- Escape from Tumor Cell Dormancy
- Thermally Targeted Delivery of a c-Myc Inhibitory Peptide in Vivo Using Elastin-Like Polypeptide
Escape from Tumor Cell Dormancy
Posted April 23, 2013
Alan Wells, M.D., University of Pittsburgh, Pittsburgh, Pennsylvania
Linda Griffith, Ph.D., Massachusetts Institute of Technology, Cambridge, Massachusetts
Metastatic cells can escape the primary breast tumor and lie dormant in distant organs for years. The triggers for the "re-awakening" of these micrometastases are not well understood. The liver is a major site of metastatic spread for breast cancer. To understand which tumor cell behaviors contribute to metastasis and disease progression in the liver, Dr. Wells and Dr. Griffith developed a three-dimensional ex vivo organotypic tissue system with funding from a Fiscal Year 2003 (FY03) Idea Award. This bioreactor allowed liver cells to grow in a device outside the body, while preserving and recreating the behaviors of living tissue, thus allowing the process of seeding, dormancy, and emergence to be followed. With subsequent funding from a FY09 Idea Expansion Award, Dr. Wells and Dr. Griffith are using this model to gain an understanding of what triggers dormant breast cancer cells to emerge, ultimately building the foundation for the development of therapeutics or prevention strategies.
The bioreactor system was successful in creating a soft gel scaffold format of desirable biological properties to seed tumor cells. The demonstrated maintenance of liver tissue function in these structures enabled the study of the microenvironment surrounding dormant micrometastasis. Dr. Wells and Dr. Griffith discovered that tumor cells produce inflammatory cytokines that cause normal liver cells to break their cell-cell attachments and enable tumor cells to intercalate between normal cells and reside. When the environment surrounding the dormant cells is induced, for example, via liver parenchymal stress, growth factors capable of relieving the resident tumor cells from suppression are produced. Moreover, as these tumor cells escape dormancy and proliferate, their oxygen uptake increases. To advance the development of the bioreactor, Dr. Wells and Dr. Griffith were able to optimize an approach for measuring oxygen, serving as a highly informative means of assessing tumor cell proliferation.
The development of the bioreactor, armed with enhanced controls and oxygen measurements, represents a unique and relevant model of micrometastatic dormancy and emergence ex vivo. The advances from this project set the stage for a National Institutes of Health-funded project involving groups from Draper Laboratories and a commercial entity, Zyoxel, committed to developing the bioreactor for widespread usage. This new project is one of 17 Tissue Chip Project Awards awarded by the National Institutes of Health National Center for Advancing Translational Sciences. The proposed work focuses on further understanding the complexity of the tumor microenvironment in cancer metastasis and developing the next-generation all-human liver bioreactor, allowing for greater advances in breast cancer drug and therapy development.Links:
Public and Technical Abstracts: An Organotypic Liver System for Tumor Progression
Public and Technical Abstracts: Escape from Tumor Cell Dormancy
Thermally Targeted Delivery of a c-Myc Inhibitory Peptide in Vivo Using Elastin-Like Polypeptide
Posted March 1, 2013
Gene Bidwell, Ph.D., University of Mississippi, Jackson, Mississippi
FY07 Era of Hope Postdoctoral Award
Most chemotherapy drugs are not specific to the tumor cells they are being used to treat, meaning that the chemotherapeutic agent has lethal effects in all cells in the body. Dr. Gene "Lee" Bidwell is working on a new drug delivery system that can preferentially deliver chemotherapeutics to cancer cells, concentrating the toxic effects at the tumor site, sparing normal cells, and reducing treatment side effects. Dr. Bidwell talks about his BCRP-funded research:
How is your research addressing the problem of toxic side effects?
We are developing a drug carrier that responds to heat and can be loaded with many types of chemotherapy drugs. The drug carrier with attached drug is administered by intravenous injection followed by application of a very mild heat (about 107 degrees Fahrenheit, just hotter than a high fever) at the tumor site. As the drug carrier circulates through the heated tumor, it forms large aggregates that get "stuck" in the tumor. When the heat is later removed, the aggregates dissolve and deliver the attached drug to the tumor cells.
In addition to this carrier, we are developing a type of anti-cancer agent called a peptide. Peptides are promising because they can be used to target any molecular pathway of interest and they can be very specific for that pathway. The agent we are working with now is specific for a protein that is often over-produced by cancer cells. Inhibiting this cancer-specific protein, therefore, will have a greater effect on the cancer cells and tend to spare normal cells of the body.
What have you accomplished so far and what is the next step to bringing your research closer to helping breast cancer patients?
With our DoD BCRP funding, we were able to validate our thermal targeting approach in an estrogen receptor-positive mouse model of breast cancer. We demonstrated that heat targeting can be used to increase the levels of our drug carrier in breast tumors in these mice. Further, we showed that the thermally targeted anti-cancer peptide can greatly reduce the progression (75 percent reduction relative to untreated tumors) of these tumors.
The next step is to test this thermally targeted anti-cancer peptide in other models of breast cancer to define what patient population(s) might benefit from treatment with this agent. After validation in multiple mouse models, we would next test our agent for safety in other larger animal models before advancing to clinical testing.
What barriers do you face in your research?
Increasingly sensitive and sophisticated molecular technology makes it possible to identify numerous potential treatment targets in individual tumors and patients; however, it is difficult to develop personalized conventional small molecule chemotherapeutics to home in on these targets.
Peptides have an advantage in that it is relatively easy to generate a peptide that will modulate a desired protein just by looking at that protein's sequence. The drawbacks of peptides are that they degrade quickly in the body and they do not penetrate into tumors well. For these reasons, there are not many peptides in clinical use today. By fusing them to our carrier, we can protect peptides from degradation and we can increase their uptake in tumors. We see peptides as very powerful potential drugs and are working to overcome these issues to make peptides available as clinical therapeutics.
How did this award help advance your research and your career as a breast cancer researcher?
With the support of the DoD fellowship during my postdoctoral training, I was able to demonstrate that I could perform quality science and publish high-impact results. After finishing my DoD-funded fellowship, I received a tenure track faculty position as Assistant Professor of Neurology at the University of Mississippi Medical Center. My DoD award not only allowed me to do interesting and cutting-edge science, it also prepared me to lead my independent research lab.Links:
