Two grants from the U.S. Department of Defense totaling $2.8 million will support Jackson Laboratory (JAX) research in one of the most deadly forms of breast cancer, known as triple-negative breast cancer (TNBC).
About 3 million American women are living 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), by definition, eludes three of the most effective therapies that target cancer-driving molecules: estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein. TNBC 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 $1,393,246 to JAX President, CEO and Professor Edison Liu, M.D., 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 TNBC. JAX Professor Karolina Palucka, M.D., Ph.D., was awarded $1,386,446 to advance her investigations into harnessing the immune system to combat TNBC.
“TNBC tumors have complex and massive changes to their entire DNA makeup, also known as the cancer genome,” says 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. Because it is much more difficult to read so many changes at once, it is also harder to identify those that are important for TNBC growth and sensitivity to treatment.”
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 TDP TNBC tumors are the same. “We now have strong preliminary data identifying subtypes of genetically different TDP TNBCs,” Liu says, “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, MBBS, Ph.D., of Beth Israel Deaconess Medical Center, Liu and his lab will use advanced computational methods to develop a more precise approach for classifying TNBC tumors, a better understanding of the formation of TDP subtypes, and novel 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 says, “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, says, Palucka, understanding the underlying mechanisms that control metastasis is of critical importance 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 says.
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 says.
And, she notes, the utility of this model extends beyond TNBC to other metastatic cancers as well. “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.”