Tigecycline

Researchers discover that quality and mix of protein in a type of pancreatic cancer is the determinant of whether the prognosis is poor or very poor. Pancreatic ductal adenocarcinoma (PDAC) is the most common and most lethal form of pancreatic cancer. The overall 5-year survival for patients with PDAC is just 7.1 percent. All cancers are different. A unique feature of PDAC is extensive tumor desmoplasia or fibrous connective tissue within the tumor, which is caused by infiltration of the tumor mass by fibroblasts and the extracellular matrix they secrete. The main component of the matrix is type I collagen or Col 1, a protein broadly used in the body to form the basic structure of bone, skin, blood vessels and connective tissues. The effect of Col 1 on PDAC development and its response to therapy has been a matter of intense debate among researchers, with some arguing that Col 1 promotes tumor growth and spread and others contending that it restricts tumor growth and protects the cancer cells from immune attack. In a new study, published October 5, 2022, in Nature, co-first authors Hua Su, PhD, a postdoctoral fellow in the lab of senior author Michael Karin. PhD, Distinguished Professor of Pharmacology and Pathology at University of California San Diego School of Medicine, and Fei Yang, PhD, a scientist working with Beicheng Sun, MD, PhD, at Nanjing University School of Medicine, settle the debate by showing that it is not the amount of Col 1 present in the tumor that matters, but its quality and nature. Specifically, they report that Col 1 that has been cleaved by matrix metalloproteases (enzymes that break down matrix proteins, such as collagen) stimulates tumor growth while intact and non-cleaved Col 1 inhibits tumor growth. "Moreover," said Su, "cleaved Col 1 activates a signaling pathway that stimulates energy production in pancreatic cancer cells by binding to a receptor protein called DDR1. Non-cleaved Col 1 inhibits this pathway by inducing the degradation of DDR1." The research was conducted using mice models and a novel culture system in which PDAC cells were plated on extracellular matrix that contained either cleaved or non-cleaved Col 1. The authors said the findings have important clinical implications. The relative amounts of cleaved versus non-cleaved Col 1 in the human PDAC stroma or connective tissue strongly affect patient survival after surgical resection. Patients whose tumors were enriched in cleaved Col 1 and whose cancerous cells expressed high levels of DDR1 fared poorly, with most succumbing to their disease within two years of surgery. This patient group represented 75 percent of the 106 patients analyzed as part of the study, using cancer specimens provided by Beicheng Sun, MD, PhD, and colleagues at the Affiliated Drum Tower Hospital of Nanjing University Medical School in China. In contrast, the 25 percent of patients whose tumors mainly contained non-cleaved Col 1 with low levels of DDR1 expression experienced much better survival prospects. "This work is important because it provides a simple way for patient stratification and suggests that patients with high levels of cleaved Col 1 and DDR1 expression need more aggressive post-surgery treatments," said Karin. "It also provides evidence that the most effective therapy for this group of patients should include inhibitors of DDR1 or key components of its signaling pathway whose activation results in increased number of mitochondria, the cellular power plants, in PDAC cells." In addition to DDR1 inhibitors not yet in clinical practice, the authors suggested another treatment option, shown to be effective in PDAC-bearing mice, is the U.S. Food and Drug Administration approved antibiotic tigecycline, which can inhibit mitochondrial protein synthesis and decrease the number of energy-producing PDAC mitochondria. Co-authors include: Rao Fu, Nanjing University Medical School; Brittney Trinh, Nina Sun, Junlai Liu, Jacopo Baglieri, Nachanok Sinchai, Jeremy Siruno, Stephen Dozier, Ajay Nair, Aveline Filliol, Sara Brin Rosenthal, Jennifer Santini, Anthony Molina, Robert F. Schwabe, Andrew M. Lowy and David Brenner, all at UC San Diego; and Avi Kumar and Christian M. Metallo, Salk Institute.

Researchers have discovered one of the causes of the multi-drug resistance of some tumors, and a potential strategy to overcome it. This new 'weak spot' can be exploited using existing drugs that kill tumor cells by activating their stress responses. One of the greatest challenges facing cancer researchers is to understand why some patients don't respond to treatments. In some cases, tumors exhibit what is known as multidrug resistance (MDR), which significantly limits the therapeutic options for patients. Researchers at the Spanish National Cancer Research Centre (CNIO) have discovered one of the causes of MDR, and a potential strategy to combat it. The work, which is mainly based on cell lines and is therefore still a long way from clinical use, is published in EMBO Molecular Medicine. Our findings "explain why many of the available therapies don't work in certain tumors, and at the same time identify the weak point of these resistant cancers," explains Oscar Fernandez-Capetillo, head of the CNIO's Genomic Instability Group and lead author of this research. "We now know that this vulnerability can be exploited using drugs that already exist." As the study shows, mutations that inactivate the function of a particular gene, FBXW7, "reduce the sensitivity to the vast majority of available therapies," the authors write, but at the same time render tumor cells vulnerable to the action of a particular type of drug: those that activate the "integrated stress response" (ISR). A very common mutation in human cancers "FBXW7 is one of the 10 most frequently mutated genes in human cancers," and is associated with "poor survival across all human cancers," the authors add. The study began by using the CRISPR technology in mouse stem cells to search for mutations that generate resistance to anti-tumoral agents such as cisplatin, rigosertib or ultraviolet light. Mutations in the FBXW7 gene emerged early on, suggesting that this mutation could confer MDR. Bioinformatic analysis of databases such as the Cancer Cell Line Encyclopedia (CCLE), with information on the response of more than a thousand human cancer cell lines to thousands of compounds, confirmed that FBXW7 mutant cells are resistant to most of the drugs available in this dataset. Regardless of mutations, further analyses in the Cancer Therapeutics Response Portal (CTRP) revealed that reduced levels of FBXW7 expression were also associated with a worse response to chemotherapy. In fact, the authors suggest using FBXW7 levels as a biomarker to predict patient response to drugs. Without FBXW7, mitochondria are stressed Having established the link between FBXW7 deficiency and multi-resistance, the researchers looked for its cause. They found it in the mitochondria, the cell organelles involved in metabolism and cellular respiration. FBXW7-deficient cells showed an excess of mitochondrial proteins, which has previously been found to be associated with drug resistance. Nevertheless, a detailed analysis of these organelles further revealed that the mitochondria of these multi-resistant cells appeared to be under a lot of stress. An antibiotic effective against tumor cells The discovery of this mitochondrial stress would be key to identifying strategies to overcome drug resistance in cells with FBXW7 mutations. Mitochondria are the remnants of ancient bacteria that fused with primitive eukaryotic cells billions of years ago; therefore, if antibiotics attack bacteria, could an antibiotic kill a cancer cell too rich in mitochondria? In fact, anti-tumoral properties of certain antibiotics have been identified in the past, but these were isolated cases and therefore potentially attributable to unknown individual mutations in patients. Fernandez-Capetillo and his group have shown that the antibiotic tigecycline is indeed toxic to FBXW7-deficient cells, opening up a new avenue of research to tackle multi-resistance. Drugs that act by hyperactivating stress responses But probably even more important is the discovery of why this antibiotic has anti-tumor properties. The authors of the just-published paper show that tigecycline kills cells by hyperactivating the integrated stress response (ISR), and further demonstrate that other drugs capable of activating the ISR are also toxic to cells with FBXW7 mutations. It is worth noting that many of these ISR-activating drugs are oncological therapies in common clinical use today, and that until now it was assumed that they worked by other mechanisms. However, the present study reveals that part of their anti-tumor efficacy is due to their effect in activating the ISR. "Our study, together with other recent works, indicate that activating the ISR could be a way to overcome chemotherapy resistance. However, much work remains to be done. Which drugs activate the ISR best and most strongly? Which patients would benefit most from this strategy? Attempting to answer these questions is what we aim to do in the immediate future," says Fernandez-Capetillo. The work has been funded by the Spanish Ministry of Science and Innovation, the Spanish Association Against Cancer (AECC) and the "La Caixa" Foundation, among others.