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Bioanalytical platform for identification and validation of ovarian cancer biomarkers in tissues and proximal fluids
PROJECT & PROGRESS SUMMARY
High-grade serous ovarian carcinoma (HGSC) is the most common subtype of ovarian malignancy. Recent studies suggest that the majority of HGSC arise from the fallopian tube. The goal of our project is to leverage model systems and relevant clinical tissues designed around this clinical observation with state-of-the-art mass spectrometry technology to identify biomarkers suitable for early detection of ovarian cancer. With our previous support from the Brozman Foundation we successfully identified several proteins secreted by fallopian tube epithelia cells genetically engineered to mimic the discrete stages of malignant transformation. Promising candidates include, Elafin, CRABP2, S100A4, FLG/FLG2. In this proposal we will (Aim 1) expand the set of oncogene drivers in our fallopian tube models and extend the notion of oncogenic excreted factors to include the protein cargo of exosomes released from these cells. As part of our renewal proposal, we will extend our studies to include clinically relevant tissues. In this Aim we will pursue identification of protein biomarker candidates in tumor-proximal HGSC ascites compared to control fluids. In Aim 2 we will explore the cell-of origin hypothesis directly in clinical tissues through proteomic analysis of paraffin embedded benign fallopian tubes and HGSC tumors. In addition, we will undertake a high-risk pilot project to identify unbiased proteomic signatures of micro dissected fallopian tube precursor lesions. Extending the ‘proteomic reach’ of our bioanalytical platform to these clinically relevant tissues provides a powerful complement for our FTSEC models and may dramatically accelerate our ability to identify candidate HGSC biomarkers for more intensive validation studies.
Q&A WITH DR. DRAPKIN
Q: How would you explain the broader significance of your research to a layperson?
A: Our lab (and the Penn Ovarian Cancer Research Center) is entirely focused on finding new ways to detect and treat ovarian cancer. We use a multi-pronged approach to achieve this goal. We try to understand some of the basic fundamental biology that makes ovarian cancer tick and leverage that knowledge towards ways to help patients. In regards to early detection, developing a tool that can achieve this is the holy grail in the field.
Q: What is the job of a scientific medical researcher on a day to day basis? For example, what did you do this morning?
A: The daily job of a scientist depends on the stage of his/her career. A graduate student spends most of their days (and sometimes nights) working on ‘the bench’ (in the lab) doing experiments and troubleshooting problems. A postdoctoral fellow also spends most of his or her time at the bench but with greater responsibility and with an eye to the future. It is as a postdoctoral fellow that you have to hone your writing and presenting skills as these will be critical in achieving and sustaining an independent career. As a lab head or principle investigator (PI), your job is to provide the scientific intellectual thrust being conducted by the graduate students and postdocs. As the PI you also spend a lot of time writing grants and fundraising for one’s own lab.
Q: Would you say that you chose ovarian cancer research or ovarian cancer research chose you?
A: When I was a postdoctoral fellow I was working in a lab that studies BRCA1, the gene responsible for many hereditary forms of breast and ovarian cancer. However, at the time, most of the focus was on breast cancer. Ovarian cancer was considered a ‘black box’ and few resources existed to support its research. Being a physician, I found this disturbing because it was such a devastating disease. I wanted to see the ‘concert for the cure’ and the ‘race for the cure’ exist for ovarian cancer just like for breast cancer. Scientifically, I thought ovarian cancer represented a great opportunity to make significant contributions and I began by attacking the most vexing problem, the lack of an early detection tool.
Q: Who have been your most influential mentors throughout your career?
A: I have been fortunate to work with some amazing scientists during my career. My undergraduate thesis advisor, Dr. James Haber, a member of the National Academy of Science, showed me how simple model systems can help us ask and answer big questions that are relevant to the human condition. My graduate adviser, Dr. Danny Reinberg, a Howard Hughes Medical Institute investigator and National Academy member, taught me the importance of hard work and being rigorous in my approach to science. My postdoctoral mentor, Dr. David Livingston, also a National Academy member, taught me the importance of being creative and thinking ‘outside the box’. My clinical mentor, Dr. Chris Crum, taught me the importance of understanding unmet medical needs and letting that drive my science. I have been tremendously fortunate to have these scientists as my mentors and colleagues.
Q: What was your proudest moment or biggest achievement during your career thus far?
A: My proudest moments include insights that I made in all three phases of my training:
1) As a graduate student I made the link between transcriptional regulation and DNA repair. We found that the xeroderma pigmentosum proteins involved in DNA repair were also playing vitally important roles in regulating gene expression.
2) As a postdoctoral fellow I showed that the HE4 biomarker is a protein that is enzymatically modified and secreted by the most common forms of ovarian cancer. These observations contributed to its eventual approval as an ovarian cancer biomarker by the FDA. I was also involved in the cloning of BRIP1/FANCJ, an important gene in the BRCA network of DNA repair proteins and showed that it is a protein that can unwind DNA.
3) As an independent investigator working together with my clinical mentor, Chris Crum, we showed that the fallopian tube is the likely site of origin for a majority of high-grade serous ovarian carcinomas. This has proven to be a paradigm shift in the field and motivated my lab to develop novel experimental model systems to study the fallopian tube and figure out what makes it susceptible to becoming a cancer.
Q: Have you been personally affected by ovarian cancer?
A: One of my good friends in high school lost his mother to ovarian cancer when we were teenagers. Cancer was more of a mystery to me at that time but I vividly remember how devastating it was for the family. Later on, as an adult, when I lost my two in-laws to cancer, I came to fully appreciate how cancer affects an entire family, not just the patient, and how good compassionate care can really help a whole family and community cope with the challenge of cancer treatment and the loss of a loved one.
Q: What do you do when you are not working?
A: I enjoy time with my wife and two kids. I also enjoy cycling, skiing, playing basketball with my daughter who is on the girls varsity basketball team, and, more recently, some ‘wicked good’ ping-pong games with my son. I am also a huge New England sports fan and love to go to games when possible.
Q: Tell us a fun fact about yourself.
A: I was born in Chile, lived in Israel for 7 years, before moving to NYC where I started elementary school in 2nd grade.