Q&A: Modeling the microenvironment
More accurate disease modeling is becoming one of the biggest points of interest in the industry of late as companies explore 3D models and lab-on-a-chip technology. In addition to giving new insights into the nature and development of diseases, disease modeling also enables early screening of drug candidates at a time when drug development costs are measured in the billions and unforeseen toxicity is the leading cause of clinical failure. And for a complex disease like cancer, a more accurate look at how a tumor grows and interacts with its surroundings is pivotal.
In hopes of answering this need, HemoShear Therapeutics recently announced the publication of research data regarding a multicellular 3D model of the tumor microenvironment for pancreatic cancer. This new model was created with the use of HemoShear's REVEAL-Tx platform and the expertise of co-author Dr. Daniel Gioeli, associate professor of Microbiology, Immunology, and Cancer Biology at the University of Virginia. Dr. Brian Wamhoff, co-founder and head of innovation at HemoShear, took the time to give DDNews a more in-depth look at the work and where it could lead.
DDNews: Can you briefly describe the nature of this model, which was described in Lab on a Chip as “a human triculture 3D in-vitro tumor microenvironment system”?
Wamhoff: Our research published in the Royal Society of Chemistry’s Lab on a Chip journal focused on our multi-cellular three-dimensional model of the tumor microenvironment for pancreatic cancer. This human triculture 3D in-vitro tumor microenvironment system (TMES) was engineered to accurately mimic the tumor microenvironment. The TMES recapitulates tumor hemodynamics and biological transport with co-cultured human microvascular endothelial cells, pancreatic ductal adenocarcinoma and pancreatic stellate cells. In our research, we demonstrate that significant tumor cell transcriptomic changes occur in the TMES that correlate with the in-vivo xenograft and patient transcriptome. Treatment with therapeutically relevant doses of chemotherapeutics yields responses paralleling the patients' clinical responses. Thus, this model provides a unique platform to rigorously evaluate novel therapies and is amenable to using patient tumor material directly, with applicability for patient avatars.
DDNews: How did HemoShear's REVEAL-Tx human biology platform enable this work?
Wamhoff: What is important to note about the HemoShear’s proprietary REVEAL-Tx platform is that this “technology” not only allows us to create a tumor microenvironment—the platform combines both biological and computational models of human disease to accelerate discovery of novel targets and successful new drug treatments. This merging of computational science with meaningful human biological data is a powerful capability.
More specifically in this research, working with our REVEAL-Tx human biology platform, we developed the tumor model, which uniquely incorporates multiple human tumor cell types, including endothelial cells, stromal fibroblasts and patient-derived tumor cells that are exposed to mechanical shear forces derived from tumor blood flow to restore the tumor’s physiological environment. Of major significance, we demonstrated that treatment with therapeutically relevant doses of chemotherapeutics in the pancreatic tumor model yields responses paralleling the patients' clinical responses, which is rarely the case in traditional cell culture and mouse cancer models.
DDNews: What are some of the differences in accuracy between this new model and existing 3D tumor models?
Wamhoff: This model appears to more closely replicate the patient transcriptome than either PDXs [patient-derived xenografts] or 2D cultures. The model also provides responses to drugs at concentrations equivalent to patient doses that reflect patient outcome, which is not possible with PDXs or 2D cultures. However, more research is required to accurately confirm these differences.
DDNews: It was noted that you are adapting the model to explore its potential in immuno-oncology; are there certain types of immune cells in particular that you're looking to integrate first?
Wamhoff: In the immuno-oncology area, we are working in collaboration with Dr. Dan Gioeli, UVA, School of Medicine Cancer Center, focusing on CAR T-cells. We have also explored the addition of myeloid-derived cells.
More broadly, there are a breadth of applications for our human tumor platform that uses human primary tumor cells, spanning from target validation to creating patient avatars for efficacy dosing, to developing a de-novo tumor microenvironment. For instance, the tumor platform can be partnered in multiple ways with multiple partners because there are so many solid tumor cancers. All that to say that we can adapt the model to explore other disease areas and solid tumor cancers that our partners and potential partners wish to collaborate on.
DDNews: Are there any cancer types that have been particularly difficult to model in the lab so far that you're hoping will be successfully recreated with this approach?
Wamhoff: To date, we have successfully validated builds for pancreatic and non-small cell lung cancer. We also have preliminary results with prostate cancer. We have focused on solid tumors, which across the board generally lack predictive in-vitro models. We are optimistic that the TMES can be applied to any solid tumor types. In fact, we have conceptualized using the system for hematologic malignancies. And we look forward to forging partnerships with companies who want to apply our platform to accelerate successful cancer drug discovery and ultimately develop more effective treatments for patients.
Brian Wamhoff, Ph.D.., is co-inventor of HemoShear's technology and was pivotal in the launch of the company's drug discovery programs in rare metabolic diseases. His efforts have also led to partnerships with Takeda, Horizon Discovery and Carnot Biosciences. In addition to co-founding HemoShear, Wamhoff has also co-founded a number of medical device and therapeutics companies.