Researchers at the University of Arizona Cancer Center are breaking new ground in the fight against resilient cancers. Jennifer Carew, PhD, is leading research aimed at exploring a treatment pathway to disrupt breast cancer’s survival in the brain, while another research team spearheaded by Noel Warfel, PhD, developed a strategy to prevent prostate cancer cells from resisting chemotherapy. Together, their work reveals promising avenues to block cancer’s defenses, paving the way for therapies that could give patients with aggressive cancers a better chance at survival.
A potential pathway to reduce breast cancer brain metastases
By studying the metabolic differences between primary breast cancer cells and those that metastasize to the brain, researchers from the U of A Cancer Center determined that autophagy was significantly upregulated in brain metastases. Autophagy is a cellular recycling process that cancer cells can use to stay alive when faced with stressful conditions such as those triggered by anticancer drugs.
“The prognosis for individuals with brain metastases from breast cancer is extremely unfavorable, and the management of breast cancer metastases in the brain remains a formidable challenge,” said Carew, the paper’s senior author. “We were able to disrupt breast cancer cells’ ability to form brain metastases by impairing the autophagy pathway.”
In the paper published in Clinical and Translational Medicine, the researchers first showed that targeting the key autophagy regulating gene ATG7 significantly reduced the ability of breast cancer cells to form brain metastases in mouse models.
With the goal of developing a strategy to bring this discovery to patients, the research team investigated whether hydroxychloroquine, a Food and Drug Administration-approved drug, could potentially be used to treat breast cancer brain metastases. Hydroxychloroquine inhibits autophagy at a later point in the pathway and, importantly, readily crosses the blood-brain barrier.
“Most drugs do not efficiently cross the blood-brain barrier, and that is one of the key reasons why brain metastases are so difficult to treat,” said Carew, who is a professor of medicine at the U of A College of Medicine – Tucson and a member of the Cancer Center’s Clinical and Translational Oncology Program.
The research team combined hydroxychloroquine with lapatinib, which is FDA-approved to treat breast cancer. They showed that this drug combination successfully reduced the number and size of breast cancer brain metastases in mouse models.
“Our group and others have shown that activation of autophagy makes it harder for many different types of cancer therapies to kill cancer cells and this promotes drug resistance,” said first author Steffan Nawrocki, PhD, co-director of the Cancer Center Clinical and Translational Oncology Program and professor in the College of Medicine – Tucson. “Because hydroxychloroquine and lapatinib are already FDA approved, we can advance this drug combination quickly into a clinical trial for patients with breast cancer brain metastases.”
Brain metastases are the most prevalent adult central nervous system tumors, with 20% to 30% of cases resulting from breast cancer patients, particularly those with triple negative and HER2 amplified disease. Managing breast cancer metastases in the brain is challenging, with only 20% of patients with breast cancer brain metastases surviving beyond five years.
Preventing prostate cancer chemoresistance
The findings of a study co-led by Warfel suggest that novel therapeutic molecules known as proteolysis targeting chimeras, or PROTACs, could help overcome resistance to a class of anti-cancer drugs that are used to treat a wide range of cancers. The results were published online in Cell Chemical Biology.
A kinase is a type of protein that cells use to perform specific functions. One specific kinase, the PIM kinase, has been connected to the survival and spread of cancer cells. To improve cancer treatment outcomes, scientists developed PIM kinase inhibitor drugs; however, some patients develop resistance to these drugs, causing their disease to progress despite treatment.
In response, researchers from the National Cancer Institute and the U of A Health Sciences created and patented PIM-PROTACs. Instead of blocking PIM activity, the PROTACs eliminate the PIM1 protein entirely.
“We developed a drug that finds PIM in the cell, binds it and degrades the whole protein away,” said Warfel, an associate professor of cellular and molecular medicine in the College of Medicine – Tucson. “We tested our PIM-PROTAC in prostate cancer models, and it works significantly better than currently available PIM inhibitors that have gone to trial.”
Warfel worked with National Institutes of Health scientists Pedro Torres-Ayuso, PhD, John Brognard, MD, and Dawid Mehlich, MD, from the National Cancer Institute’s Laboratory of Cell and Developmental Signaling and Rolf Swenson, PhD, and Venkata Sabbasani, PhD, from the National Heart, Lung, and Blood Institute’s Chemistry and Synthesis Center. Collectively, they hold the patent for the PIM PROTAC technology.
The research team found that using PIM PROTACs to break down PIM kinases was more effective at limiting tumor growth than using PIM kinase inhibitors. This was especially true when the researchers applied a chemotherapy drug in combination with PIM PROTACs. When the chemotherapy drug docetaxel was applied to the cell culture, about 12% of the cancer cells died. When docetaxel was combined with a PIM PROTAC, cell death increased to 40%.
The PIM-PROTAC has promise for addressing oncological diseases other than prostate cancer, as PIM kinases also have been found to be switched on in breast, colon, endometrial, gastric and pancreatic cancers.
