RSPO3

Investigators have identified a component in the intestine that plays a critical role in repairing damaged tissue. Investigators at Cedars-Sinai and the University of California, San Francisco (UCSF) have identified a component in the intestine that plays a critical role in repairing damaged tissue. Scientists found that endothelial cells in the lymphatic vessels produce molecules that are essential for the maintenance and regulation of stem cells and tissues in the intestine. These lymphatic endothelial cells reside near specialized stem cell niches, which are microenvironments that support stem cell regeneration. The findings were published in the peer-reviewed journal Cell Stem Cell. "It's important for us to understand niches and how lymphatics communicate with stem cells as part of the niche," said Ophir Klein, MD, PhD, senior author of the study and executive director of Cedars-Sinai Guerin Children's. "Deciphering the mechanisms that explain how the ecosystem that supports stem cells works will help to lay the foundation for future discoveries that could one day lead to therapeutic strategies to repair damaged tissue." The intestine undergoes continuous renewal to withstand the wear and tear that result from breakdown of foods, and from the presence of waste that can injure and kill cells. The intestine needs to replenish itself constantly with healthy cells, and fortunately, it has an exceptional capacity to regenerate cells. The division of intestinal stem cells to make more cells is regulated by their surrounding niche, which is comprised of several cell types and is an essential source of signals. However, it is unclear which niche cells produce signals during different states of injury. To better understand stem cell activity, the team wanted to learn which cells help the intestinal epithelial cells repair themselves -- particularly lymphatic endothelial cells. "Lymphatics are in very close proximity to the stem cells, and almost all the stem cell compartments are near lymphatics," said Brisa Palikuqi, PhD, co-first author of the study and a postdoctoral fellow in the Klein Laboratory at UCSF. "Because the two cell types are in such proximity, this made us believe that these lymphatics may play an important role." Lymphatics express several factors, including a gene, Rspo3, that is known to be important for stem cells to function. To determine whether the gene played an important role in intestinal stem cell regulation, the investigators deleted the gene in mice and then used single-cell sequencing to see how stem cells in the intestine would react without Rspo3. Initially, the stem cells did not have any response to the change in the environment. The researchers then decided to injure the system by delivering a chemotherapy drug that kills any proliferating cells wherever the drug travels through the body. "When we did this, all of a sudden the stem cells and the intestine had to proliferate a lot more and replace a lot more cells on a daily basis," said Jeremie Rispal, PhD, also a postdoctoral researcher in the Klein Laboratory at UCSF and the other co-first author of the study. The loss of the Rspo3 gene led to a lower number of stem and progenitor cells, hindering recovery after the injury. "This discovery showed us that lymphatic endothelial cells are a key component of the intestinal niche and essential for intestinal repair after cases of damage, like chemotherapy," said Klein, who also holds the David & Meredith Kaplan Distinguished Chair in Children's Health at Cedars-Sinai. Klein noted that the study demonstrates how lymphatic endothelial cells play a much larger role than previously thought in stem cell regeneration and may play a role in disease, perhaps even influencing the promotion of cancer. "We are just beginning to understand the functions of the lymphatic vasculature," Klein said. Klein previously directed the Institute for Human Genetics and served as chief of the Divisions of Medical Genetics and Craniofacial Anomalies at UCSF, where he remains an adjunct professor. Klein conducted the study at both USCF and Cedars-Sinai. Funding: The study was funded in part by the National Institutes of Health under award numbers NIH R35-DE026602 and U01-DK103147.

REDWOOD CITY, Calif., Oct. 09, 2018 (GLOBE NEWSWIRE) -- OncoMed Pharmaceuticals, Inc. (NASDAQ:OMED), a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics, today announced that interim results of its ongoing Phase 1b study of navicixizumab in combination with paclitaxel in patients with platinum-resistant ovarian cancer will be presented in a poster presentation on October 20, 2018 at the European Society for Medical Oncology meeting to be held in Munich, Germany. Poster 951P/ Abstract 1389:A Phase 1b Study of Navicixizumab & Weekly Paclitaxel in Heavily Pre-Treated Platinum Resistant Ovarian, Primary Peritoneal or Fallopian Tube Cancer  Date and Time:Saturday, October 20, 2018 from 12:30 pm to 1:30 pm CEST  Location:Hall A3 - Poster Area Networking Hub About Navicixizumab OncoMed's anti-DLL4/VEGF bispecific antibody, navicixizumab, is designed to inhibit the function of both DLL4 and VEGF and thereby induce potent anti-tumor responses while mitigating certain angiogenic-related toxicities. Navicixizumab was developed utilizing OncoMed's BiMAb™ bispecific platform technology, which enables the design of bispecific antibodies comparable to traditional monoclonal antibodies but possessing dual target-binding specificity. In preclinical studies, navicixizumab demonstrated robust in vivo anti-tumor efficacy across a range of solid tumor xenografts, including colon, ovarian, lung and pancreatic cancers, among others. Further, in preclinical studies dual inhibition of DLL4 and VEGF appeared to exhibit synergistic anti-tumor activity at doses where blockade of either target alone elicited sub-optimal activity. In a Phase 1a study with single-agent navicixizumab published in Investigational New Drugs, 19 of 66 patients with various types of refractory solid tumors had tumor shrinkage following treatment with navicixizumab. Notably, 3 of the 12 (25%) ovarian cancer patients treated in the trial achieved a partial response with single-agent navicixizumab therapy. About OncoMed Pharmaceuticals OncoMed Pharmaceuticals is a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer therapeutics. OncoMed has internally discovered a broad pipeline of investigational drugs intended to address the fundamental biology driving cancer's growth, resistance, recurrence and metastasis. Product candidates in OncoMed’s portfolio include navicixizumab (anti-DLL4/VEGF bispecific, OMP-305B83), etigilimab (anti-TIGIT, OMP-313M32), GITRL-Fc (OMP-336B11) and rosmantuzumab (anti-RSPO3, OMP-131R10). OncoMed also continues to pursue new drug discovery research. For further information about OncoMed Pharmaceuticals, please see www.oncomed.com. Forward Looking Statements To the extent that statements contained in this press release are not descriptions of historical facts regarding OncoMed Pharmaceuticals, they are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, without limitation, OncoMed's intentions and expectations regarding the ability of navicixizumab to induce potent anti-tumor responses while mitigating angiogenic-related toxicities. Such risks and uncertainties include, among others, the uncertainties inherent in the preclinical and clinical development process; OncoMed's ability to raise additional capital to support the development of its unpartnered programs; and OncoMed's dependence on its key executives. OncoMed undertakes no obligation to update or revise any forward-looking statements. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to OncoMed's business in general, see OncoMed's Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) on March 9, 2018, OncoMed’s Quarterly Report on Form 10-Q filed with the SEC on August 2, 2018, and OncoMed's other current and periodic reports filed with the SEC. Contacts Sylvia Wheeler sylvia.wheeler@oncomed.com Alexandra Santos asantos@wheelhouselsa.com