Research Interests
(1) Preclinical in vitro and in vivo evaluation of mTOR inhibitors in combination with multiple chemotherapeutic agents used for the treatment of endometrial cancer, Multidisciplinary Clinical Research Career Development NIH Roadmap K12 grant, Principal Investigator, Mentors: David Kaufman, MD, PhD and Paola Gehrig, MD

Abstract
Given the lack of effective treatment for advanced and recurrent endometrial cancer, the search has been for an additional agent, with hopefully a low toxicity profile, which could be used in combination with more traditional hormonal and cytotoxic chemotherapy to dramatically increase efficacy. Many novel agents are being investigated that target specific cellular signaling pathways that are thought to be essential in endometrial cancer progression and metastasis. One of the most promising of these for endometrial cancer are the mammalian target of rapamycin (mTOR) inhibitors. mTOR inhibitors such as rapamycin are known for their potent anti-proliferative properties stemming from their ability to modulate signal transduction pathways involved in cell cycle progression and are currently under evaluation in phase II clinical trials for a broad range of cancers.
We have previously demonstrated that rapamycin profoundly inhibits cell proliferation through G1 cell cycle arrest in endometrial cancer cell lines. In addition, we have shown a synergistic relationship between rapamycin and cisplatin in regards to both inhibition of cell growth and induction of apoptosis in these cell lines. This was further substantiated by blocking mTOR expression through mTOR siRNA and demonstrating that decreased mTOR signaling is an essential mechanism for rapamycin-induced chemosensitization and cisplatin-induced apoptosis. This suggests that rapamycin and cisplatin may be a potential effective targeted therapy for endometrial cancer. Rapamycin and its analogues have been shown to increase the efficacy of a number of cytotoxic agents in many different tumor cell types, but have not been systematically studied in endometrial cancer cells. mTOR inhibitors have shown great promise in endometrial cancer, but our hypothesis is that combination therapy may afford better alternatives for a cancer where cytotoxic and hormonal agents have had limited success.
Thus, our overall goal is to evaluate cell proliferation, G1 cell cycle arrest and apoptosis in a co-culture assay using endometrial cancer cell lines and an immortalized stromal cell line after exposure to the rapamycin derivative, AP23573 (provided by Ariad Pharmaceuticals, Cambridge, MA), in combination with cytotoxic and hormonal chemotherapeutic agents commonly used in the treatment of endometrial cancer. This unique co-culture assay is thought to better recapitulate the environment of the human endometrium in vivo than the use of cell lines alone [1, 2]. Synergistic combinations will be assessed in human endometrial cancer xenografts in vivo in an athymic nude mouse model. We hope that this will provide valuable evidence that mTOR inhibitors such as AP23573 may potentiate the effects of other cytotoxic and hormonal agents in endometrial cancer in regards to inhibition of cell growth and induction of apoptosis, and that combination therapy may be a more effective treatment option for women with recurrent or advanced stage disease. A Phase II trial of the rapamycin derivative, AP23573, in patients with recurrent or metastatic endometrial cancer recently closed at our institution in conjunction with Ariad Pharmaceuticals with promising results. The combination of mTOR inhibitors and other cytotoxic and hormonal chemotherapeutic agents would seem a logical future targeted therapy and extension of this clinical trial for endometrial cancer, and this work should provide the in vitro and in vivo foundation for rational combinations to test in subsequent clinical trials.

Research Plan

Specific Aim #1: To determine the effects of mTOR inhibitors (AP23573, Ariad Pharmaceuticals) in combination with other cytotoxic chemotherapeutic agents commonly used in the treatment of endometrial cancer, including cisplatin, carboplatin, paclitaxel, gemcitabine, topotecan, cyclophosphamide, docetaxel and doxorubicin, on cell proliferation and apoptosis in endometrial cancer cell lines.

Specific Aim #2: To evaluate the effects of mTOR inhibitors in combination with other hormonal chemotherapeutic agents commonly used in the treatment of endometrial cancer, including progestins and tamoxifen, on cell proliferation and apoptosis in endometrial cancer cell lines.

Specific Aim #3: To assess synergistic combinations of mTOR inhibitors and cytotoxic or hormonal chemotherapeutic agents, based on the CI value, using human endometrial cancer xenografts in vivo in an athymic nude mouse model.

(2) Rationale for mTOR Inhibitors and Progestins as a Potential Combined Therapeutic Strategy for Endometrial Cancer, funding pending, Principal Investigator

Abstract
In the normal endometrium, progesterone antagonizes the actions of estrogen and inhibits estrogen-induced cell growth. Consequently, progestins have had some therapeutic benefit in the treatment of endometrial cancer. Progestins have been utilized in the treatment of endometrial cancer in two diverse settings: (1) palliative treatment for advanced or recurrent disease or (2) primary treatment in premenopausal women with grade 1 tumors who are interested in preserving their fertility or in those women considered poor operative candidates. The response rate for progestin therapy in the primary setting is approximately 60% and only 10-15% in the recurrent setting. Thus, the search has been for an additional agent, with a low toxicity profile, which could be used in conjunction with progestin therapy to increase efficacy.
mTOR inhibitors such as rapamycin are known for their potent anti-proliferative effects and are currently undergoing clinical development as anti-cancer therapies. This signaling pathway has also been linked to the regulation of both the progesterone and estrogen receptor (PR and ER). Given that eventual resistance to progestin therapy for endometrial cancer is thought to be due to downregulation of the PR, a potential targeted treatment such as rapamycin that may stimulate expression of the PR would be valuable for restoring sensitivity to this hormonal treatment. mTOR inhibitors have already shown a benefit in overcoming resistance to endocrine therapies for breast cancer; and thus, it seems logical that a similar strategy could be employed for endometrial cancer.
We have previously demonstrated that rapamycin profoundly inhibits cell proliferation through G1 cell cycle arrest and decreases telomerase activity via modulation of hTERT mRNA expression in endometrial cancer cell lines [5]. Rapamycin also decreased estrogen-induced hTERT mRNA expression in ER-positive endometrial cancer cells [6]. Furthermore, we have shown that progesterone reduces estrogen-induced hTERT mRNA levels in PR-positive endometrial cancer cell lines. Thus, we hypothesize that mTOR inhibitors may potentiate the effects of progesterone on endometrial cancer cells by inhibition of cell growth and telomerase activity and possibly regulation of progesterone receptor transcription, and that dual therapy with both of these agents may be more effective in the treatment of endometrial cancer.
Our overall objective is to evaluate cell proliferation, G1 cell cycle arrest and telomerase activity in a co-culture assay using ER- and PR-positive endometrial cancer cell lines and an immortalized stromal cell line after exposure to progesterone, an mTOR inhibitor or combination therapy. This unique co-culture assay is thought to better recapitulate the environment of the human endometrium in vivo than the use of cell lines alone [1, 2]. We plan to use one of the newer derivatives of mTOR inhibitors, AP23573, as provided by Ariad Pharmaceuticals (Cambridge, MA). In order to better understand the underlying molecular mechanisms regarding the potential synergistic effect of mTOR inhibitors and progestin therapy, we will assess the effect of mTOR inhibitors on ER and PR mRNA and protein expression among the ER/PR-positive and ER/PR-negative endometrial cancer cell lines.

Research Plan

Specific Aim #1: To determine the effects of mTOR inhibitors used in combination with progestins on cell proliferation, G1 cell cycle arrest and hTERT telomerase expression among ER and PR-positive and -negative endometrial cancer cell lines.

Specific Aim #2: To assess the effect of mTOR inhibitors on ER and PR mRNA and protein expression among ER- and PR-positive and -negative endometrial cancer cell lines.

(3) The Cancer Genome Atlas (TCGA) Project
The TCGA is a network in which seven different institutions were selected to strategically characterize genomic changes involved in three types of cancer: brain (glioblastoma multiforme), lung (squamous cell) and ovarian (serous epithelial) cancer. The University of North Carolina at Chapel Hill (UNC-CH) has been selected as one of institutions to identify changes in the gene transcription profiles that occur in these cancers, and I serve as member of the working group for the ovarian cancer portion of this endeavor. Approximately 500 human ovarian tumors will be analyzed at UNC-CH for this project.

Recent Accomplishments and Honors
Fellowship

Best Fellow Presentation Award, Annual Meeting of the Mid-Atlantic Gynecologic Oncology Society, 2006
Molecular and Translational Oncology Workshop, Cancer Education Consortium, 2006

Residency

Fourth Annual OB/GYN Resident of the Year Award, 2004
Ortho Esprit de Corps Award, 2003
Felix Rutledge Fellowship, University of Texas MD Anderson Cancer Center, Department of Gynecologic Oncology, 2003
Association of Professors of Gynecology and Obstetrics Medical Education Foundation Scholar, 2003

Medical School

Susan Mellette Scholarship, 1997, 1999
School of Medicine State Discretionary Scholarship Fund, 1998, 1999
Student Honors Day Research Prize, 2nd Place, 1998
Clinical Oncology Fellowship from the American Cancer Society, 1998
Summer Research Fellowship from the American Cancer Society, 1997
Pathology Honors Society, 1997

Graduate School

UpJohns Travel Award to attend the annual meeting of the American Association for Cancer Research, 1995
Travel Award to attend the annual meeting of the American Society for Investigative Pathology, 1995
Travel Award to attend the annual meeting of the Society for Basic Urological Research, 1993
Graduate Teaching Assistantship in Pathology, 1992-1995
AD Williams Fellowship, 1991-1992

Training
POST-GRADUATE EDUCATION

7/2004 - University of North Carolina at Chapel Hill, Chapel Hill, NC
6/2007 Gynecologic Oncology Fellowship Program

7/2000 - University of North Carolina at Chapel Hill, Chapel Hill, NC
6/2004 Obstetrics and Gynecology Residency Program


8/1995 - Virginia Commonwealth University, Richmond, VA
8/1996 Department of Pathology
Postdoctoral Fellow

GRADUATE AND UNDERGRADUATE EDUCATION

8/1996 - Virginia Commonwealth University, Richmond, VA
5/2000 M.D., Medicine
8/1991 - Virginia Commonwealth University, Richmond, VA
8/1995 Ph.D., Pathology

1/1988 - Duke University, Durham, NC
5 /1991 B.S., Psychology, Certificate in Neurosciences

Publications
Bae-Jump, VL, Zhou, C, Boggess, JF, Whang, YE and Gehrig, PA, Synergistic effect of rapamycin and cisplatin in endometrial cancer cells, Submitted (2007).

Alvarez Secord, A, Havrilesky, LJ, Bae-Jump, VL, Chin, J, Calingaert, B, Bland, A, Rutledge, TR, Berchuck, A, Clarke-Pearson, DL, and Gehrig, PA, The role of multi-modality adjuvant chemotherapy and radiation in women with advanced stage endometrial cancer, Gynecologic Oncology, (In press).

Havrilesky, L, Alvarez-Secord, A, Bae-Jump, VL, Ayeni, T, Calingaert, B, Clarke-Pearson, D, Berchuck, A and Gehrig, PA, Outcomes in surgical stage I uterine papillary serous carcinoma, Gynecologic Oncology, 105, 688-82 (2007).

Zhou, C, Boggess, JF, Bae-Jump, VL and Gehrig, PA, Induction of apoptosis and inhibtion of telomerase activity by arsenic trioxide (AS2O3) in endometrial carcinoma cells, Gynecologic Oncology, 105, 218-222 (2007).

Bae-Jump, VL, Zhou, C, Gehrig, PA, Whang, YE and Boggess, JF, Rapamycin inhibits hTERT telomerase mRNA expression, independent of cell cycle arrest, Gynecologic Oncology, 100, 487-94 (2006).

Bae-Jump, VL, Bauer, M and Van Le, L, Cytologic Evaluation Correlates Poorly with Histologic Diagnosis of Vulvar Neoplasias, Journal of Lower Genital Tract Disease, 11, 8-11 (2007).

Boggess, JF, Zhou, C, Bae-Jump, VL, Gehrig, PA, Whang, YE. Estrogen receptor dependent regulation of telomerase activity in human endometrial cancer cell lines. Gynecologic Oncology, 103, 417-24 (2006).

Zhou, C, Bae-Jump, VL, Whang, YE, Gehrig, PA and Boggess, JF, The PTEN tumor suppressor inhibits telomerase activity in endometrial cancer cells by decreasing hTERT mRNA level, Gynecologic Oncology, 101, 305-10 (2006).

Boruta, DM, Gehrig, PA, Groben, PA, Bae-Jump, VL, Boggess, JF, Fowler, WC and Van Le, L, Uterine serous and grade 3 endometrioid carcinomas: Is there a survival difference?, Cancer, 101, 2214-21 (2004).

Gehrig, PA, Bae-Jump, VL, Boggess, JF, Groben, PA, Fowler, WC and Van Le, L, Association between uterine serous carcinoma and breast cancer, Gynecologic Oncology, 94, 208-211 (2004).

PERTINENT GRANTS
Preclinical in vitro and in vivo evaluation of mTOR inhibitors in combination with multiple chemotherapeutic agents used for the treatment of endometrial cancer, Multidisciplinary Clinical Research Career Development NIH Roadmap K12 grant, Principal Investigator, Mentors: David Kaufman, MD, PhD and Paola Gehrig, MD, July 2007-2010.

E-mail: vbae@unch.unc.edu
Telephone: 843-4899
FAX: 843-5387
Address: 4002 Old Clinic Bldg. Chapel Hill, NC 27599

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