New research from Memorial Sloan Kettering Cancer Center (MSK) uncovers an unknown role for immune cells in fueling triple-negative breast cancer; identifies a new strategy for fighting leptomeningeal metastases; finds trastuzumab deruxtecan shows enhanced benefit for patients with ERBB2 mutations in breast cancer; shows tumor DNA insights can help guide treatment for patients with hard-to-treat biliary tract cancers; and uses artificial intelligence (AI) to study early development.
Uncovering immune cells’ role in fueling triple-negative breast cancer
Immune cells inside tumors can supply nutrients to triple-negative breast cancer (TNBC) — keeping the cancer alive even when standard therapies try to choke off its fuel supply, a new MSK study shows.
The research team — overseen by senior authors Justin Perry, PhD, and Kayvan Keshari, PhD, at MSK’s Sloan Kettering Institute — studied how tumor-associated macrophages interact with and support the growth of TNBC, one of the most aggressive types of breast cancer and one with limited treatment options. The study was led by Nancy Santiappillai, PhD, a postdoctoral researcher in the Keshari Lab.
Using advanced spatial metabolomics, the scientists identified why drugs designed to block TNBC’s primary fuel source — the amino acid glutamine — have had limited success in the clinic. Macrophages adapted to the cancer’s low-oxygen environment, they found, can shift their metabolism to release ornithine, a nutrient that TNBC cells can use to fuel themselves in the absence of glutamine.
The team found that macrophages engaged in clearing dead cells from the tumor also release ornithine, further accelerating cancer growth.
When the researchers disrupted macrophage metabolism in mice using a drug called 6-AN, tumor growth slowed significantly in one TNBC model, but not in another — showing not all tumors respond in the same way. Interestingly, when it did work, it caused the macrophages to shift from helping the tumor into an anti-tumor state and increased the number of cancer-killing CD8+ T cells. This suggests that targeting macrophage metabolism could help boost the immune response against TNBC, the researchers say.
The approach, however, only worked against certain TNBC cells — those that express higher levels of two key enzymes (OAT and PYCR1) in the proline synthesis pathway. These enzymes help cells overcome redox stress, a harmful buildup of unstable molecules that can damage or destroy cells and make the extracellular matrix necessary for tumors to grow. This means that therapeutic strategies targeting tumor metabolism will need to account for this diversity — and consider the tumor’s broader ecosystem, rather than targeting cancer cells in isolation, the researchers note.
Meanwhile, an analysis of two large patient databases showed that TNBC patients with high levels of the two enzymes also tend to have worse survival outcomes, connecting the laboratory findings to clinical observations.
Read more in Science Advances.
A new target for fighting leptomeningeal metastases
Leptomeningeal metastasis, is a devastating complication of cancer in which the disease spreads to the cerebrospinal fluid surrounding the brain and spinal cord. One treatment option is proton craniospinal irradiation (pCSI), a form of radiation therapy. Some cancers, however, don’t respond well to it.
A research team led by MSK neuro-oncologist Adrienne Boire, MD, PhD, analyzed cerebrospinal fluid from cancer patients, both with and without leptomeningeal metastases, before and during pCSI treatment. They discovered that cancer cells produce a protein called CXCL1 that is linked to more aggressive disease and poorer response to radiation therapy. CXCL1 works through a receptor called CXCR2.
Using both genetic tools and drugs in mouse models, the researchers showed that blocking CXCR2 suppressed the growth of leptomeningeal metastases. Combining radiation with CXCR2 inhibition worked even better — and was more effective than either treatment alone. This could allow for lower radiation doses, reducing harmful side effects. Co-first authors on the paper are Ahmed Osman, PhD, and Francis He, PhD.
MSK has already opened a clinical trial to test this new approach, combining radiation therapy with a CXCR2 inhibitor called SX-682. The trial is a collaborative effort among neuro-oncologist Jessica Wilcox, MD, medical oncologist Monica Chen, MD, thoracic medical oncologist Jark Jeng, MD, PhD, and radiation oncologist Yao Yu, MD.
Read more in Science Translational Medicine.
Targeted therapy trastuzumab deruxtecan shows enhanced benefit for patients with ERBB2 mutations in breast cancer
Trastuzumab deruxtecan (also known as T-DXd or Enhertu®) is one of the most significant advances for treating metastatic breast cancer in recent years. The drug, which uses an antibody to deliver chemotherapy directly to tumor cells, has been shown to significantly improve patient survival.
But its use is currently guided almost entirely by a single measurement — how much HER2 protein is visible on the surface of tumor cells. Initially approved only for patients with high levels of HER2, the drug was later expanded for certain patients with lower levels of HER2, based on research led by doctors at MSK.
A team that included MSK breast medical oncologists Joshua Drago, MD, MS, Nicholas Mai, MD, and Sarat Chandarlapaty, MD, PhD, found another indicator that suggests a patient likely will respond to T-DXd: mutations in the gene ERBB2. This gene provides instructions for making the HER2 protein.
The researchers studied 272 women with metastatic breast cancer that did not carry high levels of HER2 but who received T-DXd as part of their treatment. They found that patients with ERBB2 mutations (about 7% of the total) benefited from T-DXd for nearly twice as long as those who did not have the mutation — an average of 11 months, compared to 6.2 months. When they studied breast cancer cells in Dr. Chandarlapaty’s lab, they found that those with the ERBB2 mutation took up the drug much more quickly and were killed more efficiently, even when there was the same amount of HER2 on the cell surface.
“This study suggests that standard HER2 testing alone may not identify a group of patients who uniquely benefit from T-DXd,” Dr. Drago says. “It underscores the importance of performing genetic testing on the tumors of all patients with metastatic cancer.”
Read more in Clinical Cancer Research.
Tumor DNA insights help guide treatment for patients with hard-to-treat biliary tract cancers
Patients with advanced biliary tract cancers experienced longer progression-free survival after being matched with a treatment tailored to their specific cancer type, according to a recent MSK study.
Biliary tract cancers, including cancers of the bile duct and gallbladder, are often diagnosed at a later stage, which can make treatment more difficult. Chemotherapy and immunotherapy are given to those with advanced disease after diagnosis, but there are few effective options when initial therapy fails. Targeted therapies have emerged as a promising approach for some biliary tract cancers that contain the DNA alterations that make them susceptible to treatment, but it’s unclear how many people with advanced disease would benefit from this type of therapy.
A study led by gastrointestinal medical oncologist James J. Harding, MD, analyzed tumors from more than 1,200 patients with previously treated advanced biliary tract cancer using MSK-IMPACT®, a test that detects tumor DNA changes in hundreds of known cancer-associated genes. The researchers found that DNA changes were common across biliary tract cancer subtypes and identified therapeutic targets, including RAS alterations, MTAP deletion, and MDM2 and MET amplification. Among patients whose tumors may be susceptible to targeted therapies, those who received a drug designed to target the exact change in their tumor experienced longer progression-free survival compared to those treated with chemotherapy alone.
By comparing tumor samples collected before treatment and after disease progression, the team also identified several mechanisms of resistance to targeted therapy. These discoveries could pave the way for effective combination therapies for those with previously treated advanced biliary tract cancer.
Read more in Clinical Cancer Research.
Using AI to study early development
Organisms begin as a single cell — one that needs to divide, move, and organize itself into a body. Mapping that process at the level of individual cells, in real time, has long been one of biology’s great technical challenges. Now, a new study led by scientists at MSK’s Sloan Kettering Institute introduces an AI system called Twin Attention that can identify, track, and analyze individual cells in a developing embryo with remarkable accuracy.
The system works by studying pairs of 3D snapshots of a growing embryo. The program learns to recognize each cell based on its position and its relationship to its neighboring cells. This generates a unique numerical “fingerprint” for every cell that captures not just where it is, but how it fits into the larger tissue.
The researchers demonstrated the approach in C. elegans, a tiny roundworm whose development has been well studied. Twin Attention correctly identified individual cells with roughly 93% to 97% accuracy as the embryo grew from just a handful of cells to more than 500.
The new approach also succeeded at an even more demanding test: screening hundreds of embryos in which specific genes had been silenced to look for subtle developmental abnormalities. Analyzing these 700 embryos manually would have taken scientists hundreds of hours of work. But Twin Attention could do it in just a few hours — flagging developmental defects across the majority of genes tested and identifying 29 where changes delayed a critical step called gastrulation, in which certain cells migrate to the embryo’s interior.
The tool could help scientists run large-scale screens for developmental defects that would otherwise be impossible to conduct by hand — with potential applications in understanding how tissues form and malfunction in human disease, says co-corresponding author Anthony Santella, PhD, a senior research scientist who specializes in computer vision and image analysis.
Read more in Cell Reports Methods.