In recent years, innovative cancer drugs that target specific molecular drivers of the disease have been embraced as the treatment of choice for many types of cancer. But despite significant advances, there is still a lack of understanding about how the complex interactions between a tumour and its surrounding environment in the body affect cancer progression. This problem has become a well-known roadblock in making novel treatments effective for more people.

Ankur Singh, professor in the George W. Woodruff School of Mechanical Engineering and the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University led an international team of researchers in the development of a promising breakthrough for targeted cancer therapies.

The team bioengineered a synthetic tumour model to understand and then demonstrate how the tumour microenvironment impacts the effectiveness of targeted therapies for a specific type of lymphoma called Activated B Cell-like Diffuse Large B cell lymphoma (ABC-DLBCL). Their synthetic tumour model could change the game for designing and testing personalised cancer therapies. The research paper, which features an interdisciplinary team from institutions across the U.S. and around the world, was published in the journal Nature Materials.

A Cutting-Edge Tumour Model

Recent treatments for ABC-DLBCL that target specific molecular signals of the disease are in clinical trials. But, while the treatments have shown to be effective in lab testing (in vitro environments) and in mice (in vivo), they have proven less effective in humans, with over 60% of patients not responding.

“We wanted to understand how specific changes that happen in the microenvironment empower the lymphoma tumours to not respond to these drugs when administered in patients,” Singh said. “The ultimate goal is to build a patient-derived tissue model that represents the tumour and can be grown outside of the body, in order to truly understand the factors and conditions that control tumour behaviour.”

To accurately test new therapies, a model tumour microenvironment should closely mimic the nuanced interactions that happen in a live tumour. But to understand those conditions, which can vary wildly from case to case, the researchers needed real patient data. 

The researchers examined more than 1,100 ABC-DLCBCL lymphoma patient samples to understand the molecular profiles of their tumours. For each sample, they used RNA sequencing and imaging to identify the composition, stiffness, and mechanical properties of the tumour tissue, along with other factors that play a role in how tumours grow and respond to treatment.

Combining what they learned from the patient data, the researchers designed a synthetic hydrogel-based model of the lymphoma tumour microenvironment. They bioengineered the model to have the specific qualities and characteristics seen in the microenvironments of the samples. Specifically, by modifying the hydrogel with cell-binding adhesive peptides and presenting immunological signals, they were able to recreate the intricate biological, chemical, and physical characteristics that are present in a live tumour microenvironment, including protein signals, tumour stiffness, and more. The customisable hydrogel proved to be supportive of tumour samples obtained from patients, a phenomenon that has not been previously demonstrated for lymphomas.

Combining Therapeutics

The team illustrated the viability of their model by testing how the tumours responded to a new type of inhibitor drug known as mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1 inhibitors) currently in human trials.

The researchers observed that, when being treated by MALT1, several tumour microenvironment factors related to the tumour cells — including T cell signal CD40 Ligand, collagen-like extracellular matrix, and the level of tissue stiffness — all empowered the tumour, helping the cancer cells resist responding to the new inhibitors even at high doses.

The researchers then sought a way to overcome the dampened tumour response by combining therapeutics that simultaneously suppress multiple aberrant oncogenic pathways in the same tumour cell. They found that when they used MALT1 and another inhibitor to target multiple pathways at the same time, they were able to promote more tumour death in the cells.

One of the major challenges is that tumours can engage multiple pathways in the cells to keep fuelling the survival of tumour cells. However, the combination treatment was so powerful that, even in the presence of tumour microenvironment factors that supported tumour survival, they could still be overcome by the combination of therapies.

To validate the results from synthetic tissues developed in lab, the researchers then implanted actual patient tumours in an immunocompromised mouse model to determine how the patient tumours responded to the new therapies.

“We live in a world where we can claim a lot based on in vitro treatments, but the obvious question is always what happens in vivo,” Singh said. “What’s amazing is that we predicted this exact result in our synthetic model.”  

Moving Forward

The researchers’ work clarifies the complex relationship between malignant ABC-DLCBL tumours and their dynamic surrounding environment, while highlighting the crucial importance of considering the tumour microenvironment when creating treatments that combine therapeutics.

The team’s work will help clinicians prioritise clinical trials of certain therapies and enable scientists to create more rational therapy combinations that could improve patient response rates to treatment. This is especially relevant for the potential of personalised treatment for lymphoma, as two individuals with the same cancer may benefit from different combinations and dosages of therapeutics.

A large portion of the patient samples used in creating the tumour models were provided by Emory through a collaboration with oncologist Jean Koff, one of the authors of the study.

“From a clinician’s standpoint, this work is very exciting because it exemplifies how findings from large genomic datasets may be translated into development of therapeutic strategies in lymphoma,” Koff said. “Singh’s cutting-edge organoid technology allows us to explore how patient-specific changes in the tumour microenvironment impact response to therapeutic agents, thus helping to deliver on the promise of precision medicine.”

The project further initiated a new partnership between teams at Georgia Tech and Emory and strengthened existing collaborations with Cornell Medicine. The teams will continue to work together to investigate molecular pathways that may be targeted to improve treatment outcomes for lymphoma patients.

The research comes at an important time in the field of drug testing. The FDA has begun to encourage alternatives to animal testing for pharmaceuticals. Singh’s powerful synthetic model that faithfully mimics real tumour environments is likely to be an example for other cancer researchers to follow for in vitro drug testing.

The research was funded by the National Institutes of Health, the National Cancer Institute, and the Wellcome Leap HOPE program.

Source: Georgia Institute of Technology