Our research over the past year has focused on the problem of ovarian cancer (OC) metastasis – the primary cause of OC related mortality. One solution to this problem would be to detect and treat (surgical removal of the tumor) the disease before it metastasizes. This has been the motivation behind the development of our MASS SPEC based diagnostic assay.
We have previously demonstrated that the assay works exceptionally well at discriminating between sera collected from OC patients vs. normal healthy women (http://www.ncbi.nlm.nih.gov/pubmed/20699376). The problem has been that the majority of samples used in this initial study were collected from patients with late stage disease (III/IV) and it is incumbent upon us to demonstrate that our assay is equally as accurate in detecting early stage disease (Stage I/II), in order to be effective as a screening test. Unfortunately, samples from early stage patients are extremely difficult to come by. We have recently made arrangements with the Fox Chase Cancer Center (Philadelphia) to obtain 40 + sera samples from early staged serous papillary OC patients.
A second possible strategy to reduce OC metastasis is to focus on the metastasizing cells themselves. Primary tumors are predominately made up of cancer epithelial cells. It is postulated that cancer epithelial cells on the surface of solid tumors undergo an epithelial-to-mesenchymal transition (EMT). The resulting mesenchymal cells loose cell adhesiveness (and hence slough off the primary tumor) and acquire resistance to standard chemotherapies and enhanced motilities.
Over the past year, we have published results confirming that OC metastasis does indeed involve EMT. We have consequently taken two strategies to attack metastasizing OC cells. The first was to screen libraries of experimental drugs for compounds that are effective in inhibiting or killing metastasizing OC cells. We identified a number of candidate drugs (some already FDA approved for other applications) that are effective in killing mesenchymal/OC stem cell-like cells .
The other approach is to induce metastasizing mesenchymal cells to undergo mesenchymal-to-epithelial transitions (MET) thereby re-establishing their sensitivity to standard “first-line” OC chemotherapies (e.g. playinum-based drugs). Treatment of mesenchymal OC cells with a class of small regulatory RNAs (the miR-200 family of microRNAs) is extremely effective in inducing MET and re-sensitizing these cells to platinum-based therapies. A paper has just been submitted showing that this strategy works effectively on metastasizing OC cells recently isolated from a Stage III ovarian cancer patient.
A third strategy is to identify drugs that can effectively treat metastatic ovarian tumors. Toward this end we are establishing a genomics-based personalized OC therapy program. Primary and metastatic samples from patients are collected and DNA and RNA are extracted and subjected to high-throughput sequencing. Genes/pathways identified as mutant and/or abnormally expressed are identified as candidates for personalized targeted gene therapy. We have initiated a pilot study using matched sets of primary, metastatic and recurrent (arising 1-2 years after initial treatment) samples from archived collection (tissue bank > 2000 OC samples) from 8 ovarian cancer patients. The initial results have demonstrated that metastatic samples can, in some patients, be genetically radically different from the primary tumor. These differences are partly due to new mutations that have arisen in the metastatic tumors but more frequently because the metastatic tumor was established from genetically distinct cells in very low frequency in the primary tumor. The bottom line is that drugs predicted to do very well on primary tumors will not work well on the metastatic/recurrent tumor. We have shown that genomic profiling of the patient’s metastatic tumors is necessary in many cases to devise the optimal therapeutic strategy for each individual patient. We are enthusiastic about continuing/expanding this project in the coming year.