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High-probability grants
According to our matching algorithm, Sanaz Memarzadeh is the likely recipient of the following grants.
| Years |
Recipients |
Code |
Title / Keywords |
Matching
score |
| 2015 — 2017 |
Memarzadeh, Sanaz |
U54Activity Code Description:
To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Parp Inhibition With Hormonal Modulation as a Therapy For Pten Driven Endometrial Tumors @ University of California Los Angeles
Abstract Endometrial carcinomas are hormonally driven and the leading gynecologic cancer in the U.S. Loss of PTEN function is identified in up to 80% of these tumors. Current therapies for advanced and recurrent cancers have limited efficacy, and outcomes are particularly poor in minorities such as black women who have a 60% greater chance of dying from uterine cancer compared to white patients. PARP inhibitors are orally administered drugs that selectively kill cells with defects in the DNA homologous repair (HR) pathway. Using an in vivo mouse model we have demonstrated that Olaparib, an oral PARP inhibitor, can effectively target endometrial tumors with PTEN-loss as a sole genetic change in an estrogen deprived hormonal milieu. We hypothesize that (a) PTEN dysfunction is sufficient to sensitize endometrial tumors to PARP inhibition despite the presence of cumulative genetic changes and (b) a hyper-estrogenic state commonly seen in endometrial cancer patients induces increased expression and function of HR pathway proteins causing resistance to PARP inhibitors. To test these hypotheses we will utilize (a) an endometrial cancer mouse model developed by our laboratory that closely recapitulates human disease and (b) human endometrial cancers banked at the Drew and UCLA bio-repositories. Both PARP and aromatase inhibitors are orally administered agents that are inexpensive, better tolerated and more easily administered compared to chemotherapy and radiation. Our proposed therapy if effective could decrease treatment disparities by making outpatient therapies for endometrial cancer more readily available to low-income and minority patients. Additionally, if PARP inhibition is found to be effective against aggressive endometrial cancers, their use could potentially increase survival outcomes for black women who are disproportionately affected by advanced cancers.
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| 2015 — 2019 |
Memarzadeh, Sanaz |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Pathobiology and Mechanism of Progesterone Resistance in Human Endometrial Cancer @ University of California Los Angeles
DESCRIPTION (provided by applicant): Endometrial cancer is a common and hormonally driven tumor. Progesterone, which exerts its effects through the progesterone receptor (PR), can be an effective therapy for subsets of endometrial cancer patients. Due to limited understanding of pathobiology of endometrial cancer, hormonal therapy is not widely embraced as a treatment option. With progression to cancer, endometrial PR signaling may change resulting in progesterone resistance. The molecular mechanisms underlying progesterone insensitivity are unknown. The overall goal of this proposal is to elucidate the pathobiology and mechanisms that cause progesterone resistance in endometrial carcinoma and to discover strategies that can broaden the clinical application of progesterone therapy. This proposal is based on following innovative observations from my laboratory: 1) Epithelial specific loss of PTEN in a physiologically relevant mouse model results in endometrial tumors that closely recapitulate human disease; 2) tumors resulting from epithelial loss of PTEN are progesterone sensitive while epithelial loss of PTEN with activation of Kras results in progesterone resistant tumors; 3) Epigenetic silencing of PR is detected in the stroma of progesterone resistant mouse tumors; 4) Stromal specific deletion of PR converts a hormone sensitive to a hormone refractory endometrial cancer; 5 ) Add-back of exogenous PR in the stroma of mouse hormone refractory tumors, sensitizes them to progesterone therapy. Our central hypotheses are that (a) silencing of PR in the tumor stroma is the primary mechanism leading to hormone resistance in human endometrial cancers and (b) stromal PR expression or signaling is a valid biomarker in prospective identification of patients with hormone sensitive tumors. Specific Aims: 1) Determine if signaling through stromal and/or epithelial ER? is essential for the anti-tumor effects of progesterone; 2) Test if pharmacologic restoration of PR in the tumor stroma sensitizes progesterone refractory mouse endometrial tumors to hormonal therapy; 3) Develop an in vivo hormone refractory human endometrial tumor model; 4) Identify biomarkers of response to hormonal therapy in human endometrial tumors. Being a physician scientist, here we plan to (a) determine if stromal PR expression is a biomarker for identifying progesterone sensitive human cancers, (b) identify independent biomarkers based on transcriptome analysis of progesterone sensitive vs. resistant tumors and (c) determine if PR is methylated in stroma of hormone refractory human tumors. These results will identify biomarkers predictive of hormonal sensitivity and define mechanisms by which human endometrial tumors become hormone refractory. In addition to gaining mechanistic insight about the pathobiology of endometrial cancer, another innovative aspect of our proposal involves translation of a disease-relevant mouse model to the analysis of patient samples using strategies pioneered by our team. The long term goal is to discover much needed but currently unavailable biomarkers of response to hormonal therapy and develop novel strategies to sensitize hormone refractory tumors to progesterone therapy.
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