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610 Charles E. Young Drive East
3017 Terasaki Life Sciences Building
Los Angeles, CA 90095
200 Medical Plaza, Suite 220
Los Angeles, CA 90095
|Professor, Obstetrics and Gynecology, Biological Chemistry|
|Member, Gynecologic Oncology, Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research, Gynecologic Endoscopy, JCCC Cancer and Stem Cell Biology Program Area, Molecular Pharmacology GPB Home Area|
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.
Soragni Alice, Janzen Deanna M, Johnson Lisa M, Lindgren Anne G, Thai-Quynh Nguyen Anh, Tiourin Ekaterina, Soriaga Angela B, Lu Jing, Jiang Lin, Faull Kym F, Pellegrini Matteo, Memarzadeh Sanaz, Eisenberg David S A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas. Cancer cell. 2016; 29(1): 90-103.
Janzen D M, Tiourin E, Salehi J A, Paik D Y, Lu J, Pellegrini M, Memarzadeh S An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nature communications. 2015; 6: 7956.
Tiourin Ekaterina, Velasco Victor S, Rosales Miguel A, Sullivan Peggy S, Janzen Deanna M, Memarzadeh Sanaz Tubal Ligation Induces Quiescence in the Epithelia of the Fallopian Tube Fimbria. Reproductive sciences (Thousand Oaks, Calif.). 2015; .
Janzen Deanna M, Paik Daniel Y, Rosales Miguel A, Yep Brian, Cheng Donghui, Witte Owen N, Kayadibi Huseyin, Ryan Christopher M, Jung Michael E, Faull Kym, Memarzadeh Sanaz Low Levels of Circulating Estrogen Sensitize PTEN-null Endometrial Tumors to PARP Inhibition In Vivo. Molecular cancer therapeutics. 2013; .
Janzen Deanna M, Rosales Miguel A, Paik Daniel Y, Lee Daniel S, Smith Daniel A, Witte Owen N, Iruela-Arispe M Luisa, Memarzadeh Sanaz Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy. Cancer research. 2013; .
Paik Daniel Y, Janzen Deanna M, Schafenacker Amanda M, Velasco Victor S, Shung May S, Cheng Donghui, Huang Jiaoti, Witte Owen N, Memarzadeh Sanaz Stem-Like Epithelial Cells are Concentrated in the Distal End of the Fallopian Tube: A Site for Injury and Serous Cancer Initiation. Stem cells (Dayton, Ohio). 2012; .
Cai Houjian, Memarzadeh Sanaz, Stoyanova Tanya, Beharry Zanna, Kraft Andrew S, Witte Owen Collaboration of Kras and Androgen receptor signaling stimulates EZH2 expression and tumor propagating cells in prostate cancer. Cancer research. 2012; .
Janzen Deanna M, Cheng Donghui, Schafenacker Amanda M, Paik Daniel Y, Goldstein Andrew S, Witte Owen N, Jaroszewicz Artur, Pellegrini Matteo, Memarzadeh Sanaz Estrogen and progesterone together expand murine endometrial epithelial progenitor cells. Stem cells (Dayton, Ohio). 2012; 31(4): 808-22.
Memarzadeh Sanaz, Cai Houjian, Janzen Deanna M, Xin Li, Lukacs Rita, Riedinger Mireille, Zong Yang, DeGendt Karel, Verhoeven Guido, Huang Jiaoti, Witte Owen N Role of autonomous androgen receptor signaling in prostate cancer initiation is dichotomous and depends on the oncogenic signal. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(19): 7962-7.
Cai Houjian, Smith Daniel A, Memarzadeh Sanaz, Lowell Clifford A, Cooper Jonathan A, Witte Owen N Differential transformation capacity of Src family kinases during the initiation of prostate cancer. Proceedings of the National Academy of Sciences of the United States of America. 2011; 108(16): 6579-84.
Lukacs Rita U, Memarzadeh Sanaz, Wu Hong, Witte Owen N Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell stem cell. 2010; 7(6): 682-93.
Memarzadeh Sanaz, Zong Yang, Janzen Deanna M, Goldstein Andrew S, Cheng Donghui, Kurita Takeshi, Schafenacker Amanda M, Huang Jiaoti, Witte Owen N Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(40): 17298-303.
Lawson Devon A, Zong Yang, Memarzadeh Sanaz, Xin Li, Huang Jiaoti, Witte Owen N Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proceedings of the National Academy of Sciences of the United States of America. 2010; 107(6): 2610-5.
Nosov Vladimir, Park Susan, Rao Jianyu, Memarzadeh Sanaz Non-Peutz-Jeghers syndrome associated ovarian sex cord tumor with annular tubules: a case report. Fertility and sterility. 2009; 92(4): 1497.e5-8.
Memarzadeh Sanaz, Xin Li, Mulholland David J, Mansukhani Alka, Wu Hong, Teitell Michael A, Witte Owen N Enhanced paracrine FGF10 expression promotes formation of multifocal prostate adenocarcinoma and an increase in epithelial androgen receptor. Cancer Cell. 2007; 12(6): 572-85.
Memarzadeh S, Lee S B, Berek J S, Farias-Eisner R CA125 levels are a weak predictor of optimal cytoreductive surgery in patients with advanced epithelial ovarian cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2004; 13(2): 120-4.
Memarzadeh S, Holschneider C H, Bristow R E, Jones N L, Fu Y S, Karlan B Y, Berek J S, Farias-Eisner R FIGO stage III and IV uterine papillary serous carcinoma: impact of residual disease on survival. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2004; 12(5): 454-8.
Memarzadeh Sanaz, Natarajan Sathima, Dandade Dipika P, Ostrzega Nora, Saber Peter A, Busuttil Ashley, Lentz Scott E, Berek Jonathan S Lymphovascular and perineural invasion in the parametria: a prognostic factor for early-stage cervical cancer. Cancer Cell. 2003; 102(3): 612-9.
Ide Hisamitsu, Seligson David B, Memarzadeh Sanaz, Xin Li, Horvath Steve, Dubey Purnima, Flick Maryann B, Kacinski Barry M, Palotie Aarno, Witte Owen N Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99(22): 14404-9.
Memarzadeh Sanaz, Kozak Katherine R, Chang Lisbeth, Natarajan Sathima, Shintaku Peter, Reddy Srinivasa T, Farias-Eisner Robin, Memarzedeh Sanaz Urokinase plasminogen activator receptor: Prognostic biomarker for endometrial cancer. Proc. Natl. Acad. Sci. U.S.A. 2002; 99(16): 10647-52.
Memarzadeh S, Berek J S Advances in the management of epithelial ovarian cancer. The Journal of reproductive medicine. 2001; 46(7): 621-9; discussion 629-30.
Behboo R, Carroll P B, Memarzadeh S, Zeevi A, Conrad B, Rastellini C, Rao A S, Ricordi C Improved long-term culture of functional human islets in serum-free medium. Transplantation proceedings. 1994; 26(6): 3301.