Daniel Siegwart, Ph.D.
DALLAS – June 23, 2022 – As they grow, solid tumors surround themselves with a thick wall of molecular defenses that are difficult to penetrate. Getting drugs past this barricade is notoriously difficult. Now, UT Southwestern scientists have developed nanoparticles capable of breaking down physical barriers around tumors to reach cancer cells. Once inside, the nanoparticles release their payload: a gene-editing system that modifies the DNA inside the tumor, blocking its growth and activating the immune system.
The new nanoparticles, described in Nature’s nanotechnology, effectively stopped the growth and spread of ovarian and liver tumors in mice. The system offers a new way forward for using the gene-editing tool known as CRISPR-Cas9 in cancer treatment, the study leader says Daniel Siegwart, Ph.D.associate professor of Biochemistry at UT Southwest.
“Although CRISPR offers a novel approach to treating cancer, the technology has been severely hampered by the low efficiency of delivering payloads into tumors,” said Dr. Siegwart, a member of the Harold C. Simmons Cancer Center.
In recent years, CRISPR-Cas9 technology has given researchers a way to selectively modify DNA inside living cells. While the gene-editing system offers the potential to alter genes that drive cancer growth, delivering CRISPR-Cas9 to solid tumors has been challenging.
For more than a decade, Dr. Siegwart and his colleagues have studied and engineered lipid nanoparticles (LNPs), small spheres of fatty molecules that can carry molecular cargo (including recent COVID-19 mRNA vaccines) around the body. human. In 2020, Dr. Siegwart’s group showed how to direct nanoparticles to specific tissueswhat had been a challenge limiting the field.
In the new work, to target cancer, the researchers started with the nanoparticles they had already optimized to get to the liver. They added a small piece of RNA (called short interfering RNA or siRNA) that could turn off focal adhesion kinase (FAK), a gene that plays a central role in maintaining the physical defenses of a number of tumors. .
“Targeting FAK not only weakens the barricade around tumors and makes it easier for the nanoparticles themselves to enter the tumor, but also opens the way for immune cells to enter,” said Di Zhang, Ph.D. , Postdoctoral Research Fellow. Fellow at UTSW and first author of the article.
Inside the newly designed nanoparticles, the researchers encapsulated the CRISPR-Cas9 machinery that could modify the gene PD-L1. Many cancers use this gene to produce high levels of the PD-L1 protein, which inhibits the immune system’s ability to attack tumors. Scientists have already shown that disrupting the PD-L1 gene, in some cancers, can remove these brakes and allow a person’s immune system to kill cancer cells.
Drs. Siegwart, Zhang and their colleagues tested the new nanoparticles in four mouse models of ovarian and liver cancer. They first showed that by adding siRNAs to deactivate FAK, the matrix of molecules around tumors was less rigid and easier to penetrate than normal. Then they analyzed the tumor cells and found that many more nanoparticles had reached the cells, effectively altering the PD-L1 embarrassed.
Finally, they found that tumors in mice treated with the nanoparticles that targeted both FAK and PD-L1 reduced to about one-eighth the size of tumors treated only with empty nanoparticles. Moreover, more immune cells infiltrated the tumors and the treated mice survived, on average, about twice as long.
Further work is needed to show the safety and efficacy of nanoparticles in a variety of tumor types. The researchers said the therapy could be useful in conjunction with existing cancer immunotherapies that aim to use the immune system to attack tumours.
“After the global success of the COVID-19 LNP vaccines, we are all wondering what else LNPs can do. Here, we developed novel LNPs capable of simultaneously delivering multiple types of genetic drugs to improve therapeutic outcomes in cancer. There is clearly great potential for LNP drugs to treat different types of diseases,” said Dr Siegwart.
Other researchers who contributed to this study include Guoxun Wang, Xueliang Yu, Tuo Wei, Lukas Farbiak, Lindsay T. Johnson of UTSW and Hao Zhu of UTSW Children’s Medical Research Institute and Alan Mark Taylor, Jiazhu Xu and Yi Hong from UT Arlington. .
Dr. Siegwart is a co-founder and consultant for ReCode Therapeutics, which has licensed intellectual property from UT Southwestern.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s leading academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes and includes 26 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 14 researchers from the Howard Hughes Medical Institute. Full-time faculty of more than 2,900 are responsible for groundbreaking medical advances and committed to rapidly translating scientific research into new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 100,000 inpatients, more than 360,000 emergency room cases, and oversee nearly 4 million outpatient visits annually.