A team of researchers led by Duke Cancer Institute scientists Steven Patierno, PhD; Daniel George, MD; Jennifer Freedman, PhD; Jiaoti Huang, MD, PhD and Amanda Hargrove, PhD have been awarded a Movember Foundation-Prostate Cancer Foundation Challenge Award. The project includes a number of key co-investigators including Terry Hyslop, PhD (Biostatistics), Michael Kelley MD and Megan McNamara MD (key clinical oncology collaborators at the Durham Veterans Administration Hospital), James Abbruzzese, MD (DCI Associate Director for Clinical Research) and Hailiang Hu, PhD (senior scientist in Pathology). Muthana Al Abo, PhD, MD, joins the teams as a PCF Young Investigator. The $1 million award will support a two-year project investigating targeting RNA splicing for therapeutic application in race-related aggressive and lethal prostate cancer in African American and Caucasian patients, including Veterans.
“There is an urgent need to identify new systemic precision treatments for metastatic, lethal prostate cancer,” said Patierno. “RNA splicing is known to be responsible for greater diversity in biology and disease than mutation or aggregate gene expression alterations, but it has been largely ignored in precision oncology, including in prostate cancer. Our goal is to show how RNA splicing drives race-related and lethal prostate cancer. We hypothesize that by targeting this biology we can reverse disease progression.”
During the normal growth and development process, cells use a limited number of genes to make a large number of proteins through an orderly process called RNA splicing. When this orderly splicing process becomes de-regulated, the cells begin producing different proteins that can cause them to grow out of control and spread, causing cancer.
“Our research team has demonstrated significant differences in expression of RNA splice variants between prostate cancer in African American and Caucasian patients,” explained Freedman. “The number of these differentially expressed RNA splice variants far exceeds the differences in aggregate gene expression in the same tissues. This data reveals that alternative RNA splicing of the PI3K-delta gene likely contributes to prostate cancer disparities.”
In addition, Huang and his research team have identified a switch in expression of alternative RNA splice variants of a metabolic enzyme that drives prostate cancer progression and development of therapeutic resistance. Toward being able to specifically modulate RNA splicing for therapeutic application, the Patierno, Freedman and George research team and the Hargrove research team are developing novel splice-switching oligonucleotides and RNA-targeted small molecules, respectively.
“The collaboration is why I came to Duke,” explained Huang. “Here, we are all located near each other and attend the same meetings that allow us to interact and share what our labs are studying, utilizing the expertise of different specialties’ and individuals. These partnerships allow us to move science forward to patients while continuing to discover groundbreaking research.”
With the funding provided by this award, the researchers will develop novel treatments against the aforementioned splicing-related targets by conducting human and xenograft/patient-derived xenograft (PDX) trials and in vitro and in silico studies of additional promising prioritized splicing-related targets.
Five teams, from Duke’s Department of Medicine, Department of Pathology, Department of Biostatistics and Bioinformatics, Department of Chemistry, and Durham VA Medical Center will collaborate on the project.
To learn more about the research behind the project — “Targeting RNA Splicing in Race-Related Aggressive and Lethal Prostate Cancer” — visit the Prostate Cancer Foundation website.