Over the last five years my research interests have changed dramatically from purely cellular molecular biology to much more clinically relevant research. I have been very fortunate in interacting with a number of clinicians in the Des Moines area that have a strong interest in clinical research, but have questions that are beyond their abilities to answer. Teaming up has led to some fruitful collaborations. The current projects that I am involved in are outlined below.
- HIPEC – HIPEC stands for Hyperthermic intraperitoneal chemotherapy. HIPEC is a procedure that utilizes the combination of heat and chemotherapy to kill malignant cells of peritoneal carcinomas that may not be completely removed during cytoreductive surgery. This is done via catheters that have been inserted into the intraperitoneal cavity. Chemotherapy that is heated to 41°C is circulated through the peritoneal cavity. Although this technique has led to a doubling of survival time (approximately eight months to 16 months), a clear understanding of the mechanism of action does not exist. We have developed an in vitro model of HIPEC using HeLa cells. Although not identical, this model exhibits features similar to in vivo treatment. In response to doxorubicin, HIPEC causes significantly greater cell death at effective drug concentrations. Interestingly, there is no difference in the dose response curves for another commonly used chemotherapeutic agent, mitomycin C. Using this model, we have begun investigating which genes are up and down regulated in response to HIPEC treatment. Our first investigations have looked at the heat shock proteins; HSP90 and HSP70. Both proteins are upregulated by HIPEC treatment. We have further characterized the role of HSP90 in this model, by blocking its activity with 17-AAG (an inhibitor of HSP90). We hypothesized that since HSP90 is involved in stress response for the cells, blocking its action would make HIPEC a more effective treatment modality. Our results showed that there was no effect on blocking HSP90 activity on cell death in our model.
We are currently experimenting on blocking HSP70 to see if we can see an effect of this protein on survival in our model. Our goal is to better understand this treatment, and to identify modifications to the treatment that will make it more effective. - Pancreatic Cancer Biomarkers – Pancreatic cancer is one of the most lethal forms of cancer known. Typical five-year survival rates approach five percent. In up to 80 percent of cases, metastasis has already occurred at the time of diagnosis. Following surgery, patients are typically put on one of two different chemotherapy regimens. However, it is common that patients are switched between regimens because they do not respond well to the regimen they were first started on. Because of the lethality of this disease, identifying additional markers to detect this cancer earlier and inform treatment options are very important. In collaboration with Pathology Department at Mercy Medical Center in Des Moines, we have access to tissue blocks of approximately 100 patients who were diagnosed and treated for pancreatic cancer. All of these patients have died, so additionally; we have all the statistical information about stage, grade, treatments, and time to death for this cohort. Using Immunohistochemistry techniques (IHC) we are looking at two different aspects of this cancer. First, we have identified a number of important pathways involved with the two different chemotherapeutic regimens. We want to determine if drug uptake, metabolism, or targets are responsible for the varied responses seen for the two primary chemotherapy regimens. If a common defect can be identified, then patients can be assessed for this defect prior to the start of chemotherapy, thus increasing the likelihood that the therapy will be effective. Secondly, we are looking at markers for metastasis. We have shown that E Cadherin expression closely associates with tumor progression and survival. We care currently looking at downstream targets of the E Cadherin/-catenin signaling pathway to help us understand the role of this pathway in the metastatic processes of pancreatic cancers. Within our laboratory, we are developing techniques to look at tissue arrays of pancreatic cancers to more accurately assess the levels of expression for these genes. We hope to be able to put 50-100 small sections of tissue on each slide so that we can minimize inter experimental variation in staining. This will enable a much stronger interpretation of the results.
- Glioblastoma Multiforme (GBM) – In collaboration with the Surgery Department and Neurosurgery at Mercy Medical Center, we have collected 10 patient tumor samples of GBM. With funding from the Sea-Spine foundation we are using a metastatic Proteome Profiler kit that examines the expression of 55 metastatic proteins. Using these kits, we are examining the metastatic markers of these patient samples, and connecting that information to patient outcomes. We hope to create a more robust picture of the process and effects of metastasis in GBM.