Funded Research: 2019
Kalpana Deepa Priya Dorayappan
Targeting the PGE2 EP4 receptor as a mechanism for improved chemotherapeutic response in epithelial ovarian cancer
Ovarian cancer is the most lethal of the gynecological cancers. The high mortality rate arises from the lack of effective methodologies for early detection of the disease; thus, the majority of patients present at an advanced stage. This urges the need for early diagnosis to decrease the morbidity and mortality of ovarian cancer. Earlier studies have shown the elevation of Acute-phase proteins (APP) in ovarian cancer but currently none are used as a specific bio-marker in ovarian cancer due to lack of specificity and sensitivity in the detection. Sustained oxidative stress produces reactive oxygen species that lead to chronic inflammation by triggering the release of pro-inflammatory mediators or acute phase proteins which in turn could mediate chronic diseases such as cancer. This study is an attempt to investigate a specific signature of APR in the cancer exosomes from ovarian cancer cell lines detected by Mass spectrometry and analyzed by Bio-informatics tools – Ingenuity Pathway Analysis (IPA) to be considered as potential candidates for biomarkers. For this we are using an orthotopic mouse tumor model to confirm the presence of this protein signature at the pre-clinical level by different laboratory techniques and further confirm these proteins at the clinical level in the patient’s serum exosome samples along with the existing gold standard CA-125 by developing an exosome based protein array (EPA). This study will lead to the finding of exosome based sensitive and specific acute phase protein markers for early detection in ovarian cancer thus reducing the mortality rate.
Application of Photoreactive Probes and Fiberoptic Devices for Detection of Fallopian Tube. Transformation in Organotypic Model of Ovarian Cancer.
Continuous metastatic evolution and adaptation of high-grade serous ovarian carcinoma (HGSOC) to therapy remain a significant clinical challenge in treating patients presenting with disseminated disease. Therefore, it is of the highest importance to develop strategies that would identify transformed epithelial cells before dissemination occurs. Recent studies have traced the origin of disseminated HGSOC to mutant p53 (m-p53) positive fallopian tube secretory epithelial cells (FTSEC). Our group provided evidence that the transformation of human FTSEC with m-p53 promoted cell surface expression of integrins and matrix that supported anchorage-independent survival and mesothelial clearance the phenotypes associated with dissemination of HGSOC. These reports highlight the importance of utilizing FTSEC as a model system of early events of ovarian carcinogenesis. We recently found that FTSEC expressing m-p53 (m-p53-FTSEC) have significantly upregulated other cell surface molecules that could be exploited for early detection of FTSEC transformation. Based on these findings and motivated by the studies that implicate utilization of tissue surface staining to detect cell surface of early esophageal cancer cells, we hypothesize that early transformation of FTSEC leads to upregulation of cell surface molecules that can be detected in live FTSEC organotypic cultures using photo-chemically modified ligands and optical tools that uniquely recognize malignant cells confined to a small area. This collaborative project among the laboratories of Marcin Iwanicki (Chemical Biology) Jinho Kim (Bioengineering), Sunil Paliwal (Chemical Biology) will utilize chemistry, organotypic culture, live-cell microscopy, fiberoptic, and matrix engineering to develop tools for detection of fallopian tube cell transformation in organotypic cultures composed of normal and transformed FTSEC.
Zvi Yaari, Ph.D,
Implantable Nanosensor for Early-Stage Detection of Ovarian Cancer
Dr. Zvi Yaari is currently a postdoctoral research fellow at the Memorial Sloan Kettering Cancer Center, (MSKCC) New York City, NY in the laboratory of Dr. Daniel A. Heller. Dr. Yaari received his B.Sc., M.Sc and Ph.D in Chemical Engineering from the Technion – Israel Institute of Technology. During his Ph.D studies, Dr. Yaari designed a high-throughput screening technology for selecting cancer patients with the most potent anticancer agent in a personalized manner. The technology is based on barcoded liposomes that contain various anticancer agents and a unique dsDNA as a barcode that corresponds with the drug activity. This technology allows screening various of agents simultaneously inside the patient’s body and has a single cell resolution. Dr. Yaari found out that the goal of his life is to harness his engineering skills to create new technologies for improving cancer care in general and help cancer patients in particular. For him, Memorial Sloan Kettering Cancer Center (MSKCC) is the ultimate institution to achieve this goal.
Dr. Yaari’s current research focus is on creating an implantable nanosensor for early-stage detection of ovarian cancer. He is designing a nano sensor that is based on Single Walled Carbon Nanotubes (SWCNTs). The SWCNTs allow detection in very high sensitivity and precision due to their unique photoluminescence properties in the near infrared (NIR) range. Currently he is studying how the interactions of the SWCNTs with various of ovarian cancer biomarkers can cause a shift in the emitted wavelengths or affect the emitted intensity. The goal is to implant the sensor inside an intrauterine device (IUD) and to monitor the initiation and progression of ovarian cancer. Dr. Yaari is mentoring graduate students and collaborating with clinicians and product engineers.
Dr. Yaari received several awards for his graduate work, including the Dan David Prize, Rappaport Prize, Jacobs Excellence Award, Prize for Excellence in Science from the Department of Chemical Engineering and the 1st Prize for outstanding graduate research from The Israeli Chapter of the Controlled Release Society (ICRS).