Breast cancer awards advance efforts to address metastasis and harness immune system
Tuesday, November 8, 2016
A surprise discovery about a previously unknown function of a protein could save the lives of thousands of cancer patients.
Yi-Chieh Nancy Du, Ph.D., an assistant professor of Pathology and Laboratory Medicine at Weill Cornell Medicine, will be able to test her hypothesis about the role of protein Bcl-xL in deadly cancer metastasis thanks to a Breakthrough Award from the Department of Defense’s Breast Cancer Research Program, recommended for $1 million funding.
Bcl-xL exists in the mitochondria of healthy cells, and scientists believed its primary function is to prevent cell death (apoptosis). Cancer cells have an even higher amount of Bcl-xL than healthy cells, so researchers thought the protein promoted cancer metastasis by helping cancer cells to survive. Several drugs have been developed to inhibit this anti-apoptotic function of Bcl-xL, but they have not proven very effective in halting cancer progression.
It turns out, the drug makers may not have been targeting the metastatic function of Bcl-xL.
In a study published Jan. 20 in Nature Communications, Du’s team demonstrated how Bcl-xL also amasses in the nucleus of cancer cells, and they believe this is where it works to promote the spread of cancer, independent of its anti-apoptotic function.
They will now collaborate with colleagues at Baylor College of Medicine in Houston, including principal investigator partner Yi Li, Ph.D., to further explore this mechanism of metastasis and to find ways of suppressing it to prevent and treat metastasis, the main killer of cancer patients.
“There is an urgent need to better understand drivers of breast cancer metastasis and to identify novel therapeutic targets,” Du said. “At the time of primary breast cancer diagnosis, tumor cells in 50 percent of patients have already spread to distant organs and will become metastatic disease if left untreated. Once metastatic disease is diagnosed, patients can no longer be cured with currently available therapies.”
As part of the project, the team has designed an experimental approach to screen FDA-approved drugs and other chemical compounds – more than 276,000 in total – for potential therapies to block the metastatic functions of Bcl-xL. They will then test the drugs on classic and newly-designed in vitro, in vivo and patient-derived xenograft models of several types of breast cancer, including HER2 and triple negative lines.
Du, who also studies metastasis in pancreatic cancer, is optimistic that the findings will be applicable to many types of cancers.
"Metastatic disease occurs in many cancers and it accounts for 90 percent of deaths in patients with solid tumors," Du said. "Understanding the molecular mechanisms underlying metastasis will help us save these patients."
Enhancing the target
Another award from the Department of Defense’s Breast Cancer Research Program may help breast cancer patients respond to the immunotherapy that has eluded them thus far.
While “checkpoint inhibitor” drugs have returned remarkable results in combatting many hard-to-treat cancers, advanced breast cancer patients have yet to benefit because of the biology of their disease.
Erik Wennerberg, Ph.D., hopes to overcome some of these challenges using a combination of radiation and drug therapy.
Immune checkpoint inhibitors work by removing the blinders produced by tumors that prevent cancer-killing T-cells from finding their targets. They are most effective in tumors that are heavily infiltrated by anti-tumor T-cells.
Patients suffering from advanced breast cancer often have little or no immune cell infiltration, rendering immune checkpoint inhibitors largely ineffective.
What they do have is high levels of immunosuppressive factors, including adenosine. The accumulation of adenosine in cancer cells interferes with the activation of dendritic cells, an immune cell subset that are essential for initiating an anti-tumor immune response.
Wennerberg, a postdoctoral researcher who works closely with Sandra Demaria, M.D in the Weill Cornell Medicine Department of Radiation Oncology, would like to use radiotherapy to help trigger the immune system to attack tumor cells and increase the efficacy of checkpoint inhibitors in cancers that have previously failed to respond to the drugs.
But first, he will have to limit the effect of adenosine.
He has identified two potential targets: CD73, the rate-limiting enzyme responsible for adenosine generation, and the A2AR receptors through which dendritic cells take up adenosine.
With the help of a Breakthrough Fellowship from the DoD, he will now investigate how to transform this information into therapy.
“We hope to discern how adenosine signaling regulates the immune response in irradiated tumors, and to lay a foundation for the implementation of adenosine blockade in combination with radiation therapy as a means to induce tumor-specific immune responses in breast cancer patients, making them responsive to immune checkpoint inhibitors,” Wennerberg said.