image: Debanjan Bhattacharya, PhD.
Credit: Photo/Joseph Fuqua II/UC Marketing + Brand
University of Cincinnati Cancer Center researchers will present abstracts at the American Association for Cancer Research annual meeting 2024, April 5-10 in San Diego, California.
Drug increases radiation effectiveness in preclinical study
Advanced stage non-small cell lung cancer often spreads to the brain, and the National Institutes of Health reports patients with these brain metastases have a median survival rate of about 12 months.
Radiation therapy is an important component of the current standard of care to treat the brain metastases, but challenges to this treatment include significant side effects and overcoming radiation resistance.
A research team led by Debanjan Bhattacharya, PhD, and Soma Sengupta, MD, PhD, tested whether administering a brain-permeable drug called AM-101 with radiation treatment improves the effectiveness of radiation.
The drug is designed to activate GABA(A) receptors in the brain, which have been found to weaken non-small cell lung cancer cells. For the first time, the researchers found the drug sensitizes the brain metastatic tumors to radiation and significantly improves survival in a preclinical animal model.
“In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce the toxicity of radiation treatment,” said Bhattacharya, research instructor in the Department of Neurology and Rehabilitation Medicine in UC’s College of Medicine.
Bhattacharya said the study also found the specific mechanism that weakens the cancer cells, as the drug activating the GABA(A) receptors triggers a domino effect of dysregulation in mitochondria, the cell’s power source, which induces autophagy, the cell’s recycling process. Activation of a selective autophagy function increased the effectiveness of radiation treatment and improved tumor control in the animal model.
Moving forward, Bhattacharya said these results pave the way to begin clinical trials in the near future testing AM-101 combined with whole brain radiation treatment for lung brain metastatic patients.
“The therapeutic effect of this combination has promise that can lead to improved survival compared to stand-alone whole brain radiation therapy, which in a majority of cases is palliative and has responses which are not durable,” he said.
Targeting multiple mutations controls tumor growth in cell lines, patient samples
Approximately 53,000 Americans died of colorectal cancer (CRC) in 2023, and many colorectal tumors have one or more gene mutations that contribute to their growth.
First author Mary Kate Kilroy said a team of researchers in the lab of Joan Garrett, PhD, is studying the co-occurrence of two mutations, called KRAS and HER3, in CRCs. About 41% of all colorectal tumors contain a KRAS mutation, about 6% of all tumors contain a HER3 mutation and both mutations can help the tumors grow unchecked at an accelerated rate.
After an analysis of publicly available data, the research team found there was a significant co-occurrence of HER3 and KRAS mutations in colorectal cancer.
“We were looking to see if co-targeting HER3 along with mutant KRAS would inhibit tumor growth in colorectal cancer,” said Kilroy, a doctoral candidate in Garrett’s lab in UC’s James L. Winkle College of Pharmacy.
The researchers found that a drug that targets the KRAS G12D mutation (which accounts for 29% of KRAS mutations in CRCs) led to an increase in HER3 activation in cell lines and patient-derived samples. However, when the KRAS-targeting drug was combined with several different drugs that inhibit the HER family of proteins, there was a decrease in tumor cell growth.
“In the future, we are hoping to test an antibody drug conjugate targeting HER3 itself in combination with KRAS inhibitors and observe if there is an effect on tumor proliferation,” Kilroy said. “Our lab is very excited about this project and I am looking forward to moving it forward.”
Researchers identify protein as potential target for subset of breast cancer
Another team of researchers in Garrett’s lab studied the role of a protein called NMIIA in driving cancer growth in a subset of breast cancers with a specific genetic mutation called PIK3CA.
Abstract first author Wasim Feroz said lab member Samar Alanazi, PhD, found that NMIIA interacts with the HER3 protein that promotes cancer growth, and this interaction is increased when the tumors are treated with drugs that target the HER family of proteins. Additionally, higher levels of NMIIA were associated with worse survival outcomes for patients with the PIK3CA mutation compared to those with low levels of NMIIA.
“Loss of NMIIA reduced HER3 protein levels and downstream signaling, suggesting that NMIIA may be a crucial factor in promoting cancer growth in these types of breast cancers,” said Feroz, a graduate assistant in Garrett’s lab.
Moving forward, Feroz said the team plans to further study the interaction between NMIIA and HER3, as well as whether inhibiting NMIAA can increase the effectiveness of other therapies that target HER3 and PIK3.
“This research holds promise for identifying new therapeutic targets and improving treatment outcomes for breast cancer patients, particularly those with HER2-positive tumors or mutations in the PIK3CA gene,” Feroz said. “By understanding the underlying mechanisms driving cancer growth and resistance to current therapies, the findings from this study could ultimately lead to the development of more effective treatments and better management of breast cancer in the clinic.”
Researchers examine different ways fibroblasts aid melanoma drug resistance
Researchers in the lab of Yuhang Zhang, PhD, study the role of cancer-associated fibroblasts (CAF), a type of cell often found in the area around melanoma cells within the tumor microenvironment. While normal fibroblasts provide structural support, CAFs change their behavior in response to signals from the cancer cells around them.
“CAFs are known to play diverse roles in cancer progression, including promoting tumor growth, invasion, metastasis, the formation of new blood vessels and therapeutic resistance,” said Bruna da Silva Soley, PhD, abstract first author and a postdoctoral fellow in Zhang’s lab in the College of Pharmacy.
Previous research found that one of the most common drugs used to treat melanoma, called BRAF inhibitors, boost the CAF’s activity.
“It is as if CAFs are giving the cancer cells a way to resist the treatment designed to fight them,” Soley said.
The researchers found BRAF inhibitors specifically cause an accumulation of a certain protein within CAFs that helps activate the processes that aid cancer cells in escaping treatment. In contrast, two other common melanoma treatments did not lead to the same protein accumulating within CAFs.
Additionally, the team learned that targeting this protein within fibroblasts can suppress melanoma progression in animal models. Moving forward, the team will aim to learn more about this mechanism in order to develop new therapies to be combined with other targeted therapies and immunotherapy drugs.
“Unraveling the biology of CAFs in melanoma holds promise for developing innovative therapeutic strategies that target both the tumor cells and their microenvironment,” Soley said. “That could mean more effective treatments and better outcomes for patients.”
Another research team in Zhang’s lab took a different angle to examine how CAFs influence melanoma drug sensitivity.
“Melanoma stands out as one of the most aggressive forms of skin cancer in the United States, with many patients developing drug resistance relatively quickly,” said Yao Xiao, abstract first author and a research assistant in Zhang’s lab. “This phenomenon occurs because melanoma cells possess the ability to adapt and evade targeted therapies, making it crucial to identify alternative avenues for treatment.”
The team focused on the role of a protein called YAP1 that has been previously found to play a critical role in regulating melanoma progression and protecting the cancer cells from treatment through its function in CAFs. In the most recent study, they additionally identified another protein, PRMT1, that binds with YAP1 to reinforce drug resistance.
When CAFs were treated with BRAF inhibitors, they underwent significant changes that helped bolster drug resistance. But when YAP1 and PRMT1 were blocked, this process was suppressed, leading to less drug resistance.
Xiao said PRMT1 is a potential additional target within CAFs to improve melanoma treatment.