Engineering hope for women with cancer
We are on a mission to help patients with gynecologic cancers. Our research is focused on two understudied and aggressive epithelial gynecologic cancers that affect thousands of women each year: ovarian and endometrial carcinomas. Making discoveries that will improve treatment of these diseases and potentially save lives is the ultimate goal of our work.
In the GO Discovery Laboratory, we are taking a multifaceted approach, collaborating with other leading scientists to solve complex challenges. Explore below how we are working to make discoveries that may improve the lives of patients diagnosed with gynecologic cancers.
Clinical Challenges in Ovarian Cancer
Ovarian cancers an aggressive gynecologic disease that is understudied. Though these tumors are called "ovarian" the vast majority arise from the fallopian tube or endometrium. Despite initial positive response to surgery and platinum-based chemotherapy, up to 85% of patients with ovarian cancer experience relapse of disease. Understanding mechanisms of therapy resistance, identifying subpopulations of tumor cells responsible for tumor recurrence, and testing novel combination therapies are the main focus of our work.
Our Research in Ovarian Cancer
To address these clinical challenges in ovarian cancer, our research group is exploring the following focus areas:
1. Testing drug combinations that may better target cancer cells
2. Genetically profiling tumors
3. Identifying therapy resistant tumor cells
4. In vitro drug assays that can predict response to therapy
5. Exploring ways to enhance immunotherapies in ovarian cancer
The backbone of treatment for epithelial ovarian cancers is platinum-based chemotherapy called carboplatin. While this drug can be initially effective, many patients experience relapse associated with the emergence of platinum resistant disease. The emergence of platinum resistance is a major clinical challenge in the treatment of this disease. We are exploring potential drugs (small molecules, peptides, and others) that may mitigate mechanisms of platinum resistance and result in increased efficacy when combined with carboplatin.
A major goal of our research is to better understand development of epithelial ovarian tumors from platinum sensitive to platinum resistant. Like with other epithelial cancers of the prostate and lung, aggressive therapy resistant ovarian cancers may resemble a more de-differentiated small cell neuroendocrine-like (SCN) phenotype. By genetically profiling matched human ovarian tumors before and after chemotherapy, we can define the similarities and differences between platinum sensitive and platinum resistant cancer cells. We can also leverage data from other cancers to potentially identify new treatments that can better target platinum resistant disease. This project is in collaboration with other researchers at UCLA.
Identifying Therapy Resistant Cells using CyTof
We hypothesize that platinum resistant ovarian cancer cells may have unique properties and characteristics compared platinum sensitive cells. To better understand the identity of tumor cells that evade chemotherapy, we are utilizing mass cytometry (CyTof) to identify a potential unique antigenic signature for platinum resistant tumor cells. This signature may help isolate and characterize pathways that lead to drug resistance.
In Vitro Assays to Predict Therapy Response
We are testing the ability of an in vitro 3D organoid drug assay to predict clinical response to cancer therapies using tumor biopsies from ovarian cancer patients. Such predictive in vitro assays (also called "disease in a dish" models) can be invaluable tools for the testing and implementation of precision medicine approaches for cancer therapy.
Within the tumor, there are many cell types that comprise the tumor microenvironment. Among these are immune cells that can be harnessed to help target tumor cells. In collaboration with other investigators at UCLA, we are exploring two mechanisms that utilize immune cells to target ovarian tumors: (1) ways to empower cytotoxic T cells to enhance the immune system's ability to fight cancer, and (2) developing a stem cell-derived immune cell (called an iNKT cell) that can specifically target ovarian tumors expressing mesothelin, a cell-surface protein that tends to be highly expressed in this disease.
Clinical Challenges in Endometrial and Other Uterine Cancers
The endometrium is a hormonally regulated and highly proliferative tissue, undergoing over 500 cycles of growth and shedding throughout a woman’s reproductive life. However, when pathways controlling this process become de-regulated, endometrial carcinoma (a tumor arising from epithelial glands lining the uterine cavity) may result. Endometrial cancer is the most common gynecologic cancer in the United States.
A major goal of our research is to identify regenerative stem populations of the endometrium. Dysregulation of pathways that control the growth of these cells could have major implications in development of many disease including benign conditions like endometriosis or infertility and also cancers of the endometrium.
Our Research in Endometrial and Other Uterine Cancer
To address clinical challenges in endometrial and other uterine cancers, our research group is focused on the following areas:
1. Identify a regenerative stem population of cells in the endometrium
2. Characterize genetics pathways that can initiate cancer
3. Developing models of uterine carcinosarcomas and testing new therapies for these tumors.
Identifying a Regenerative Stem Population of Endometrial Cells
Our group has established and published an in vivo murine endometrial regeneration model from dissociated endometrial epithelium and stroma. This is a malleable system that provided the means to investigate the regenerative capacity of specific subsets of endometrial cells. We are leveraging our expertise in this murine system to develop a similar model to uncover identity and pathways that regulate growth of human endometrial stem cells.
Genetic Pathways that can Initiate Gynecologic Cancers
In collaboration with other researchers at UCLA, we are exploring specific genetic alterations that can initiate cancer in normal gynecologic tissues. Using a combination of targeted genetic alterations, in vitro organoid models, and in vivo murine xenograft models, we are assessing the capacity for normal gynecologic cells of the endometrium, ovary, and fallopian tube to become cancerous.
Development of Models of Uterine Carcinosarcomas
Carcinomcarsomcas are another aggressive subtype of uterine cancer with limited treatment options. These tumors are characterized as having a dual phenotype with both epithelial (carcinomatous) and stromal (sarcomatous) features. Our group is (1) developing in vitro and in vivo models to study this disease, (2) studying potential ways to target carcinosarcomas, and (3) characterizing endometrial cells that may be precursors for these cancers.