Principal Investigator Tyler Jacks
Lung cancer is the leading cause of cancer-related death worldwide with a five-year survival rate of 15%. A major obstacle to successful treatment is intrinsic and acquired resistance to chemotherapy. To improve cancer treatment, we need the ability to predict chemotherapy response and overcome mechanisms of resistance. However, the molecular mechanisms that govern tumor response to chemotherapy are poorly understood. The majority of studies investigating chemotherapy response have been performed with cell lines or xenograft models, which have often been ineffective in predicting response in humans. Using in vivo micro-CT imaging, we found that the majority of Kras driven-lung tumors respond to an initial dose of cisplatin. However, after prolonged therapy with cisplatin, most lung tumors acquire resistance to cisplatin (Oliver et al, in preparation). We are working toward the understanding the mechanism of resistance in these mice, using gene-set enrichment analysis and DNA copy number analysis (in collaboration with David Mu and Scott Powers at Cold Spring Harbor Laboratories).
Ovarian cancer is relatively chemotherapy sensitive with a response rate of ~80%. The most common first-line treatment regimens for ovarian cancer are platinum-based, with cisplatin and carboplatin being the most widely used. However, only ~20% of patients survive more than 5 years following treatment. The vast majority of patients acquire drug resistance and die from their disease. It is again critical to understand the molecular and cellular mechanisms of chemotherapy response and resistance in order to design more effective therapies for ovarian cancer patients.
We have generated a mouse model of endometroid ovarian cancer (Dinulescu et al., 2005). To monitor drug effects on tumor size over time, we explored two types of noninvasive bio-imaging: ultrasound imaging and luciferase-based bioluminescent imaging. We have generated LSL-KrasG12D/+/PTEN fl/fl that carry an additional allele, LSL-firefly luciferase. This allele was knocked into the ROSA26 locus, with expression of the enzyme luciferase behind the ubiquitous CAGGS (CMV-Chicken B-actin) promoter, which is prevented by the LoxP-stop-LoxP cassette (unpublished mouse, available from the MMHCC Mouse Repository at the NCI). In these mice, exposure of cells to Cre recombinase allows expression of activated K-ras, PTEN loss, and ubiquitous expression of the luciferase enzyme. Treatment of mice with the substrate, luciferin, allows noninvasive bioluminescent detection of tumor cells in vivo. Tumors and metastasis can be imaged by this method, allowing us to identify cisplatin sensitive and resistant tumors for genomic analysis. Mouse ovarian tumors are sensitive to cisplatin treatment similar to the human disease (Oliver et al, in preparation), but it is as yet unclear whether tumors from these mice acquire resistance after prolonged therapy, or whether a subset of tumors are inherently resistant.