June 20, 2023 | Recent years have seen the emergence of new cancer treatments that target specific molecular pathways, but plenty remains to be learned about how a tumor and its surrounding environment interact—and how this interplay affects disease progression. As the field of bioengineering progresses, emerging technologies are aiming to mimic tumors more effectively and pave the way toward improved cancer treatments.
These technologies are becoming even more relevant in light of the Food and Drug Administration Modernization Act 2.0, which enables the use of animal testing alternatives for the study of drug safety and effectiveness. “If we can mimic some of the animal models under in vitro conditions, then we can use those tests and validation for clinical trials,” Akhilesh Gaharwar, a Texas A&M University biomedical engineering professor, told Diagnostics World.
One of the main problems with animal testing is that animals cannot “recapitulate human pathophysiology,” he said. Some of the diseases that impact humans do not affect animals, for example, and animals have different vascular patterns.
These types of differences help explain why some therapies have shown such promise in lab settings but do not fare as well in human patients—a major issue for the pharmaceutical industry. The Modernization Act is providing another option, Gaharwar added, considering researchers having been coming up with improved models known as microphysiological systems.
Organ-on-a-chip technology enables the development of a mini version of an organ that can be used to simulate human physiology with applications ranging from disease modeling to drug discovery and toxicity testing, Gaharwar noted in a Nature Materials paper (DOI: 10.1038/s41563-023-01511-6). And 3-D bioprinting makes it possible to print biomaterials and living cells in a structure that can lead to models more closely resembling real tumors.
Because many of these engineered systems utilize human cells, they can be used to help determine the effect of drugs in a human condition while avoiding some of the drawbacks commonly associated with animal models, he added.
Lymphoma Organoids Used to Explore Targeted Therapies
In the Nature Materials paper, Gaharwar also commented on recent work by an international group of researchers who have built a model to understand how the tumor microenvironment affects targeted therapies for a specific type of lymphoma.
Emerging treatments for Activated B Cell-like Diffuse Large B cell lymphoma (ABC-DLBCL) that zero in on specific molecular signals are in clinical trials. Although they have shown promise in lab experiments and testing with mice, treatments have been less effective in humans.
“We wanted to understand how specific changes that happen in the microenvironment empower the lymphoma tumors to not respond to these drugs when administered in patients,” senior author Ankur Singh, a mechanical and biomedical engineering professor at Georgia Institute of Technology, said in a news release.
Singh and colleagues explored the molecular profiles of over 1,100 patients with ABC-DLBCL. They used this information to create a synthetic hydrogel-based lymphoma organoid model that can be used to understand how the tumor microenvironment impacts the efficacy of targeted drug therapy.
They tested their model by studying how the tumors responded to a new inhibitor drug currently in human trials. After finding that various tumor microenvironment factors bolstered tumor survival, they discovered an improved response when combining therapeutics to target multiple pathways.
To validate their results, the researchers then implanted patient tumors in a mouse model to see how patient tumors responded to the new therapies. Their findings are detailed in a Nature Materials study (DOI: 10.1038/s41563-023-01495-3).
“The ultimate goal is to build a patient-derived tissue model that represents the tumor and can be grown outside of the body, in order to truly understand the factors and conditions that control tumor behavior,” Singh added.
Texas A&M’s Gaharwar noted that the model developed by Singh and colleagues “highlights the role of the tumor microenvironment in designing combinatorial therapies” and “represents a potentially valuable tool for designing drug therapies.”
Tumor Model Offers Insight into Bone Cancer Drug Resistance
To better understand how tumor cells behave, Rice University researchers have developed a model that includes osteosarcoma cells along with immune cells (macrophages). The 3D structure is intended to resemble bone.
“Existing tumor models used to test drug performance do not mimic the actual environment in the human body closely enough,” bioengineer Antonios Mikos said in a news release. “We are trying to create an environment for the experiment that is closer to what is happening in the organism of actual patients.”
In their study, published in Biomaterials (DOI: 10.1016/j.biomaterials.2023.122076), they discovered that inflammation caused by macrophages limited the effectiveness of a therapeutic agent used to treat osteosarcoma—the most common type of bone cancer. “Tumor-associated macrophages account for the largest fraction of the infiltrating immune cells in many solid tumors and are of growing interest as a target for anti-cancer agents, including for osteosarcoma,” the authors wrote.
Osteosarcoma is a complex disease that shows up differently in each patient, and the researchers hope to pave the way toward personalized medicine approaches. An underlying aim of their research is to develop testing platforms where the unique qualities of a patient’s tumor are relied upon to come up with a therapeutic model geared toward that particular individual.
The researchers see promise in models that can better mimic tumors and help point the way to more effective treatments that target both the cancer cells and the immune cells—or that get immune cells to alter their function.
“The tumor microenvironment clearly plays an important role in how disease progression and treatment unfold,” Mikos added. “That is why we strive to develop an optimal level of complexity that captures the bigger picture of what actually happens inside a live organism.”
Head and Neck Tumoroid Challenges and Opportunities
Although they share a categorization, head and neck cancers emerge in various sites within the head and neck region and have different manifestations, according to a group of Australian researchers. This type of variability likely contributes to the high treatment failure and death rates seen with these forms of cancer.
In a paper published in the British Journal of Cancer (DOI: 10.1038/s41416-023-02167-4), Basnayake et al. detail the opportunities and challenges involved in head and neck cancer patient-derived tumoroid cultures—3D cell cultures meant to mimic actual tumors.
“From discovery and development through to FDA post-market drug safety monitoring, the typical development of a successful anti-cancer drug takes more than a decade and costs on average US$1 billion,” the authors noted, and only a fraction of potential drugs ever see the light of day.
They argue that this is largely due to the current reliance on animal and 2D cell culture models. “To date, there is a significant gap between in vitro and clinical research,” they noted, and there remains a need for an effective cell culture method.
Tumoroids could serve as an effective model for drug testing, considering their ability to emulate the 3D cell and tissue architecture of tumors and to maintain their heterogeneity. However, they believe a variety of limitations and drawbacks still need to be overcome.
It is important to limit the amount of fungal and bacterial contamination, for instance, which can impact treatment response. Another issue is the current lack of standardized protocols to help guide the development of tumoroids. In addition, while tumoroids can simulate the tumor microenvironment better than 2D cell culture, they “lack vascular and neuronal networks,” the researchers noted.
Despite these and other challenges, the authors see potential as they consider the future outlook of tumoroids, indicating that there is reason to believe that they “can be used as a robust preclinical tool for drug screening, precision medicine, and developing anti-cancer drug treatments.”
Researchers Reveal Portable 3D Bioprinter
A group from the University of Cambridge and King’s College London have developed a portable machine that can print tumoroids for cancer research. The tool, called BioArm, is designed to be inexpensive and easy to transport or store, and can “print” tumoroids to help test possible immunotherapy treatments. The researchers believe it could play a key role in the future development of approaches to cancer drug testing.
A paper published in Biofabrication (DOI: 10.1088/1758-5090/acb1db) details their exploration of the interaction between immune cells and tumoroids, as well as their study of the relationship between the immune system and immunotherapy.
On average, the tool takes about 90 seconds to print each tumoroid. As its robotic arm moves, bio-ink emerges from the printhead to make 3D soft material creations on a petri dish. (This study involved samples meant to mimic mice tumors.) Whereas many bioprinters can be challenging to move or reassemble, this tool was built with portability in mind and can be assembled and taken apart in under 15 minutes.
The researchers envision its potential to make 3D bioprinting available to a broader research community. “While we tested immunotherapy, this platform has potential to screen a wide range of tumor therapies and monitor the therapeutic response in not only tumor cells, but also in the adjacent stroma,” the researchers noted.
As a small, light-weight, and foldable machine, BioArm has some advantages over existing options, co-first author Yaqi Sheng, a PhD student in the Department of Engineering at the University of Cambridge, told Diagnostics World.
When bioengineers collaborate with biologists, for example, sensitive cells or living tissues need to be transferred between labs, which can pose a danger to those materials. Instead of moving living cells, BioArm makes it possible to relocate the printer instead. And because it is open source, she said that customized functions can be added as needed.
Corrado Mazzaglia, a research associate in the Biointerface Research Group at the University of Cambridge, pointed out that BioArm is less expensive than current commercial options in addition to highlighting its portability and programmability.
“These are key factors in expanding the spread of a technology that has huge potential and in which many researchers have interest,” he told Diagnostics World. “I hope in the future, BioArm will help lower the accessibility barrier of the technology and reach as many researchers as possible.”
According to Mazzaglia, the main limitations of BioArm are shared with all extrusion-based bioprinters and relate to issues of resolution and complexity. “Extrusion 3D bioprinting can create structures with limited complexity in air,” he explained, although some limitations can potentially be overcome using embedded printing in supportive baths.
Looking ahead, the researchers plan to build upon this line of work by modeling human tumors to validate their technique for clinical purposes.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.