Ed Liu, president and CEO of The Jackson Laboratory. Liu and another researcher at the lab, Karolina Palucka, have received grants from the Department of Defense to support their research into breast cancer diagnostics and treatment. ISLANDER FILE PHOTO

Triple-negative breast cancer target of DoD grants

BAR HARBOR — Grants of nearly $2.8 million have been awarded by the U.S. Department of Defense to researchers at The Jackson Laboratory for research into triple-negative breast cancer.

About 3 million American women live with breast cancer. Advances in understanding the biological and genetic profiles of individual cancers have contributed to better screening and more targeted treatments, leading to a steady rise in the overall five-year survival rate following a breast cancer diagnosis to about 89 percent.

However, triple-negative breast cancer (TNBC) eludes three of the most effective therapies that target cancer-driving molecules. It accounts for up to 20 percent of all breast cancers and is associated with poor outcomes for patients because of this resistance and its capacity for aggressive growth and high recurrence.

A grant of nearly $1.4 million to lab President, CEO and Professor Edison Liu will fund further exploration of his discovery of a characteristic of TNBC tumors, with the goal of developing better diagnostics and more targeted treatments for patients with this cancer. Laboratory Professor Karolina Palucka also was awarded nearly $1.4 million. She will use the money to advance her investigations into harnessing the immune system to combat triple-negative breast cancer.

“TNBC tumors have complex and massive changes to their entire DNA makeup,” said Liu. “By analogy, where a single change might be seen as a misplaced letter in a gene, many cancer genes in TNBC are misspelled, repeated wholesale or deleted in many different places.”

Last year, Liu discovered that TNBC tumors and certain other deadly cancers of women (including serous ovarian cancer and endometrial carcinomas) share a genomic configuration described as a tandem duplicator phenotype (TDP). Moreover, they showed that tumors with this configuration respond to a specific chemotherapy, cisplatin.

Since that discovery, the Liu lab has found that not all of these tumors are the same. “We now have strong preliminary data identifying subtypes of genetically different TDP TNBCs,” Liu said, “and for each subtype, we have found genes that likely drive these genetic differences and for which specific therapies are already FDA-approved or in development.”

With the new grant, and in collaboration with Ralph Scully of Beth Israel Deaconess Medical Center, Liu and his lab will develop a more precise approach for classifying triple-negative breast cancer tumors, a better understanding of the formation of tandem duplicator phenotype subtypes and new treatment regimens tailored to specific TDPs that will be ready for testing in a clinical setting.

“Our research shows that while TDP TNBC is highly complex,” Liu said, “we have the tools to unpack this complexity in a way that creates unprecedented opportunities for better classifying, treating and curing TNBC cancers.”

Almost 90 percent of deaths due to breast cancer are attributed to metastatic disease (cancer cells spreading to distant organs), and treatments used to shrink or slow metastatic tumors provide only temporary relief: There is no cure for metastatic breast cancer. While some TNBC patients respond initially to conventional therapies, nearly half will experience recurrence and metastasis within two to three years.

Thus, said Palucka, understanding the underlying mechanisms that control metastasis is critical for the discovery and development of new, targeted treatments and for the increased survival of TNBC cancer patients.

“One promising entry point for understanding progression to metastasis—and determining how to prevent it—is to focus on the interplay between the immune system and cancer cells,” she said.

Palucka has developed a special mouse model that replicates the human immune system to better understand its effect on the tumor microenvironment, cancer cell longevity and metastatic spread to other organs.

In preliminary results, she has discovered that the presence of human cytokines (proteins that stimulate immune cells) induces cancer cells to spread to distant organs; in fact, metastasis did not occur in the mice lacking human cytokines. “This distinction will allow us to precisely define immune cells or signals that drive cancer cells to spread—signals that could represent promising therapeutic targets for intervention,” Palucka said.

The utility of this model extends beyond TNBC to other metastatic cancers as well, she said. “The potential benefit of this work could be the identification of new treatment targets for limiting metastasis in at-risk patients, possibly improving the ability to cure patients with this devastating disease.”

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