Analisa DiFeo
Job Description
Our laboratory’s work spans the translational research continuum, beginning with an in-depth analysis of patient tumors and progressing to a functional assessment of key genetic drivers of ovarian cancer progression and the development of a novel therapeutic approach to abrogate these drivers to uncover therapies that will improve ovarian cancer patient survival. To accomplish this, we focus on three major areas: 1) generation of clinically relevant gynecological cancer models, 2) discovery of potent genetic drivers with a focus on microRNAs involved in tumor initiation, drug resistance and recurrence, and 3) development of novel or re-purposed drugs.
1) Generation of clinically relevant gynecological cancer models.
Since the inception of the DiFeo lab, we have devoted a substantial amount of time to fostering collaborations with clinicians in order to build a well-integrated research program that would promote patient-focused, impactful research ideas and permit the development of a large repository of gynecologic tumors. Therefore, I have organized several translational research programs focused on gynecological cancer in New York, Cleveland, and Michigan. Currently, I am the Director of the Michigan Ovarian Cancer Science and Innovation Consortium (MOSAIC) and the co-PI of the gynecologic cancer tumor repository through these programs my laboratory has been able to collect over 500 advanced stage uterine and ovarian tumors. Most importantly, we have developed and fully characterized numerous patient-derived cell lines, organoids, and xenografts (PDX) which conserve original tumor characteristics such as heterogeneous histology, clinical biomolecular signature, malignant phenotypes and genotypes. Given that several studies have shown that many of the commercially available ovarian cancer cell lines do not recapitulate the genomic signature of patient tumors this resource has been used by investigators across the country. We have shared these models with numerous collaborators in the scientific community as well as licensed these models to various company’s, which has led to the discovery of novel therapeutic targets, biomarkers, patent applications, and drugs. In addition, the DiFeo lab has established numerous sponsored research agreements with pharmaceutical company’s to identify biomarkers and determine drug efficacy in ovarian and uterine PDX models.
2) Identifying functional drivers involved in ovarian cancer progression.
Our lab played a central role in defining KLF6 and its novel oncogenic splice variant, KLF6-SV1, as a key regulator of several human malignancies. Our findings were the first to demonstrate that the large majority of ovarian cancer tumors have increased expression of the oncogenic KLF6-SV1 isoform and high levels of this protein correlated with increased tumor aggressiveness. Furthermore, through these studies we discovered the KLF6-SV1 was a novel anti-apoptotic protein that targets the pro-survival molecule NOXA for degradation and its targeted inhibition extends survival ovarian cancer. These studies resulted in 18 publications during my doctoral and early post-doctoral studies in journal such as Science Translational Medicine, Journal of Clinical Investigation, Cancer Research, Clinical Cancer Research and Oncogene.
Currently, our laboratory is focused on uncovering functional microRNA:mRNA pathways driving ovarian cancer chemotherapy resistance and disease recurrence. We uncovered that microRNA-181a is a oncoMIR wherein it is frequently overexpressed in recurrent, platinum-resistant high-grade serous ovarian cancer (HGSC) and correlates with shorter time to recurrence and poor overall survival. Mechanistically, miR181a contributes to cellular transformation, metastasis initiation, and tumor recurrence by modulating chromosomal instability, EMT, and stemness factors via direct regulation of STING, TGFβ, and Wnt. Most recently, we have shown that in both immunodeficient and immunocompetent HGSC mouse models, targeted inhibition miR181a resulted in decreased tumor dissemination, ascites accumulation and increased sensitivity to immunotherapy. These studies have resulted in the numerous publications including two in Nature Communications. In addition, this research provides the rationale for determining whether pharmacological inhibition of miR181a can simultaneously inhibit the key signaling pathways implicated in cancer progression and significantly enhance patient survival. This work has resulted in the development of novel tools, such as a miR181a biosensor and a miR181a transgenic mouse, thereby laying the groundwork for future scientific endeavors and resources.
3) Development of novel or re-purposed drugs to treat platinum-resistant cancer.
The development of resistance to first-line chemotherapeutics most notably platinum-based therapies leaves few options for the clinical management of advanced ovarian cancer. Therefore, circumventing tumor resistance to commonly used first-line agents represents a very important aspect of multiple initiatives to eliminate ovarian cancer. Thus, another focus of our laboratory is to uncover the underlying mechanism of platinum resistance and to develop therapeutic strategies to treat recurrent, chemotherapy resistant disease. Through the development of numerous platinum resistant isogenic primary cell lines as well as patient-derived xenograft models we have uncovered several targetable pathways that can sensitize cells to platinum-based therapies. For example, we are the first to show that altered glutamine metabolism contributes to platinum resistant ovarian cancer and that targeting glutamine metabolism together with platinum-based chemotherapy offers a potential treatment strategy particularly in drug resistant ovarian cancer. Furthermore, we have recently found that small molecule mediated stabilization of protein phosphatase 2A (PP2A) modulates the Homologous Recombination pathway and potentiates DNA damage-induced cell death. These studies led to the discovery that PP2A modulators can surmount PARP inhibitor insensitivity, and that the combination of PP2A modulators and PARP inhibitors is a novel therapeutic approach for treating recurrent ovarian cancer. The findings from this research also culminated to a patent application, two grants from the Department of Defense, and a sponsored research agreement with Rappta Therapeutics, the company that licensed these drugs.
