CircosVariant frequenciesCNVsTrees

Applied Genomics & Cancer Theraeputics (AGCT)

Funding (active)

  • American Cancer Society, Research Scholar (2014-2018)
  • Department of Defense Ovarian Cancer Research Program, Pilot Award (2014-2016)
  • Department of Defense Ovarian Cancer Academy Program (2010-2016)
  • National Science Foundation (2013-2015)
  • KU Endowment (2012-2017)
  • KU Cancer Center Program Project Grant Development (2014-2015)

Current Research


The primary objectives of my research program are to understand the genetic basis of ovarian cancer and to translate this knowledge into clinical applications to improve the early detection and the treatment of ovarian cancer. To support these objectives, my current research focuses on three areas: Cancer Genomics, Functional Genomics, and Molecular Cancer Therapeutics.

Cancer Genomics

Although genetic alterations are considered a hallmark of cancer, certain genetic alterations serve as "drivers" in cancer progression while others are considered "passenger" mutations.  Advances in the identification of "driver" genetic alterations in cancer will lead to the development of novel therapeutic targets to effectively treat cancer and it is a prerequisite in the era of "Personalized Medicine" or "Precision Cancer Medicine." My research focuses on the characterization of genetic mutations from cancer genomes to identify driver mutations and the development of experimental therapeutics that target driver genes in ovarian cancer. We are applying transcriptomic sequencing, whole genome sequencing, whole exome sequencing, targeted exon sequencing, and low-pass whole genome sequencing to characterize somatic sequence variations and to identify common sequence variations associated with ovarian cancer.  This approach is coupled with the principle of forward genetic screens in Functional Genomics to identify potential driver genes in ovarian cancer.  Advances in this area of research will allow us to develop more effective therapies that target these driver genes in ovarian cancer. This work is being funded by the Department of Defense Ovarian Cancer Academy program (W81XWH-10-1-0386), National Science Foundation (NSF-III1149697), and the American Cancer Society Research Scholar grant (125618-RSG-14-067-01-TBE). 


Figure 1. Cancer Genomics. To comprehensively characterize somatic mutations in ovarian cancer genomes, we are analyzing genetic alterations in primary and recurrent tumor samples.  This analysis identifies novel fusion transcripts that are detected in patient-matched primary and recurrent tumor samples (red lines across the circos digrams) as well as fusion transcripts that are unique to recurrent tumor samples (yellow lines across the circos digrams). In addition, from multi-region sequencing and fusion transcript analysis, we identified truncal fusion transcripts that are present in all spatially separated tumor samples from each paitent.

 


Functional Genomics

Genomic studies have provided us with frequently mutated genes in cancer genomes.  To translate this genetic information into biological insights and therapeutic targets that exploit genetic defects in cancer, it is important to understand the effect of these mutations and develop drugs to exploit these defects. Currently, we are performing functional genetic screens and selections to systematically characterize the effect of somatic mutations in specific cancer genes. The ultimate goal is to develop a catalogue of mutations in specific cancer genes and identify drugs that can precisely target these mutations.

Resistance to chemotherapy in a metastatic disease setting is a major contributing factor to the high-rate of mortality in ovarian cancer.  Therefore, it is important to identify genes and biological pathways regulating ovarian cancer metastasis and chemotherapy resistance, as well as to develop novel therapeutics to treat advanced ovarian cancer. Toward these goals, we are currently performing phenotype (drug resistance) screens using a tumor-derived ORF library established from 10 tumor samples collected from women with chemotherapy resistant ovarian cancer to identify driver genes that promote chemotherapy resistance (Figure 2).  In addition, we are using complementary genome-wide RNAi screening to identify genes that modulate ovarian cancer metastasis and chemotherapy resistance, and to identify synthetic lethal phenotypes to overcome chemotherapy resistance. Advances in this area of research will allow us to identify critical biological pathways and molecular targets modulating chemotherapy resistance, and will facilitate the development of effective and durable treatment options.  This work is being funded by the Department of Defense Ovarian Cancer Academy Program (W81XWH-10-1-0386), the American Cancer Society Research Scholar grant (125618-RSG-14-067-01-TBE), and NIH Center of Biomedical Research Excellence (COBRE) pilot grant (P30 GM 110761). 

 
Figure 2. Functional Genomics. We have developed "Genome-wide cancer toolkits" to investigate genetic determinants of cancer phenotypes.  We are using these toolkits identify somatic mutations associated with pathobiology of cancer as well as therapeutics that can target these mutations.

 


Molecular Cancer Therapeutics

Integrated genomic studies by the Cancer Genome Atlas identified FOXM1 as a candidate gene that is deregulated in 84% of high-grade serous ovarian cancer.  High levels of FOXM1 expression in this disease suggest it may serve as a therapeutic target; analogous to Her2 in breast cancer, Abl in leukemia, and Braf in melanoma, serving as therapeutic targets in respective diseases.  We are evaluating two FOXM1 inhibitors to characterize their cytotoxic effects in ovarian cancer cells and to understand how these agents affect FOXM1 expression, DNA single-strand repair (SR), and homologous recombination (HR) repair pathways to induce cytotoxic effects in cancer cells. We are also investigating how p53 and FOXO transcription factors co-regulate FOXM1 expression in cancer cells.  Finally, we are investigating how these agents may synergize with anti-PD-L1 immunotherapy to enhance immune cell-mediated tumor clearance.  Advances in this area of research will allow us to repurpose FDA-approved drugs to facilitate the development of targeted therapies in ovarian cancer. This work is being funded by the Department of Defense Ovarian Cancer Research Program (W81XWH-14-1-0116).

Another area that we are developing is the exploitation of vulnerabilities in cancer for therapeutic benefits.  Toward this goal, we are focusing on the unfolded protein response (UPR) pathway to induce cytotoxic effects in cancer cells.  An interesting aspect of this pathway is that cell death induced by ER stress is associated with immunogenic response.  Since immune systems plays a critical role in enhancing the effect of chemotherapy, the UPR pathway is an attractive target for cancer therapy that has the potential to harness the power of the host's immune system for complete tumor eradication. In particular, we are interested in vulnerability generated by the loss of HTRA1 in cancer.  HTRA proteases were originally identified in bacteria and are essential for the survival of bacteria under heat-induced unfolded protein response and stress, hence the name, High temperature requirement A (HTRA). Since HTRA1 is lost in approximately 50% of ovarian cancer, elevated protein stress due to HTRA1 loss may be further exacerbated by inhibition of p97 AAA ATPase, a critical component in degradation of unfolded proteins.   

   
Figure 3. Targeted Pathways in Ovarian Cancer. Two biological pathways that we are currently investigating are FoxM1-TP53 axis and Unfolded Protein Response (UPR). We are investigating drugs that inhibit FoxM1 pathway and those that activate UPR pathway.
Last modified: Jul 10, 2015
ID=x7756