Ovarian Cancer Chip Model Reveals Drug Repurposing Opportunities
August 11, 2021 | A novel organ-on-a-chip model of ovarian cancer has been used to showcase the sinister activities of tumors, including use of circulating platelets to fuel their growth and undermine treatment with chemotherapeutic drugs. The model also demonstrated the potential of an anti-platelet drug, currently in clinical trials for a different condition, to fight back, according to Abhishek Jain, Ph.D., assistant professor of biomedical engineering in the College of Engineering and department of medical physiology in the College of Medicine at Texas A&M University as well as director of the Bioinspired Translational Microsystems lab.
His hunch is that the ovarian tumor microenvironment-chip (OTME-Chip) could play a “crucial role” in navigating through clinical trials, making them faster and more efficient and predictive. Inclusion of basic physiology in the chip—specifically, interactions between platelets and tumor under the influence of flow and the vascular endothelium—is a first in the field, Jain says.
As was recently described in Science Advances (DOI: 10.1126/sciadv.abg5283), the microdevice can be used to visualize and analyze the dynamics of platelet extravasation—or leakage—from a blood vessel into tumors. “Tumors are using these platelets against us,” says Jain, pulling them out of circulation and into the tumor ecosystem where they stick to cancer cells through the binding of the platelet surface receptor GPVI to the tumor-expressed galectin-3.
Several other microfluidic platforms aim to mimic the tumor microenvironment, but only a handful of them have considered how blood cells and blood vessels contribute to tumor proliferation and metastasis, he continues. Studies in mice as well as clinical observations suggest that blood platelets, whose main function is to stick to the lining of blood vessels to help stop or prevent bleeding, are also involved in “energizing” tumors and aiding in metastasis.
The U.S. Food and Drug Administration has been “looking very closely at microphysiological systems… and the enthusiasm is only increasing,” says Jain, noting that the agency is already a partner in the Tissue Chip for Drug Screening program of the National Institutes of Health and helps to fund development of organ-on-chip models. The focus currently is on how tissue-engineered methods could potentially reduce, and in some cases circumvent, the need to rely on large animals to mimic human biology in the preclinical setting.
Microphysiological models offer a “bottoms-up [simple to incrementally complex] approach” to biological system design, making them particularly well suited for mimicking longitudinal cancer events and preclinical drug discovery, say Jain. The OTME-Chip, like many microchips, is also transparent, allowing it to provide a “window on the [tumor] microenvironment… at the single-cell and gene levels” via high-resolution microscopy. With animal models, sophisticated imaging tools are needed to view the ovary—if it is possible at all.
The OTME-Chip is also a good companion to other advanced biomedical technologies. For example, the CRISPR-Cas9 gene editing technique was used to produce a galectin-3 knockout cancer cell line in a couple of weeks versus the months or years it takes to create a knockout mouse model, Jain shares.
Next-generation gene sequencing and differential gene expression analysis were also harnessed to validate study findings, he continues. This gave researchers a “complete [genotypic] picture of what happens when the tumor interfaces with the platelets, when chemotherapy is introduced, and when chemotherapy and anti-platelet drugs are introduced together.”
The ovarian cancer microenvironment was purposefully chosen because it is challenging to model, says Jain. Like every microphysiological system recapitulating the tumor microenvironment, no more than two or three variables can be emphasized because “including all the complexity would actually defeat the purpose of the modeling itself.” The focus of prior systems includes the matrix and angiogenesis rather than the blood components and mechanical forces driving platelet functions associated with tumor growth and metastasis.
Using the OTME-Chip, Jain and his colleagues could assess platelets in circulation for many days and “very specifically visualize how [they] break the vascular human barrier to get out of the blood vessel and into the tumor.” They then characterized the signaling pathway and showed the platelet GPVI expression is shear-dependent and binds to tumor galectin-3.
When chemotherapeutic drugs were introduced to prevent the tumor from spreading, nearby platelets reduced their therapeutic effectiveness, he says. Fascinated, the research team then added the antiplatelet drug Revacept (advanceCOR GmbH, Germany) that had been successfully evaluated against collagen-mediated platelet adhesion in phase 1 clinical trials of atherosclerosis and stroke.
In its first-ever use as a cancer drug, Revacept used along with chemotherapy resulted in visible tumor regression, reports Jain. Together, they “attacked not just the cancer cells but the microenvironment to make tumors less proliferative and metastatic.”
As previously reported in Clinical Pharmacology & Therapeutics (DOI: 10.1002/cpt.742 and DOI: /10.1002/cpt.1054), the research team used one of its organ-on-chip platforms (pulmonary thrombosis-chip) to help Janssen study drug-associated thrombosis risk otherwise seen only in primate models, says Jain. He expects multiple pharma companies developing drugs for cardiovascular symptoms might now be interested in using OTME-Chip to see if some of them can be repurposed as treatments for cancers where platelets are known to play a role.
“We are trying to spur new clinical trials, or maybe make clinical trials more effective, with this platform,” Jain says. If funding can be secured to initiate a clinical study of Revacept, it would potentially be led by Anil Sood, M.D., professor and vice chair for translational research in the departments of gynecologic oncology and cancer biology at MD Anderson Cancer Center. Sood is a leader in the field of ovarian cancer research and collaborates with Jain.
Each OTME-Chip functions for two to three weeks, says Jain, adding that “we’re now working toward extending the lifetime of these chips even longer.” That could enable scientists to start asking more of microdevices that used to require an animal model, including how the chronic stressors of disease and aging influence biological dysfunction, as well as to conduct longer term pharmacokinetic and pharmacodynamic studies.