Funded Research: 2015

RACHEL N. GRISHAM, M.D.
Gynecologic Medical Oncology Service
Memorial Sloan Kettering Cancer Center

Deciphering the Biologic Predictors of Response to Targeted Therapy in Low Grade Serous Ovarian Cancer

Low-grade serous (LGS) ovarian cancer is a rare type of ovarian cancer that is profoundly resistant to standard chemotherapy options. Patients with LGS ovarian cancer typically present at a young age, have a protracted clinical course, and frequently display mutations in the MAP Kinase pathway, a pathway that can lead to cancer cell growth. Studies have shown promising results for the use of targeted therapies that inhibit the MAP Kinase pathway for treatment of LGS ovarian cancer. LGS ovarian cancer has also been shown to display a high level of expression of the estrogen, progesterone, and/or androgen receptors; however whether these correlate with response to hormonal therapy remains unclear. The current project aims to determine biologic markers that predict for response to targeted therapy with either MEK inhibitors (a class of drugs that inhibit the MAPK pathway) or hormonal therapies.

Firstly archived tumor and blood from patients with LGS ovarian cancer who were treated with MEK inhibitors will be evaluated utilizing a specialized sequencing approach to determine what molecular alterations predict for response to treatment with MEK inhibition.
Secondly, immunohistochemistry will be utilized to determine the level of estrogen, progesterone, and androgen receptor positivity in the archived tumor samples from patients with LGS ovarian cancer who were treated with hormonal therapies and receptor positivity correlated with response. The overarching goal of these efforts is to determine which patients are most likely to benefit from treatment with targeted therapies, allowing for a personalized approach to treatment of this chemotherapy-resistant disease.

Lilie Lin, M.D.
Assistant Professor of Radiation Oncology at the University of Pennsylvania

Pilot Study of a Novel PARP Inhibitor PET Tracer in Ovarian Carcinoma

Ovarian cancer represents the most common cause of death from gynecologic cancer. The majority of women  (>70%) are diagnosed with advanced stage (stage III/IV) and despite standard treatment, the majority of  patients recur and die from their disease. Targeted agents such as poly ADP ribsose polymerase (PARP)  inhibitors are actively being tested alone or in combination with chemotherapy or radiotherapy, however, we  know that not all patients will benefit from these therapies. Ideally, incorporation of such targeted drugs into  therapy for ovarian cancer would be reserved for patients who are most likely to benefit, however, current  technologies are unavailable to identify a priori which patients may benefit. Given these considerations and  others, it becomes apparent that the clinical management of ovarian cancer would be greatly aided by  biomarkers that can predict at the time of relapse, whether a patient has cancer that is either resistant or  sensitive to the targeted agent. The goal of this project is to test whether a novel PARP inhibitor Positron  Emission Tomography (PET) tracer can co-localize to areas of known ovarian cancer and will correlate with  PARP1 activity in tumor biopsies of patients as well as in an in vivo rodent model of ovarian carcinoma.  Developing a non-invasive method to image ovarian cancer patients and identify those who have elevated  PARP activity is the first step in helping us validate this novel PARP PET tracer as a predictive biomarker and  would thereby allow us to better select patients that may benefit from PARP inhibitor therapies

2015 Grant Recipient for Continued Funding: George Preti, Ph.D.
Monell Chemical Senses Center

A Novel Multidisciplinary Approach to Development of an Effective Ovarian Cancer Screening Diagnostic using Volatile Biomarkers.

My laboratory is perhaps the only one in the United States performing basic research into the nature, biogenesis and function of human body odors. We apply organic-analytical chemistry techniques to human subjects, in vivo. In addition to performing collaborative research in the chemical senses. I have a career-long interest in the chemistry of human body odors and how human diseases produce and may be recognized from the odorants they produce. I have more than forty years of experience in the operation, maintenance and interpretation of data from mass spectrometers, beginning with my graduate training in the laboratory of Professor Klaus Biemann, at MIT. Therefore, we focus upon a mass spectrometry-enabled approach into the nature and origin of human odors, particularly those from the skin, underarm (axillae) and the oral cavity. We have also done extensive collaborative research with Monell’s sensory scientists to examine the sensory qualities of human odorants, their olfactory thresholds and how to block their perception.
Because of our fundamental studies into human odor production, our laboratory is the focal point for referrals of individuals with long-standing malodor production of unknown origin. Our analytical and sensory techniques, applied to these patients, have revealed a large, undiagnosed population of people with trimethylaminuria. We have also developed methods for symptom amelioration in these patients. Consequently, working with and sampling human subjects is a routine activity in the Preti lab.
Our lab is also pursuing the structures of the active pheromone constituents via a bioassay-guided isolation procedure as well as employing gas chromatography-mass spectrometry to generate metabolic profiles (“metabolomics”) of human blood, skin, cerumen and axillary secretions to identify biomarkers of disease (skin and ovarian cancer), individual identity (human odorprints) and stress-related odors.

Dr. Cynthia Otto
University of Pennsylvania,
School of Veterinary Medicine