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Repeats of DNA sequences, often referred to as 'junk DNA' or 'dark matter,' that are found in chromosomes and could contribute to cancer or other diseases have been challenging to identify and characterize. Now, researchers have developed a novel approach that uses machine learning to identify these elements in cancerous tissue, as well as in cell-free DNA (cfDNA) -- fragments that are shed from tumors and float in the bloodstream. This new method could provide a noninvasive means of detecting cancers or monitoring response to therapy. Repeats of DNA sequences, often referred to as "junk DNA" or "dark matter," that are found in chromosomes and could contribute to cancer or other diseases have been challenging to identify and characterize. Now, investigators at the Johns Hopkins Kimmel Cancer Center have developed a novel approach that uses machine learning to identify these elements in cancerous tissue, as well as in cell-free DNA (cfDNA) -- fragments that are shed from tumors and float in the bloodstream. This new method could provide a noninvasive means of detecting cancers or monitoring response to therapy. Machine learning is a type of artificial intelligence that uses data and computer algorithms to perform complex tasks and accelerate research. In laboratory tests, the method, called ARTEMIS (Analysis of RepeaT EleMents in dISease) examined over 1,200 types of repeat elements comprising nearly half of the human genome, and identified that a large number of repeats not previously known to be associated with cancer were altered in tumor formation. The investigators also were able to identify changes in these elements in cfDNA, providing a way to detect cancer and determine where in the body it originated. A description of the work is to be published March 13 in Science Translational Medicine. "When you think about existing cancer genes and the DNA sequences around them, they're just chock full of these repeats," says Victor E. Velculescu, M.D., Ph.D., a professor of oncology and co-director of the Cancer Genetics and Epigenetics Program at the Johns Hopkins Kimmel Cancer Center, who led the study with Akshaya Annapragada, an M.D./Ph.D. student at the Johns Hopkins University School of Medicine, and Robert Scharpf, Ph.D., an associate professor of oncology at Johns Hopkins. "Until ARTEMIS, this dark matter of the genome was essentially ignored, but now we're seeing that these repeats are not occurring randomly," Velculescu says. "They end up being clustered around genes that are altered in cancer in a variety of different ways, providing the first glimpse that these sequences may be key to tumor development." In a series of laboratory tests, the researchers first examined the distribution of 1.2 billion kmers (short sequences of DNA) defining unique repeats, finding them enriched in genes commonly altered in human cancers. For example, of 736 genes known to drive cancers, 487 contained an average fifteenfold higher than expected number of repeat sequences. These repeat sequences also were significantly increased in genes involved in cell signaling pathways that are commonly dysregulated in cancers.Using next-generation sequencing, technology that allows researchers to rapidly examine the sequences of entire genomes, the researchers also looked to see if repeat sequences were directly altered in cancers. They used ARTEMIS to analyze over 1,200 distinct types of repeat elements in tumor and normal tissues from 525 patients with different cancers participating in the Pan-Cancer Analysis of Whole Genomes (PCAWG), and found a median of 807 altered elements in each tumor. Nearly two-thirds of these elements (820 of 1,280) had not previously been observed as being altered in human cancers. Then, they used a machine-learning model to generate an ARTEMIS score for each sample to provide a summary of genome-wide repeat element changes that were predictive of cancer. ARTEMIS scores distinguished the 525 PCAWG participants' tumors from normal tissues with a high performance (AUC=0.96) across all cancer types analyzed, where 1 is a perfect score. Increased ARTEMIS scores were associated with shorter overall and progression-free survival regardless of tumor type. The investigators next evaluated ARTEMIS' potential for noninvasive detection of cancer. They applied the tool to blood samples from 287 individuals with and without lung cancer participating in the Danish Lung Cancer Screening Study (LUCAS). ARTEMIS classified patients with lung cancer with an area under the curve (AUC) of 0.82. But when used with another method called DELFI (DNA evaluation of fragments for early interception) -- an assay previously developed by Velculescu, Scharpf and other members of their group that detects changes in the size and distribution of cfDNA fragments across the genome -- the combination model classified patients with lung cancer with an AUC of 0.91. Similar performance was observed in a group of 208 individuals at risk for liver cancer, in which ARTEMIS detected individuals with liver cancer among others with cirrhosis or viral hepatitis with an AUC of 0.87. When combined with DELFI, the AUC increased to 0.90. Finally, they evaluated whether the ARTEMIS blood test could identify where in the body a tumor originated in patients with cancer. When trained with information from the PCAWG participants, the tool could classify the source of tumor tissues with an average 78% accuracy among 12 tumor types. The investigators then combined ARTEMIS and DELFI to assess blood samples from a group of 226 individuals with breast, ovarian, lung, colorectal, bile duct, gastric or pancreatic tumors. Here, the model correctly classified patients among the different cancer types with an average accuracy of 68%, which improved to 83% when the model was allowed to suggest two possible tumor types instead of a single cancer type. "Our study shows that ARTEMIS can reveal genome-wide repeat landscapes that reflect dramatic underlying changes in human cancers," Annapragada says. "By illuminating the so-called 'dark genome,' the work offers unique insights into the cancer genome and provides a proof-of-concept for the utility of genome-wide repeat landscapes as tissue and blood-based biomarkers for cancer detection, characterization and monitoring." Next steps are to evaluate the approach in larger clinical trials, says Velculescu: "You can imagine this could be used for early detection for a variety of cancer types, but also could have uses in other applications such as monitoring response to treatment or detecting recurrence. This is a totally new frontier." Additional study co-authors were Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda and Jillian Phallen. The work was supported in part by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Stand Up to Cancer (SU2C) in-Time Lung Cancer Interception Dream Team Grant, SU2C-Dutch Cancer Society International Translational Cancer Research Dream Team Grant (SU2C-AACR-DT1415), the Gray Foundation, The Honorable Tina Brozman Foundation, the Commonwealth Foundation, the Mark Foundation for Cancer Research, the Cole Foundation, a research grant from Delfi Diagnostics and U.S. National Institutes of Health grants CA121113, CA006973, CA233259, CA062924, CA271896 and 1T32GM136577. Annapragada, Scharpf and Velculescu are inventors on patent applications submitted by The Johns Hopkins University related to genome-wide repeat landscapes in cancer and cfDNA. Annapragada, Bruhm, Adleff, Mathios, Foda, Phallen and Scharpf are inventors on patent applications submitted by The Johns Hopkins University related to cell-free DNA for cancer detection that have been licensed to Delfi Diagnostics. White is the founder and owner of Resphera Biosciences LLC and serves as a consultant to Personal Genome Diagnostics Inc. and Delfi Diagnostics Inc. Cherry is the founder and owner of CMCC Consulting. Phallen, Adleff and Scharpf are founders of Delfi Diagnostics, and Adleff and Scharpf are consultants for this organization. Velculescu is a founder of Delfi Diagnostics, serves on the board of directors and owns Delfi Diagnostics stock, which is subject to certain restrictions under university policy. Additionally, The Johns Hopkins University owns equity in Delfi Diagnostics. Velculescu divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. He is an inventor on patent applications submitted by The Johns Hopkins University related to cancer genomic analyses and cell-free DNA for cancer detection that have been licensed to one or more entities, including Delfi Diagnostics, LabCorp, Qiagen, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. Under the terms of these license agreements, the university and inventors are entitled to fees and royalty distributions. Velculescu is also an adviser to Viron Therapeutics and Epitope. These arrangements have been reviewed and approved by The Johns Hopkins University in accordance with its conflict-of-interest policies.

EMERYVILLE, Calif.--(BUSINESS WIRE)-- Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T-cell therapies to treat cancer, today announced it has entered into a license agreement with the National Cancer Institute (NCI), part of the National Institutes of Health, to develop and commercialize a novel antibody targeting mesothelin (MSLN) in combination with Eureka’s proprietary ARTEMIS® T-cell receptor platform. MSLN is a cell-surface protein overexpressed in many solid tumors, including mesothelioma, ovarian, pancreatic, breast and lung cancers, making it a promising target for cancer therapies. The NCI antibody licensed to Eureka has shown potential in preclinical studies to selectively bind to and kill cancer cells expressing MSLN while sparing normal cells, which could make it an effective cancer treatment. Eureka has previously demonstrated that its proprietary ARTEMIS T-cell receptor platform has several advantages over conventional chimeric antigen receptors (CARs), including better tumor infiltration, safety, and T cell persistence. By combining the newly licensed MSLN-targeting antibody with the ARTEMIS T-cell receptor platform, Eureka and NCI intend to develop a next-generation T-cell therapy that can effectively target and eliminate MSLN-expressing cancer cells. “We are excited to add this promising antibody to our ARTEMIS receptor portfolio and to advance the development of a potentially transformative T-cell therapy for solid tumors,” said Dr. Cheng Liu, President and CEO of Eureka Therapeutics. “Our goal is to develop safe and effective T-cell therapies to treat MSLN-expressing cancers. We believe the combination of our ARTEMIS platform and this novel antibody targeting MSLN is a promising approach to achieve this goal.” “The license of NCI’s MSLN-targeting antibody highlights our commitment to advancing promising cancer therapies,” said Dr. Ira Pastan, Chief Emeritus of the Laboratory of Molecular Biology and Head of the Molecular Biology Section at the NCI Center for Cancer Research. “Such partnerships have the potential to bring transformative therapies to patients.” Eureka plans to continue preclinical development of the antibody to support an investigational new drug (IND) application with the US Food and Drug Administration (FDA). ABOUT EUREKA THERAPEUTICS, INC. Eureka Therapeutics, Inc. is a privately held clinical-stage biotechnology company focused on developing novel T-cell therapies to treat cancers. Its core technology centers around its proprietary ARTEMIS® cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of solid tumors and hematologic malignancies. The company currently has two clinical programs, ET140203 (ARYA1 for adults and ARYA2 for pediatrics) and ECT204 (ARYA3), in Phase I/II US trials in patients with advanced liver cancer. Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit . ARTEMIS and E-ALPHA are registered trademarks owned by Eureka.

Ten young children born without functioning immune systems and lacking the ability to fight infections are on track for healthier lives thanks to a new gene therapy treatment. Ten young children born without functioning immune systems and lacking the ability to fight infections are on track for healthier lives thanks to a new gene therapy treatment pioneered at UC San Francisco, reports a Dec. 22 study in the New England Journal of Medicine. The children have Artemis-SCID, a very rare genetic disorder that is typically treated with a bone marrow transplant from a healthy donor, ideally a matched brother or sister. The new gene therapy allows researchers to treat newly diagnosed babies with their own cells -- adding a healthy copy of the Artemis gene to the baby's harvested marrow stem cells, then infusing the corrected stem cells back into their bodies -- in hopes of avoiding many of the short- and long-term complications of the standard treatment, including death. The children in the trial -- all under the age of 5 -- are living at home with their families, attending daycare and preschool, playing outside, and living normal lives, said Mort Cowan, MD, UCSF pediatrics professor and the trial's lead investigator. "Already, the course of their illness is so much better than with the typical treatment," said Cowan, who has treated more than 30 children with Artemis-SCID using standard bone marrow transplants. "I've never seen results like this in any of the other kids. It's amazing." Gene correction has been used before in patients with other genetic forms of SCID, but its use in Artemis-SCID is significant because these patients usually respond more poorly to standard bone marrow transplants. Complications can include rejecting the marrow graft, graft-vs.-host disease -- in which the donor T cells attack the recipient's tissues -- chronic infections leading to organ damage, stunted growth, and premature death. Signs of Stronger Immunity The first outcome of the Phase I/II trial involved the safe transfusion of gene-corrected cells that would differentiate into white blood cells by 42 days after infusion. Researchers theorized patients would need less chemotherapy to prepare their marrow for transfusion when their own cells were being used; thus only 25% of a full dose of busulfan was administered. The second outcome was T-cell reconstitution at 12 months, a measurement of the strength of the immune system. All 10 patients were safely transfused with their own gene-corrected stem cells that gave rise to corrected peripheral blood cells within 42 days. All 10 were growing their own T cells and B cells by 12 weeks, and four of nine (excluding a patient who received a second treatment) achieved full T-cell immune reconstitution by 12 months. Four of nine also achieved full B cell immunity by 24 months, allowing them to discontinue immunoglobulin replacement and receive standard childhood vaccinations. An additional three patients, who were followed for fewer than 24 months, had promising B cell development when compared to previous outcomes for donor-transplanted patients. One child required a second infusion of gene-corrected bone marrow due to a persistent infection with cytomegalovirus prior to gene therapy but is now infection free with good T- and B-cell immunity. "All of the results are better than those previously seen with Artemis-SCID patients who received donor bone marrow transplants," noted Jennifer Puck, MD, UCSF pediatrics professor and co-lead investigator in the study. "Having patients in the trial achieve full T-cell immunity is outstanding. B-cell recovery takes longer, but so far it looks as if the patients also have a far better chance for B-cell reconstitution than they would with a regular bone marrow transplant," Puck said. "Successfully using less chemotherapy is also a big win, minimizing the harmful side effects of full dose busulfan in small infants." Better B-cell immunity could help avoid issues such as chronic lung disease that often develop later in childhood for Artemis-SCID patients who receive a standard bone marrow transplant, Cowan added. The children in the trial are currently between the ages of 18 months and 4.5 years; nine were born in the U.S. and were diagnosed following newborn screening for SCID; one was born in Canada and diagnosed at five months of age with clinical illness. Four patients are of Navajo/Apache Native American descent, where the Artemis-SCID mutation is more common. Median follow-up was 31.2 months. At the time of study publication, six patients had been followed for at least 24 months. "We're pioneering gene therapy in this very rare disease right now, but we are using techniques that can be exported to other situations and can help many other conditions worldwide," said Puck. "Every new innovation happens one patient at a time." Co-authors: Also contributing to this research from UCSF were: Jason Yu, PhD; Carol Fraser-Browne, BA; Ukina Sanford, MS; Misako Kawahara, BA; Wendy Chan, BS; Shivali Chag, MS; and Robert Currier, PhD, of the UCSF Department of Pediatrics; Jess Oh, MS, of the UCSF Benioff Children's Hospital San Francisco; Jasmeen Dara, MD; Janelle Facchino, NP; Christopher Dvorak, MD, of the UCSF Department of Pediatrics and UCSF Benioff Children's Hospital San Francisco; Joan Hilton, DSc, MPH, of the UCSF Department of Epidemiology and Biostatistics; and Janel Long-Boyle, PharmD, PhD, of UCSF's Department of Pediatrics, School of Pharmacy and UCSF Benioff Children's Hospital San Francisco. Please refer to the paper for additional co-authors.