The overarching theme of my research is overcoming mechanisms of therapy resistance in gynecologic cancers. As a clinician-scientist, my career goal is to develop more effective and less toxic therapies for women impacted by these tumors. 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 cancer treatment in general and we hope to move them into clinical trials.
A. Characterizing and profiling therapy resistant ovarian cancer tumor cells
Ovarian cancer has an annual incidence of about 22,000 cases in the United States. Carboplatin, a platinum-based chemotherapy, is the frontline treatment. Patients respond to this treatment initially, but experience relapse with therapy-resistant disease. The inability to predict response to carboplatin poses a clinical challenge. Patients are classified as having resistant disease after the tumor fails to respond or when relapse of disease occurs within 6 months of its administration. At this point, non-platinum based standard chemotherapies (Taxol, topotecan, and Doxil), or biologic agents (such as bevacizumab) are used with limited response. Given this clinical challenge, national guidelines recommend enrolling patients with platinum-resistant ovarian cancer into clinical trials. Rational design of these trials, which will entail testing combination therapies, require understanding unique therapeutic vulnerabilities in platinum-resistant ovarian cancer cells.
To understand the emergence of platinum-resistance in ovarian cancer, we are focused on identifying the unique antigenic signature of therapy-resistant ovarian cancer cells using cyTOF. A large panel of antigens is being investigated across different ovarian cancer cell lines and primary patient tumor samples. This may potentially lead to identification of biomarkers that may be utilized to predict a patient’s response to platinum-based chemotherapy. In parallel, we are utilizing an in vitro 3D miniring organoid assay to test the platinum sensitivity of patient ovarian cancer tumor samples. This may be adopted as a potential tool to predict chemotherapy response of the patients before drug administration.
Most chemoresistance studies in ovarian cancer are also limited by lack of a suitable in vivo models that can recapitulate the evolution of ovarian cancer cells during the course of chemotherapy. To address this problem, we are developing in vivo models using platinum-resistant patient-derived xenografts (PDX) to model the disease starting from proliferative cells to recurrent cells after platinum treatment. This research approach will offer a unique opportunity to investigate the therapy-induced changes in cancer cells using genetic and proteomic analyses.
B. Therapeutic targeting of platinum resistant gynecologic and ovarian cancer tumor cells
Resistance to platinum-based chemotherapy poses a significant clinical challenge for the treatment of patients diagnosed with aggressive gynecologic cancers. Development of platinum resistance is a complex and multifaceted process. We are investigating two potential reasons for therapy resistance in the laboratory: (1) overexpression of inhibitors of apoptosis proteins (IAPs) which can promote cancer cell survival by blocking apoptosis, and (2) alterations in the tumor suppressor p53 commonly found in aggressive gynecologic tumors. To address these two potential mechanisms that may mediate therapy resistance, we are investigating whether degradation of IAPs using a small molecule inhibitor can sensitize platinum-resistant ovarian cancer cells to the cytotoxic effects of carboplatin. In addition, we are investigating the efficacy of a structure-based peptide, called ReACp53, in targeting p53-mutated tumors of the gynecologic tract. We are testing if such combination therapies can better target ovarian cancer tumor cells.
C. Studying interactions between epithelia and stroma in normal and cancerous tissue.
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 preclinical model. 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. Using this model we found that deletion of PTEN in endometrial epithelia can initiate endometrial cancers that closely resemble human disease and progesterone hormone anti-tumor effects may be mediated through the stroma. In studying human samples we learned that levels of progesterone receptor expression in stroma could correlate with response to progesterone therapy in endometrial hyperplasia and cancer.
D. Ongoing collaborations
We are fortunate to collaborate with a multidisciplinary team of scientists at UCLA.
Ongoing collaboration with Dr. Lili Yang
Research focus: investigating strategies that may increase the ability of the body’s immune system to fight ovarian cancer
Ongoing collaboration with Dr. Thomas Graeber
Research focus: investigating the genetic profile of tumor cells before and after administration of chemotherapy to better understand mechanisms of therapy resistance
Ongoing collaboration with Dr. Owen Witte
Research focus: understanding genetic alterations that can transform normal human gynecologic tissues
Ongoing collaboration with Drs. Zoran Galic and Alex Garcia
Research focus: understanding the identity of therapy resistance tumor cells using CyTOF
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, the Veterans Administration, and several foundations including The Ovarian Cancer Circle/Inspired by Robin Babbini have helped fund her work. 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 and the Los Angeles City Council recognition for commitment to ovarian cancer research 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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