Five new cancer-focused research studies are being funded by one-year grants from the UMass Cancer Center Pilot Project Program.
“Pilot grants support exciting discoveries at their earliest stage prior to their readiness for external support and facilitate further development of the project to a stage when they can obtain external support,” said Michael R. Green, MD, PhD, the Lambi and Sarah Adams Chair in Genetic Research, chair and professor of molecular, cell & cancer biology, vice provost for strategic research initiatives, director of the UMass Cancer Center and co-director of the Li Weibo Institute for Rare Diseases Research.
The UMass Cancer Center, the Department of Population & Quantitative Health Sciences and the National Cancer Institute provided funding for the pilot projects.
Projects range from developing computational models for detecting blood cancer earlier to uncovering epigenetic vulnerabilities of triple-negative breast cancer. Details of the projects follow.
Developing computational methods of genome-wide detection of fusion circular RNAs in chronic myeloid leukemia
Principal investigator: Chan Zhou, PhD, assistant professor of population & quantitative health sciences
Co-investigator: Minggang Fang, PhD, assistant professor of molecular, cell & cancer biology
Chronic myeloid leukemia (CML), a type of chronic blood cancer, can go unnoticed or undiagnosed for months or even years because patients initially have no symptoms. The front-line treatment for CML works best in early-phase patients, but drug resistance develops following prolonged treatment. Recent studies suggest that fusion circular RNAs (fusion-circRNAs) confer drug resistance in acute blood cancer and promote cancer-cell migration in lung cancer. Dr. Zhou is working to develop new computational methods and software to identify fusion-circRNAs. These fusion-circRNA genes come from at least two chromosomes and have a ring rather than a linear shape. Zhou wants to identify them and predict how they relate to cancer progression and drug resistance.
“There is no genome-wide systematic study of this type of molecules,” Zhou said. “If we can develop systematic methods and algorithms to detect them, and then study their role in cancer, we can quickly advance early cancer diagnosis and therapy.”
Using psychophysiological technology to develop a mood-tailored intervention for smoking cessation (Adapt2YourMood)
Principal investigators: Rajani S. Sadasivam, PhD, professor of population & quantitative health sciences; and Elise M. Stevens, PhD, assistant professor of population & quantitative health sciences
Drs. Sadasivam and Stevens are looking at how mood impacts the way in which someone responds to a message about smoking cessation. They are sending online surveys to 600 smokers and observing another 120 in the lab for psychophysiological responses to the messages. The researchers will first induce a mood by making study participants feel positive, negative or neutral. Then the researchers will show participants a cessation message and see how they respond. In the lab, the researchers will be able to monitor changes to heart rate, sweat activity and how long eyes look at the message. The findings could guide messaging for text- and app-based interventions.
“If you look at it closely, people who are smoking are socioeconomically disadvantaged. This is a population that’s really difficult to reach. For whatever reasons, they are not participating in other forms of intervention,” Sadasivam said. “Quit lines are available throughout the country, but 1 to 2 percent of ex-smokers have used them. As you have more and more of these intervention options, hopefully it gets easier to get people to stop smoking.”
Does intratumoral injection of AIM2 siRNA enhance the response of immune checkpoint inhibitor for melanoma?
Principal investigators: John Harris, MD, PhD, chair and professor of dermatology and founding director of the Autoimmune Therapeutics Institute; and Anastasia Khvorova, PhD, the Remondi Family Chair in Biomedical Research and professor of RNA therapeutics
Co-investigator: Tasneem Ali, MD, assistant professor of medicine
This project aims to take the findings of Keitaro (Keith) Fukuda, MD, PhD, a dermatologist and oncologist from Japan who studied melanoma as a postdoctoral researcher in Dr. Harris’s lab a step further. Harris is one of the nation’s foremost authorities on the treatment and study of vitiligo, an autoimmune disease that causes white spots on skin. Vitiligo is the opposite of melanoma; if you successfully treat melanoma, you will often get vitiligo, which has been dubbed the “white armor” for this effect.
Dr. Fukuda discovered a way to enhance the immune response responsible for vitiligo in melanoma patients. When AIM2 knockout mouse immune cells were converted to dendritic cells, exposed to melanoma antigens and injected into mice with melanoma in order to stimulate their immune systems, the melanoma would shrink. Harris is working with Dr. Khvorova on a siRNA therapeutic, which showed efficacy using the same process as above in the mouse model.
“The problem is that the whole process of taking out your blood, making dendritic cells and giving them siRNA is just not practical in the clinic,” Harris said. “So one of the questions we had is can we eliminate this process and just give siRNA against AIM2 to the whole individual? Will we be able to make that siRNA in a way that it homes to the tumor, finds the dendritic cells that are already there and does the same job?”
Using single-cell chromatin profiling to uncover epigenetic vulnerabilities of triple-negative breast cancer
Principal investigator: Thomas G. Fazzio, PhD, professor of molecular, cell & cancer biology
Many tumors are a mixture of different types of cells, some of which are more important for tumor growth and malignancy than others. Different cell types are created when genes are turned on within them. Dr. Fazzio’s lab recently developed a new technology that allows researchers to identify the features that turn genes on and off in individual cells. For this project, he is using the lab’s technology to identify different cell types in aggressive breast tumors and understand how these cells become metastatic.
“Most studies examine all cells in the tumor together, causing the different patterns in each cell to be mixed together,” Fazzio said. “Our approach will allow these patterns to be seen separately, giving us a much clearer picture of what is driving the aggressive population. Ultimately, the results from this study could be used to identify weaknesses that are particular to the cell types most important for tumor aggressiveness, with the goal of exploiting these weaknesses therapeutically.”
Nanoparticle delivery of innate immune agonists to remodel the tumor microenvironment and potentiate T cell-activating therapies in PDAC
Principal investigators: Marcus Ruscetti, PhD, assistant professor of molecular, cell & cancer biology; and Prabhani Atukorale, PhD, adjunct assistant professor of molecular, cell & cancer biology
Drs. Ruscetti and Atukorale are interested in finding new ways to activate the immune system to target pancreatic cancer. They will combine Atukorale’s nanoparticle technology to deliver compounds to activate the innate immune system directly to tumors with tumor-targeting therapy strategies Ruscetti has devised to activate adaptive T cell immunity.
“Pancreatic cancer is devastating. There are no real treatment options,” Ruscetti said. “We and many others have shown that activating the immune system can be a powerful approach to eradicate even the most aggressive of cancers. Our goal here is to combine to orthogonal strategies to activate both the innate and adaptive arms of the immune system to detect and abolish pancreatic cancer. If successful in mice we hope to translate these approaches and test them in early phase clinical trials at UMass Memorial Medical Center.”
The UMass Cancer Center comprises hundreds of professionals at UMass Chan Medical School who have a common goal of alleviating the suffering caused by cancer and identifying new approaches to treatment, control, prevention and cause. Its mission is to advance the cancer control continuum—from etiology through survivorship—in patients of all ages and with all types of cancer. Research programs are organized into three main areas: basic science, translational and clinical research, and cancer prevention and control.
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