|Neil St. John Forbes
Assistant Professor of Chemical Engineering, University of Massachusetts
Ph.D.: University of California, Berkeley
Engineering Tumor-Targeting Therapies
Research in the Forbes group specializes in utilizing fundamental engineering principles to understand the innate biological mechanisms of tumors and using that knowledge to develop cancer therapies. While most of our focus is on strategies against cancer, many of our advances and techniques could be applied to other diseases and bioengineering problems. Despite decades of research and billions of dollars in funding, cancer is still the second leading cause of death in the United States. Over the last century, researchers have discovered many of the genetic causes of cancer and yet hundreds of thousands of people die each year. Many patients do not respond well to current therapies because most solid human tumors contain subpopulations of cells that are resistant to therapeutics. The application of core engineering principles is necessary to understand how nutrient diffusion and cellular metabolism gives rise to resistant cells.
In our group the cancer problem is being addressed in two ways: we use experimental and computational methods to understand the cellular mechanisms that give rise to drug resistance in tumors and we use engineering methods to design therapeutic strategies to overcome resistance in tumors. We are primarily working to create genetically modified bacteria that target the therapeutically resistant regions of tumors and secrete cancer-killing compounds. We call this approach intratumoral therapeutic delivery. Our ultimate goals are to generate computational tools capable of predicting optimal therapeutic strategies for cancer patients and to create treatment modalities that effectively treat patients with resistant tumors. Succeeding at these goals will increase therapeutic efficiency and increase the live expectancy of cancer patients.
Our research group is unique because it is a interdisciplinary program that combines elements from multiple fields, including chemical engineering, tumor biology, microbiology, veterinary science and oncology. The elements that we combine from these fields include 1) mathematical modeling, 2) in vitro tumor model development, 3) micro-scale device fabrication 4) genetic manipulation, and 4) small animal experimentation. We believe this combination of these elements is necessary to achieve our goal to understanding and overcoming drug resistance in tumors.
In our research we use experimental and computational methods to understand the cellular mechanisms that give rise to drug resistance in tumors and we use engineering methods to design therapeutic strategies to overcome resistance in tumors. These goals are divided into five main projects. A synopsis of each is presented below.
To date the major advances of our group has been 1) determination of the mechanisms that control the localization of therapeutic bacteria in tumors; 2) development of therapeutic bacteria that secrete an anti-cancer protein and dramatically increase survival in mice; 3) quantification of the effects of spatial heterogeneity on tumor metabolism, cell survival, and cell cycle progression; 4) development of computation tools to analyze the interactions of therapeutics with tumors; and 5) demonstration that the properties of nanoparticles can be tuned to enhance tumor targeting.
1. Mechanisms of Bacterial Accumulation in Tumors
We have shown that the accumulation of S. typhimurium in tumors is controlled by two mechanisms: 1) chemotaxis towards compounds produced by quiescent cancer cells and 2) preferential growth within tumor tissue. We have also shown that individual chemoreceptors target S. typhimurium to specific regions of tumors by controlling their chemotaxis towards specific tumor microenvironments. This improved understanding of the mechanisms that control Salmonella migration in tumors will enable us to develop bacterial therapies with improved targeting to therapeutically inaccessible regions of tumors.
2. Quantification of Tumor Metabolism
We have shown that HIF-1a does not affect cell survival and metabolism in the center of spheroids. This discovery was surprising because HIF-1a affects many aspects of cell behavior including, survival, apoptosis, and many metabolic enzymes. We had a clue, however, that HIF-1a would not affect cell behavior in tumor tissue because preliminary experiments had shown that HIF-1a action is dependent on glucose availability. Many investigations have shown that regions of spheroids and tumors that have low oxygen concentrations also have low glucose concentrations.
Using metabolic flux analysis we determined that cell survival and intracellular metabolism were not different between wild-type and HIF-1a-null tissues. We also determined that small spheroids, which contain less quiescent cells and are less nutritionally limited, have increased carbon flux through the biosynthetic pentose phosphate and pyruvate carboxylase pathways. These results show how nutrient gradients affect cell growth and metabolism in spheroids and suggest that metabolic microenvironment should be taken into account when developing HIF-1a-based therapies.
3. Development of In Vitro Tumor Models
4. Mathematical Model of Tumor Metabolism and Therapeutic Efficacy
We have used the model to determine the extent of quiescence in tumors with different cellular characteristics and to determine the critical cell survival parameters that have the greatest impact on overall spheroid physiology. We have shown with the model that 1) oxygen transport has a greater effect than glucose transport on the distribution of quiescent cells, 2) drugs with intermediate diffusion coefficients are more effective at reducing spheroid volume than fast or slow diffusing drugs, and 3) tumors with less proliferating cells are more responsive to chemotherapeutics than tumors with more proliferating cells because of cell re-population.
5. Nanoparticles for targeted cancer therapy