(BOSTON) — Esophageal adenocarcinoma (EAC), a major form of esophageal cancer, ranks as the sixth deadliest cancer globally, lacking effective targeted therapies. Patients often rely on chemotherapy, administered as “neoadjuvant chemotherapy” (NACT) before surgery, to shrink or control tumors. However, resistance to NACT is common, leading to poor outcomes.
Despite the lack of therapeutic alternatives, both responders and non-responders continue receiving chemotherapy without certainty of its efficacy. Even among responders, chemotherapy may not fully halt tumor progression or metastasis and can cause toxic side effects. A personalized precision oncology model to predict patient responses to NACT is a critical unmet need.
Researchers have previously developed “organoids” from biopsied EAC cells—3D mini-organs formed with tissue-specific stem cells. However, these lack key components of a patient’s tumor microenvironment (TME), such as stromal fibroblasts and collagen fibers, resulting in different responses to NACT compared to actual tumors.
Breakthrough in Personalized Medicine
Now, a research collaboration led by Donald Ingber, M.D., Ph.D., at Harvard University’s Wyss Institute, and Lorenzo Ferri, M.D., at McGill University Health Centre, has advanced a personalized medicine solution to enhance chemotherapy for EAC patients.
The researchers utilized the Wyss Institute’s human Organ Chip microfluidic culture technology, co-culturing EAC organoids with stromal cells from the same biopsies obtained by McGill’s team. This created patient-specific, TME-inclusive Cancer Chip models. By replicating some TME complexities in vitro, the team accurately predicted patient tumor responses to standard NACT more effectively than static 3D organoid models.
The approach delivers results within 12 days, allowing rapid stratification of EAC patients into responders and non-responders. It also facilitates investigation of non-standard NACTs for resistant patients within a clinically useful timeframe. The findings are published in the Journal of Translational Medicine.
“This patient-centered approach strongly builds on our previous successes using human Organ Chip technology to recapitulate each individual cancer patient’s TME outside their body so that we can identify the drug combination that will work best for that very patient,” said Ingber.
Modeling Esophageal Pathologies
Ingber’s and Ferri’s teams began collaborating in 2023 on an earlier study modeling Barrett’s esophagus in a microfluidic Organ Chip, supported by the National Institutes of Health (NIH) and Cancer Research UK. Barrett’s esophagus, a potential precursor to EAC, results from pathological changes in the esophageal epithelial lining, often starting with inflammation induced by acid reflux.
These malignant changes are driven by molecular and cellular processes in the epithelial lining and underlying “stroma,” composed of fibroblast cells, immune cells, and blood vessels. The stroma communicates with cancer cells through a constant molecular exchange.
“Whereas in our earlier work, we faithfully recapitulated the earlier stages of the pathological process potentially leading to EAC, namely Barrett’s esophagus, in our new study we fast-forwarded to its cancerous end result,” said Elee Shimshoni, Ph.D., a Postdoctoral Fellow in Ingber’s team.
From Patients to Cancer Chips and Back
The team engineered their TME-mimicking EAC Chip by generating personalized EAC organoids from biopsies of newly diagnosed, untreated EAC patients. Sanjima Pal, Ph.D., and other McGill team members, mastered creating patient-matched esophageal organoids with high consistency.
They removed the organoids from culture dishes, broke them into constituent cells, and cultured them in one of two parallel-running channels of a microfluidic chip. Tumor-associated fibroblasts from the same patients were added to the other channel, forming an adjacent tumor stroma. A porous membrane allowed free molecular exchange between cancer and stromal tissues, simulating actual tumor conditions.
The researchers introduced a docetaxel-based triplet chemotherapy cocktail into the stromal channel’s nutrient fluids, using drug concentrations and exposure times replicating EAC patient chemotherapy cycles.
For eight patients, EAC Chips accurately predicted NACT responses within 12 days. In four chips, chemotherapy killed EAC cells; in the other four, cells survived. These results perfectly matched patient responses and survival rates post-surgery.
Other study authors include Salvador Flores Torres, Mingyang Kong, Kulsum Tai, Veena Sangwan, Nicholas Bertos, Swneke Donovan Bailey, and Julie Bérubé. The study was funded by a Cancer Research UK Grand Challenge STrOmal ReprograMing (STORMing Cancer) grant, the Montreal General Hospital Foundation, and a Department of Defense Impact Grant award.
This development represents a significant step towards personalized cancer treatment, potentially applicable to various cancer types. The Organ Chip platform not only offers a predictive model for chemotherapy response but also serves as a pre-clinical testbed for developing new therapies and discovering biomarkers to optimize drug effects.
