, and NIH scientists want to change the status quo.

DrMarugan and his colleagues are committed to changing the status quoTogether with other partners, they found a small molecule drug called metarrestin that showed effects on a variety of solid tumor models that inhibited tumor metastasisNow, they are pushing the compound into clinical trials, targeting pancreatic cancer, the "king of cancer." DrMarugan's NCATS is dedicated to addressing the "pain points" in conversion research and improving the efficiency of turning breakthrough research into patient-beneficial therapiescancer metastasis - a complex and unclarified processcancer metastasis is a complex, multi-step processInitially, cancer cells become aggressive, breaking through the barriers formed by epithelial tissue and invading blood vesselsAfter the blood circulation is transferred to other parts of the body, they also need to leave the blood circulation and invade into the distant tissuesCancer metastasis does not occur in all tissues, and previous studies have shown that the environment of specific tissues in the human body is more conducive to the survival and implantation of metastasized cancer cellsThe environment in which these metastatic cancer cells are suitable for survival is called pre-metastatic nichesCancer cells that survive in pre-metastasis habitats may lurk for a long time, and then, stimulated by specific factors, the cancer cells amplify and become metastatic colonizationspecific target cancer metastasis means that multiple nodes in this complex process can be targetedSince the first step in cancer cell metastasis becomes aggressive, the process has become one of the focus of scientists' researchStudies have shown that internal changes in a variety of tumor cells can lead to increased aggression in their enthesible, including epithelial-mesenchymal transition,EMT), protease generation and migrationmultiple steps of cancer metastasis (Photo: References)However, due to the genetic instability of metastasis cancer cells, there may not be a dominant signaling pathway to control cancer metastasis in most cancer types Our understanding of cancer metastasis is far from complete 'We know some of the mechanisms associated with the epithelial hypertheration process, and the basic receptors and factors associated with this process,' Dr Marugan said However, this knowledge is not yet sufficient to provide a "panorama" for the development of targeted cancer metastasis a different way, using phenotype screening to find new therapeutic molecules
Since drugs could not be developed for specific molecular targets, Dr Marugan's team decided to use phenotype screening to identify drugs that could affect cancer attack They found that highly evolved cancer cells had a structure called perinucleolar ar, PNC PNC is a subnuclear small body connected to the nucleus of a cell No 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 PNC under an electron microscope (Photo: References) , Dr Marugan's team conducted a high-throughput phenotype screening to look for small molecules that could break up the PNC but would not kill the cells They found a small molecular compound, later called metarrestin, that can be very effective in disassembling PNC in solid tumors, so what effect does it have on cancer metastasis? in mouse animal models of cancer, researchers found that if tumors in animals have not metastasized, metarrestin can prevent metastasis and significantly improve the animal's survival If the metastasis has begun, metarrestin can reduce the number of metastases and extend the lifespan of animals Metarrestin inhibits metastasis in mouse models without cancer metastasis (Figure A), reduces the number of metastases and extends animal life span in mouse models with cancer metastasis (Picture Source: References3) 2018, Dr Marugan's team published a study on Metarrestin in Science Translational Medicine Further research found that metarrestin's target, which was combined with a protein called eEF1A2, controls the function of RNA polymerase 1 (Pol 1) Pol 1, on the other hand, is essential for the synthesis of ribosome RNA So in cancer cells, eEF1A2 can help improve the biosynthesis of ribosomes, which are important for the rapid proliferation, division, and evolution of cells Metarrestin blocks the production of neonucleosomes in highly evolved cancer cells by blocking eEF1A2 zhicheng, sword refers to the "king of cancer" Dr Marugan said the current preclinical trial of metarrestin has been completed and the IND application is to be submitted to the FDA The emergence of this drug candidate is the result of collaboration between multiple research institutions The original idea for phenotype screening using PNC came from Professor Sui Huang of Northwestern University The Specialized Chemistry Center at the University of Kansas helped conduct medical chemistry research The National Center for the Promotion of Translational Science has undergone preclinical development, including GMP's expanded production, toxicology research and formulation They will also work with the National Cancer Institute (NCI) for Phase 1 and Phase 2 clinical trials the National Institutes of Health (NIH) has patented metarrestin, and Dr Marugan plans to push the therapy to Phase 2 clinical trials and then work with pharmaceutical companies to get FDA approval While metarrestin has produced excellent results in both animal models of metastatic prostate cancer and breast cancer, Dr Marugan said they will focus on developing metarrestin to treat pancreatic cancer Pancreatic cancer is known as the "king of cancer" because of its high mortality rate, and 90% of patients do not survive a year after diagnosis "There are already some treatments for prostate and breast cancer, and most of these two types of cancer can be found at an early stage," says Dr Marugan That's why we decided to focus on pancreatic cancer , Dr Marugan is also exploring a combination of metarrestin-based therapies and biomarkers for early diagnosis of pancreatic cancer in an effort to treat the "King of Cancer" more effectively at an earlier stage of cancer 's efforts to address the two "pain points" of transformational research to discover new drugs and push them into clinical trials is certainly a welcome thing, but for Dr Marugan, it's just a side effect of his research At the National Center for the Advancement of Translational Science (NCATS), his job is to understand why conversion studies fail so high that 90 percent of drugs entering human clinical trials fail NCATS' goal is not only to validate new strategies, but also to better understand why previous drug development strategies have failed , in Dr Marugan's view, there are two main reasons for the number of failures in the past One is that the (animal) models used to validate research and development strategies and candidate molecules do not really represent the human body "We don't know how many times we've cured Alzheimer's disease in mouse models, " he said " " ,35%1,35%。 Toxicity in mouse models cannot be equated with toxicity in humans , Dr Marugan's team is developing models that are more similar to humans, including the generation of human pluripotent stem cells and their differentiation into various somatic cells, as well as the development of organoids, bioprinting and biochip technologies the reason for the second failure is related to the way we choose our treatment target In most cases, we select targets through correlation studies For example, select a group of patients (such as people with Parkinson's disease) and compare them with healthy people who are not sick This correlation study can reveal that mutations in the LRRK2 or PINK1 genes may be associated with a risk of Parkinson's disease In reality, however, 90% of people with Parkinson's disease are iexclusivetrius, meaning we don't know why they're on the disease the situation is very similar for other diseases, so Dr Marugan's team's strategy is to look at the onset of the disease from a different perspective This angle is to think of disease as the loss of the human body's dynamic balance Dynamic balance refers to the ability of cells to cope with different stressors, which may include genetic variation, environmental factors, or aging based on this philosophy, Dr Marugan's team developed treatments designed to improve the cell's ability to respond to a variety of stress factors, including oxidative stress, endoscosis stress, protein folding, waste delivery, and removal "The new strategies we have developed to select therapeutic targets hope to look at the problem from a more holistic perspective, without sticking to a specific genetic mutation," dr For example, if we find factors that regulate neurons' ability to remove waste, it can not only treat Parkinson's disease, but also Huntington's disease, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease! References: Anderson et al., (2018) A framework for the development of the effective anti-metastatic agents Nature Reviews Oncology, Slusarczyk et al., (2011) Structure and Function of the Perinucleolar Compartment in Cancer Cells Cold Spring Harbor Symposia on Quantitative Biology, DOI: 10.1101/sqb.2010.75.026 frank eowski al., (2018) Metarrestin, a perinucleolar a Science Translational Medicine, DOI: 10.1126/scitranslmed.aap8307 the Peculiarity of The Cancer Metastasis May be The Key to Controlling the Disease Retrieved September 22, 2019, from