The overarching theme of my research is overcoming mechanisms of therapy resistance in carcinomas. As a clinician-scientist, my career goal is to develop more effective and less toxic therapies for women impacted by epithelial tumors of the gynecologic organs. We are making progress in this woefully understudied area by discovering the molecular and cellular underpinnings of these cancers and exploiting existing vulnerabilities pharmacologically. Our discoveries have broad applications to carcinomas in general and are moving into clinical trials.
A. Therapeutic targeting of platinum resistant tumor initiating cells in ovarian cancers
The development of effective therapies for ovarian cancer is crucial as outcomes have not improved significantly over the last several decades. The most prevalent and aggressive subtype of ovarian tumors is high-grade serous cancers (HGSC) a disease that more recently has been discovered to originate from the fallopian tube. A major challenge in treating HGSC is relapse of disease despite standard therapies.
This clinical observation suggests that a subset of HGSC cells with tumor initiating potential are resistant to therapy. Guided by our previous work in isolation of fallopian tube epithelial progenitors (Paik et al., 2012), we have characterized a sub-population of HGSC tumor cells with cancer initiating potential. The tumor initiating sub-populations of HGSCs do not express cell surface CA125, the most common biomarker used for detection of ovarian cancers. These cells are resistant to carboplatin standard therapy (Janzen, 2015). Current work in my laboratory is aimed at uncovering mechanisms of therapy resistance utilized by this cancer initiating population and finding pharmacologic strategies that can be used to eliminate them. For example with the addition of birinapant (a drug that degrades inhibitors of apoptosis proteins) to carboplatin we can eradicate the tumor initiating HGSC cells (Janzen, 2015). This therapy was effective in up to 50% of tumors tested in pre-clinical models. Other strategies are being tested including the efficacy of reactivating p53 mutated in 90% of HGSCs as a therapeutic approach (Soragni et al., 2016). We envision that our work in HGSCs will define new and more effective standards of treatment for patients with this aggressive cancer.
B. Defining mechanisms of hormone sensitivity and resistance in endometrial cancers
Hormonal therapy can be effective in up to 50% of endometrial tumors, but is not widely embraced in clinical practice due lack of lack of reliable biomarkers that can predict a favorable clinical response.
Estrogen drives endometrial carcinogenesis and the progesterone hormone opposes this effect. As a first step to gain mechanistic insight into stromal vs. epithelial signals that may modulate hormonal sensitivity, we established an endometrial cancer preclincal model (Memarzadeh et al., 2010). The power of this system is that we can independently induce genetic changes in epithelium or stroma in order to accurately recapitulate mutational patterns occurring in human tumors (Memarzadeh et al., 2010). Using this model we have made three key discoveries: (a) deletion of PTEN in endometrial epithelia can initiate endometrial cancers that closely resemble human disease (Memarzadeh et al., 2010), (b) progesterone hormone anti-tumor effects are mediated through the stroma and loss of stromal progesterone receptor expression is sufficient to induce progesterone resistance (Janzen et al., 2013b), and (c) PTEN-null endometrial tumors were sensitized to PARP inhibition in a low estrogenic hormonal milieu as estrogen levels modulated Rad51 protein expression and function (Janzen et al., 2013a).
The overall goal of our ongoing work is to elucidate mechanisms that govern progesterone sensitivity or resistance in endometrial carcinoma and discover strategies that can broaden the clinical utility of hormonal therapy in this disease. We hope that based on insights gained through our ongoing work we can develop a diagnostic tool that can help identify patients best suited for hormonal therapy.
Dr. Sanaz Memarzadeh is a board certified clinician-scientist. In the clinic she is a highly skilled cancer surgeon and cares for women with gynecologic cancers (ovarian, endometrial, vulvar, cervical and tubal cancers). In the laboratory, she is the director of the G.O. Discovery Laboratory team. She has an eye for research that is immediately applicable and translatable to patient care. In fact, every question asked in her laboratory is a biologic question born out of an important yet unanswered question from the clinic. She and her team thrive on doing research that will impact lives of patients from bench to bedside and back. The NIH, the American Cancer Society and several foundations fund her laboratory. She also has collaborations with the community to raise awareness and funds for women’s cancer research. She is the recipient of multiple awards including an APGO excellence in teaching award, STOP cancer career development and seed awards, a Kimmel Translational Scholar’s award, a Concern Foundation award to name a few. One of her major goals is to help train the next generation of scientists that will help revolutionize medicine as practiced today.
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