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Eight labs who were recipients of the University Cancer Center’s funding in December for projects advancing cancer research will use the funds to delve into cancer biology, cancer therapeutics and population science.
Four of the eight projects are investigating immunotherapy for gastrointestinal cancers, the tumor environment’s impact on cancer cell growth, the potential application of an FDA-approved Parkinson’s drug to treat glioma brain tumors and the ability of a novel drug to target cancer cells that exhibit heightened aggressiveness following immunotherapy, The Herald previously reported.
The Herald spoke with three of the four other principal investigators that received grants.
The Khan lab: Blocking cellular resistance to immune checkpoints
Assistant Professor of Medicine Hina Khan’s pilot project will study the effects of blocking the antibody for chitinase 3-like-1, or CHI3L1, in advanced non-small cell lung cancer. CHI3L1 is a protein that plays an important role in tissue repair, and elevated levels of the protein indicate poor outcomes in advanced stage cancer patients. The researchers will test whether blocking the antibody — a molecule that binds CHI3L1 — will prevent cell resistance to immune checkpoint inhibitors in this type of lung cancer.
The Liang lab: Studying blood cancer differences between the sexes
Assistant Professor of Medicine Olin Liang is interested in exploring women’s ability to fight off leukemia and other blood diseases later in life relative to men. While the effect of aging on blood cancer development has been well-studied, not much research has gone into studying sex differences, Liang said.
Past work from the Liang lab has shown that the bone marrow environment remains healthier longer in women, leading to better blood cell production and immune response. By transplanting bone marrow stem cells from young male mice into middle-aged male and female mice, the researchers were able to compare the expression of these cells amongst the two sexes. They found higher expression in female middle-aged mice, which is indicative of a healthier bone marrow environment. This observation was due to receptors — molecules that can interact with hormones to produce a response in a cell — on the surface of bone marrow stem cells that were uniquely responsive to sex hormones predominantly found in women.
“We have narrowed it down to two sex hormone receptors that may play a role,” Liang said, referring to the receptors for follicle-timulating hormone and androgen hormone. The lab plans to use the Cancer Center pilot project funds to further study the importance of these receptors.
Using gene editing technology, the researchers plan on removing genes that code for these hormone receptors from model organisms. This step will allow them to test the effect that the loss of one or both of the receptors has on female stem cell expression levels. If the elimination of the sex hormone receptor diminishes stem cell expression, that may indicate that the receptor plays a regulatory role.
The Liang lab believes that results from these experiments will not only offer greater insight to the development of blood cancers, but also help in the formulation of sex-specific treatments. Liang hopes this research leads to treatments that “enhance the male (blood cell producing) system to reduce risk of age-related blood cancer, or even other diseases.”
The Yajima lab: Collaborating to investigate developmental molecules’ role in cancer
Assistant Professor of Molecular Biology, Cell Biology and Biochemistry Mamiko Yajima studies the expression of germline molecules, which are normally only expressed during development, and how they contribute to plasticity, or the cell’s adaptability. Her pilot project will focus on the specific germline factor DEAD-Box Helicase 4 (DDX4), which has been found to be abnormally expressed in the tumors of certain cancers, such as small cell lung cancer and melanoma.
Yajima’s lab has previously studied the expression of DDX4 in cells and organisms like sea urchins and mice. She plans to “test if (DDX4) actually contributes to plasticity in the context of cancer.” Yajima believes that as a germline factor, DDX4 may increase cancer cells’ adaptability, allowing them to develop drug resistance and migrate throughout the body more frequently.
The Yajima lab plans on using the Cancer Center funding to partner with Director of Thoracic Oncology at Rhode Island Hospital Christopher G. Azzoli and Associate Professor of Pathology and Laboratory Medicine Maria L. Garcia-Moliner to analyze DDX4 expression in cancer patient samples.
“I applied for this funding with the specific goal to have access to clinical samples,” Yajima said. This next stage of the project will “facilitate collaboration between me, a basic biologist, and physician scientists that have the expertise to help me answer the question I want to study in a clinical setting.”
To identify whether DDX4 expression correlates with patient survival, the lab will also use the funds to conduct clinical data mining of patient gene expression using the University’s supercomputer.
The Cho lab: Connecting citrus to cancer
Associate Professor of Dermatology and Epidemiology Eunyoung Cho studies the role of dietary factors in the development of chronic diseases. Previous work from Cho’s lab found that eating foods containing high levels of citrus, such as grapefruits, oranges and figs, is associated with an increased risk of skin cancer. The Cho lab plans to use the Cancer Center pilot project funds to determine the component of citrus fruit responsible for the increased risk of melanoma, the most fatal type of skin cancer.
Cho believes that furanocoumarins, a class of compounds present in high levels in citrus fruits, are what lead to the higher rates of skin cancer. These compounds can absorb ultraviolet radiation from sunlight and become activated, damaging DNA and causing mutations that can result in cancer.
To test this hypothesis, Cho has partnered with Associate Professor of Medical Science Elena Oancea, who specializes in melanoma research at the molecular level. They plan on measuring whether melanin-forming skin cells show increased levels of DNA damage when exposed to furanocoumarins and UV light.
If their data supports that furanocoumarins increase risk of cancer, this could open the door to population-based studies. Cho described one potential future direction as assessing whether furanocoumarin levels in human urine samples are indicative of melanoma risk.
“It’s very interesting to think about — citrus fruit is something you eat all the time,” Cho said. “People don’t understand that when you eat grapefruit (and) then go into the sunlight, you may actually increase your chance of (getting) skin cancer.”
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