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JAX vs. TNBC
BAR HARBOR, Maine—About three million American women are living with breast cancer. While advances in understanding the biological and genetic profiles of individual cancers have contributed to better screening and more targeted treatments, triple-negative breast cancer (TNBC) eludes three effective therapies that target cancer-driving molecules.
TNBC accounts for up to 20 percent of all breast cancers. Patients tend to have poor outcomes because of TNBC’s resistance and capacity for aggressive growth and high recurrence. Two grants from the U.S. Department of Defense (DOD), totaling $2.8 million, will support research by The Jackson Laboratory (JAX) in TNBC.
A $1,393,246 grant to JAX President and CEO Dr. Edison Liu—who also is a professor at JAX—will fund further exploration of his discovery of a characteristic of TNBC tumors to help develop better diagnostics and more targeted treatments. JAX professor Dr. Karolina Palucka received $1,386,446 to advance her investigations into harnessing the immune system to combat TNBC.
“TNBCs are breast tumors that do not express the hormone receptors for estrogen (ER) or progesterone (PR) or the HER2 protein (a member of the epidermal growth factor receptor family) on their cell surfaces,” explained Liu.
Because TNBCs lack ER and PR receptors, they do not respond to hormonal therapies, such as tamoxifen or aromatase inhibitors. Similarly, they do not respond to therapies that target the HER2 protein, such as Herceptin. This limits treatment options. While potential therapies under investigation may improve outcomes in TNBC patients, there is no proven single agent with demonstrated efficacy against different types of TNBCs.
According to Liu, “TNBC tumors have complex and massive changes to their entire DNA makeup, also known as the cancer genome. 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.”
In 2016, Liu discovered that TNBC tumors and certain other deadly cancers of women share a genomic configuration described as a tandem duplicator phenotype (TDP). His research team found 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 alike. As he explained, “We now have strong preliminary data identifying subtypes of genetically different TDP TNBCs, 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.”
The new grant will help Liu and his lab to collaborate with Dr. Ralph Scully of Beth Israel Deaconess Medical Center in using 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. As Liu said, “While TDP TNBC is highly complex, we have the tools to unpack this complexity in a way that creates unprecedented opportunities for better classifying, treating and curing TNBC cancers.”
Because nearly 90 percent of deaths from breast cancer are from metastatic disease, and current treatments provide only temporary relief, understanding the underlying mechanisms that control metastasis is very important for the discovery and development of new, targeted treatments and for the increased survival of TNBC cancer patients. According to Palucka, “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.”
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. She has found that the presence of human cytokines induces cancer cells to spread to distant organs. Metastasis did not occur in the mice lacking human cytokines.
As Palucka explained, “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. The utility of this model extends beyond TNBC to other metastatic cancers. 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.”
Studying TNBCs using cultured tumor cell lines has limitations, because the cells that grow in the animal host do not adequately recapitulate the complexities of the tumorigenic process or the heterogeneity of the cells present in human tumors. Patient-derived xenograft (PDX) models better resemble the tumor structure and gene-expression patterns, copy number variations and the patient tumor’s response to anticancer treatments. By engrafting the tumorigenic cells in the context of their microenvironment, the xenografts closely resemble the patient’s tumor, and the engrafted mice can be considered surrogate patients or avatars.
Several groups of oncologists are using PDX models in small-scale preclinical studies to decide which drug or combination of drugs has the best chance of resulting in tumor remission in the patient. Because growth of specific human tumors in mice can take several months, these studies typically take place while the patient is being treated with standard drugs.
“More and more, PDX models are contributing to the personalized selection of existing anticancer treatments,” Palucka concluded. “The driving factor is the improved predictability of efficacy that candidate drugs show when administered to patients in the clinic following demonstrated efficacy in vivo in preclinically engrafted mice. This approach offers clear advantages to both patients and clinicians, because different candidate drugs can be tested for efficacy in mice engrafted with the patient’s tumor without subjecting patients to ineffective treatments.”