Engineering hope for women with cancer
The clinical problem
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. Exposure to estrogen, unopposed by progesterone, is one mechanism by which endometrial cancer can occur. Endometrial carcinoma can also occur spontaneously as a result of genetic changes in the endometrial epithelia or stroma. Currently, the standard treatment for endometrial cancer entails surgical removal of the uterus.
Administration of progesterone is an alternative treatment option for patients who want to preserve fertility or as an alternative to chemotherapy if the cancer is recurrent. Clinical response to progesterone can range from 11-50% in recurrent cancers, and is higher in low grade cancer and hyperplasia. There are currently no reliable biomarkers that can predict a favorable response to this treatment. In tumors that do demonstrate a positive response to progesterone therapy, the anti-tumor mechanism and site of action for progesterone remain unknown. Therefore, even though endometrial cancer is hormonally driven, hormonal therapy continues to be underutilized in this disease.
"We are completely committed to making advancements in the treatment of gynecologic cancers."
Work in our laboratory is focused on: (1) discovering why some endometrial cancers can be effectively treated with progesterone therapy while others cannot and (2) finding determinants that can predict this response. We are also looking to discover alternative non-surgical therapeutic options that can be used for the treatment of progesterone resistant endometrial cancers.
To facilitate examination of pathways involved in normal endometrial regeneration and endometrial cancer, we established 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. Using this model, we uncovered a signature that marks the epithelial progenitors of the endometrium that have regenerative capacity. We found that this pool of cells expanded in response to estrogen and progesterone as the uterus prepared for implantation of embryos, and decreased if pregnancy was not established. We are working toward setting up a similar in vivo regeneration system using human tissue.
This model can also be used to test the consequences of cell autonomous or paracrine genetic changes and assay for in vivo therapeutic response in established tumors. In this model, epithelial-specific deletion of the PTEN tumor suppressor (the most common genetic change found in endometrial cancer) resulted in the formation of tumors that recapitulated features of human endometrial carcinomas. These tumors were exquisitely sensitive to progesterone therapy. However, addition of a single common genetic change to these epithelial cells (activation of Kras) resulted in the formation of tumors that were refractory to progesterone therapy. We found that the dichotomous response to these to tumors to progesterone therapy resulted from differential expression of Progesterone Receptor (PR) in the tumor stroma. This finding led to the discovery that stromal PR expression was necessary and sufficient to mediate a therapeutic response to progesterone in this mouse model of endometrial cancer. Currently, our laboratory is investigating whether these findings will translate to human disease.
The endometrial regeneration system has been utilized to test other therapies for endometrial cancers. Deletion of PTEN has been suggested to compromise the ability of cells to undergo homologous recombination (HR) DNA repair. This defect could make these cells susceptible to synthetic lethal cell death when treated with PARP inhibitors such as Olaparib. We found that endometrial tumors driven by epithelial deletion of PTEN were resolved with Olaparib therapy, but only when the drug was administered in conjunction with estrogen depletion. High levels of estrogen counteracted Olaparib therapy through increased metabolism of the Olaparib drub and upregulation of HR repair pathway proteins. This finding contrasts sharply with progesterone therapies in the endometrial regeneration model, where we found co-administration of estrogen and progesterone was essential for successful therapy. Current work in the laboratory is exploring the role of estrogen signaling through estrogen receptor alpha in maintenance and therapy of endometrial tumors.
The clinical problem
High grade serous ovarian carcinoma (HGSC), the most common form of ovarian cancer, is an aggressive and highly metastatic cancer of the ovarian epithelia. Despite initial positive response to surgery and platinum based chemotherapy, up to 85% of patients relapse. We have identified a subset of tumor cells that are resistant to therapy and are able to regrow the tumor after treatment. Targeting these therapy resistant, regenerative cancer cells using novel combination therapies is a main focus of our work.
"By sharing the stories of these women, people are going to see what ovarian cancer is."
Our work in this field is roughly divided into two components: (1) identifying the tumor cells and cellular mechanisms responsible for therapy resistance and relapse of cancer and (2) discovery of new combination therapies that target these cells and mechanisms of resistance. This work began by investigating the regenerative cells of the normal fallopian tube (a known precursor for serous ovarian cancer). Determining the cell surface expression profile of regenerative cells in the fallopian tube epithelia led to the identification of a subset of cells found in all HGSC tumors tested that were resistant to platinum-based chemotherapy and tumor initiating.
In collaboration with the labs of Dr. David Eisenberg and Dr. Alice Soragni (both UCLA), we have also worked to develop an additional novel combination therapy that targets a commonly mutated gene found in up to 90% of HGSCs: p53. Known as the guardian of the genome, p53 regulates many cell functions including gene transcription, apoptosis, and cell proliferation. Mutations in p53 are implicated in many cancers and can cause either a loss of p53 tumor-suppressing function or a gain of function that results in increased tumor cell proliferation. One subtype of p53 mutation causes a misfolding of the protein, exposing hydrophobic amino acid residues which results in aggregation of misfolded p53 within the cytosol. Aggregation of the protein prevents p53 from entering the nucleus and performing its gene-regulatory function. Ongoing work is focused on investigating ReACp53 which can rescue the wild-type phenotype of p53 carrying an aggregating mutation in combination with platinum therapy.
We also seek to better understand the cellular composition of HGSCs and how individual cellular subtypes within the tumor contribute to the overall pathogenesis of this disease. We’ve identified potential factors that are highly enriched in the tumor cells that are most therapy resistant and tumorigenic. These factors may play an essential role in the initiation and/or maintenance of HGSC tumors. In parallel, we are investigating how cells of the tumor microenvironment support tumor growth and possibly mediate therapy efficacy. Part of this work is examining the role that tumor infiltrating immune cells may play in sensitizing HGSCs to targeted therapies.