Targeted tumors attack not-innocent bystanders
Rice-led project's antibody-drug conjugate also kills non-targeted neighboring tumor cells
2021-06-22
(Press-News.org) HOUSTON - (June 22, 2021) - How do you kill tumor cells that can't be targeted? Get their more susceptible neighbors to help.
The Rice University lab of synthetic chemist K.C. Nicolaou, in collaboration with AbbVie Inc., has created unique antibody-drug conjugates (ADCs) that link a synthetic uncialamycin analogue to antibodies that target cancer cells.
Once they enter the targeted tumor cells, these ADCs exhibit a "significant bystander effect," according to the study. In other words, cancerous neighbor cells that aren't directly attacked by the drugs are also affected.
The study in the Proceedings of the National Academy of Sciences presents "an intriguing opportunity in the tumor-targeting therapeutics development area," according to the researchers.
"The bystander effect is expected to improve the efficacy of the ADC drug by killing, in addition to the targeted cancer cells, a significant number of nearby, nontargeted cancer cells usually found within or in close proximity to malignant tumors," Nicolaou said.
Nicolaou's lab, which specializes in the synthesis of molecules found in nature that have medicinal properties, first reported in 2016 its development of a method to simplify its synthesis of uncialamycin, an enediyne compound isolated from a strain of marine bacteria. Once inside the nucleus of a cell, it produces radicals that cut both strands of the target's DNA.
The earlier study produced 13 analogues of uncialamycin and tested them on lung, gastric, ovarian and multidrug-resistant cancer cell lines with "remarkably high potency," the researchers reported at the time, suggested they showed promise as ADC payloads and chose one for further development.
That promise is now paying off. In tests on solid tumors, the best of a variety of ADCs killed not only the cell that expressed the target protein but also "neighbor" cancer cells that didn't.
"That is unique within the enediyne payload-carrying ADCs, and in contrast to the currently employed ADCs containing N-acetyl calicheamicin payloads, which do not exhibit this killing effect," Nicolaou said.
Importantly, he said, the majority of clinically approved ADCs demonstrate bystander killing effect.
The study found ADCs made with cleavable linkers that are stable in the bloodstream but release their payloads in the tumor microenvironment were most effective at decreasing the size of small-cell lung cancer tumors in PDX mouse models.
INFORMATION:
Authors of the paper are research scientist Stephan Rigol and former postdoctoral fellows Dipendu Das, Yong Lu and Subhrajit Rout of Rice; visiting scientist Emmanuel Pitsinos from the National Center for Scientific Research, Agia Paraskevi, Greece; and Alexander Schammel, Dane Holte, Baiwei Lin, Christine Gu, Hetal Sarvaiya, Jose Trinidad, Nicole Barbour, Amanda Valdiosera, Joseph Sandoval, Christina Lee, Monette Aujay, Hanan Fernando, Anukriti Dhar, Holger Karsunky, Nicole Taylor, Marybeth Pysz and Julia Gavrilyuk of AbbVie.
Nicolaou is the Harry C. and Olga K. Wiess Professor of Chemistry and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar.
AbbVie, CPRIT and The Welch Foundation supported the research.
Read the abstract at https://doi.org/10.1073/pnas.2107042118.
This news release can be found online at https://news.rice.edu/2021/06/22/targeted-tumors-attack-not-innocent-bystanders/.
Follow Rice News and Media Relations via Twitter @RiceUNews.
Related materials:
Rice scientists streamline synthesis of potential cancer drug: http://news.rice.edu/2016/06/23/rice-scientists-streamline-synthesis-of-potential-cancer-drug-2/
Nicolaou Research Group: https://nicolaou.rice.edu/
Department of Chemistry: https://chemistry.rice.edu
Wiess School of Natural Sciences: https://naturalsciences.rice.edu
Images for download:
https://news-network.rice.edu/news/files/2021/06/0628_BYSTANDER-1-web.jpg
(Credit: Illustration by the Jenna Kripal/Nicolaou Research Group)
https://news-network.rice.edu/news/files/2021/06/0628_BYSTANDER-2-WEB.jpg
CAPTION: K.C. Nicolaou. (Credit: Rice University)
Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation's top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,978 undergraduates and 3,192 graduate students, Rice's undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger's Personal Finance.
Jeff Falk
713-348-6775
jfalk@rice.edu
Mike Williams
713-348-6728
mikewilliams@rice.edu
[Attachments] See images for this press release:
ELSE PRESS RELEASES FROM THIS DATE:
2021-06-22
Researchers at the University of Cincinnati College of Medicine have developed a blueprint for a protein that plays an important role in the development and regulation of reproductive organs.
The knowledge advances our understanding of the protein anti-Müllerian hormone hormone (AMH), which helps form male reproductive organs and in females regulates follicle development and ovulation in the ovaries, explains Thomas Thompson, PhD, professor in the UC Department of Molecular Genetics, Biochemistry and Microbiology.
Scientists have been looking to regulate AMH because it might play a role in developing a novel contraceptive, aid in treatments for infertility ...
2021-06-22
An enzyme found in fat tissue in the centre of our bones helps control the production of new bone and fat cells, shows a study in mice published today in eLife.
The findings may help scientists better understand how the body maintains fat stores and bone production in response to changing conditions, such as during aging. They may also suggest new approaches to treating conditions that cause bone loss in older adults.
Fat cells, including those found in the bone marrow, are increasingly recognised as an important part of the body that helps regulate body weight, insulin sensitivity and bone mass. Fat tissue ...
2021-06-22
DETROIT - Jessica Damoiseaux, Ph.D., an associate professor with the Institute of Gerontology at Wayne State University, recently published the results of a three-year study of cognitive changes in older adults. The team followed 69 primarily African American females, ages 50 to 85, who complained that their cognitive ability was worsening though clinical assessments showed no impairments. Three magnetic resonance imaging scans (MRIs) at 18-month intervals showed significant changes in functional connectivity in two areas of the brain.
"An older adult's perceived cognitive decline could be an important precursor to dementia," Damoiseaux said. "Brain alterations that underlie the experience of decline could reflect ...
2021-06-22
(Boston)--Lung cancer remains the leading cause of cancer-related deaths. Non-small cell lung cancer (NSCLC) accounts for 80-85 percent cases of lung cancer and when diagnosed early, has a five-year survival rate of 50-80 percent. Black patients have lower overall incidence of NSCLC than white patients, but are more likely to be diagnosed at later stages. They also are less likely to receive surgery for early-stage cancer.
Now a new study from Boston University School of Medicine (BUSM) highlights the impact that structural racism and residential segregation has on NSCLC outcomes.
The researchers analyzed patient data from the Surveillance, Epidemiology and End Results Program--a database of Black and white patients diagnosed with NSCLC from 2004-2016 in the 100 ...
2021-06-22
PROVIDENCE, R.I. [Brown University] -- What motivated Americans to wear masks and stay socially distanced (or not) at the beginning of the COVID-19 pandemic? More often than not, it was partisanship, rather than perceived or actual health risk, that drove their behavior, according to a new study co-authored by researchers at Brown University.
By analyzing the results of two online surveys of more than 1,100 adults in total, Mae Fullerton, a Class of 2021 Brown graduate, and Steven Sloman, a professor of cognitive, linguistic and psychological sciences, found that in spring and fall 2020, political partisanship was the strongest predictor of whether someone ...
2021-06-22
An analysis of survey data from more than 280,000 young adults ages 18-35 showed that cannabis (marijuana) use was associated with increased risks of thoughts of suicide (suicidal ideation), suicide plan, and suicide attempt. These associations remained regardless of whether someone was also experiencing depression, and the risks were greater for women than for men. The study published online today in JAMA Network Open and was conducted by researchers at the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health.
"While we cannot establish that cannabis use caused the increased suicidality we observed in this study, these associations warrant further research, especially ...
2021-06-22
What The Study Did: Researchers report their study found no association in SARS-CoV-2 positivity rates among health care workers wearing respirator masks compared with medical masks when performing nonaerosolizing routine patient care.
Authors: :Aldon Li, M.D., of the Southern California Permanente Medical Group in Riverside, California, is the corresponding author.
To access the embargoed study: END ...
2021-06-22
WASHINGTON, June 22, 2021 -- Two COVID-19 pandemic curves emerged within many cities during the one-year period from March 2020 to March 2021.
Oddly, the number of total daily infections reported during the first wave is much lower than that of the second, but the total number of daily deaths reported during the first wave is much higher than the second wave.
This contradiction inspired researchers from the University of Nicosia in Cyprus to explore the uncertainty in the daily number of infections reported during the first wave, caused by insufficient contact tracing between March and April 2020.
In Physics of Fluids, ...
2021-06-22
WASHINGTON, June 22, 2021 -- Emerging open-source programming language Julia is designed to be fast and easy to use.
Since it is particularly suited for numerical applications, such as differential equations, scientists in Germany are using it to explore the challenges involved in transitioning to all-renewable power generation.
Decarbonization implies a radical restructuring of power grids, which are huge complex systems with a wide variety of constraints, uncertainties, and heterogeneities. Power grids will become even more complex in the future, so new computational tools are needed.
In Chaos, from AIP Publishing, Potsdam Institute for Climate Impact Research (PIK) scientists describe a software package they built to enable the simulation of general dynamical ...
2021-06-22
WASHINGTON, June 22, 2020 -- Most models explaining how viruses are transmitted focus on viral particles escaping one person to infect a nearby person. A study on the role of microscopic particles in how viruses are transmitted suggests pollen is nothing to sneeze at.
In Physics of Fluids, by AIP Publishing, Talib Dbouk and Dimitris Drikakis investigate how pollen facilitates the spread of an RNA virus like the COVID-19 virus. The study draws on cutting-edge computational approaches for analyzing fluid dynamics to mimic the pollen movement from a willow ...
LAST 30 PRESS RELEASES:
[Press-News.org] Targeted tumors attack not-innocent bystanders
Rice-led project's antibody-drug conjugate also kills non-targeted neighboring tumor cells
