Faculty Publications

L-Buthionine sulfoximine (BSO) is a potent inhibitor of glutathione biosynthesis and studies have shown that it is capable of enhancing the apoptotic effects of several chemotherapeutic agents. Previous studies have shown that long-term antihormonal therapy leads to acquired drug resistance and that estrogen, which is normally a survival signal, is a potent apoptotic agent in these resistant cells. Interestingly, we have developed an antihormone-resistant breast cancer cell line, MCF-7:2A. which is resistant to estrogen-induced apoptosis but has elevated levels of glutathione. In the present study, we examined whether BSO is capable of sensitizing anti hormone-resistant MCF-7:2A cells to estrogen-induced apoptosis. Our results showed that treatment of MCF-7:2A cells with 1 nM E2 plus 100 mu M BSO combination for 1 week reduced the growth of these cells by almost 80-90% whereas the individual treatments had no significant effect on growth. TUNEL and 4',6-diamidino-2-phenylindole (DAPI) staining showed that the inhibitory effect of the combination treatment was due to apoptosis. Our data indicates that glutathione participates in retarding apoptosis in antihormone-resistant human breast cancer cells and that depletion of this molecule by BSO may be critical in predisposing resistant cells to estrogen-induced apoptosis. (C) 2009 Published by Elsevier Ltd.

Estrogen is a potent stimulus for growth in its target organs: the uterus, vagina, and some estrogen receptor-positive breast cancers. However, estrogen is also able to control menopausal symptoms and maintain bone density in postmenopausal women. Until recently, there was also believed to be a link between estrogen and the prevention of cardiovascular disease. For these reasons, hormone replacement therapy (HRT) with an orally active estrogen and progesterone has been used routinely for more than 50 years to maintain physiologic homeostasis after menopause. Not surprisingly, HRT Increases the risk of developing breast cancer. The link between estrogen and breast cancer growth served as the incentive to develop long-term tamoxifen therapy and, subsequently, the aromatase inhibitors (AIs) as successful "anti-estrogenic" treatments. Unfortunately, the consequence of exhaustive therapy is drug resistance. Laboratory studies have defined the evolution of tumor drug resistance to tamoxifen, raloxifene (used for breast and osteoporosis chemoprevention), and the AIs. Remarkably, the long-term exposure of breast cancers to antihormonal therapy also exposes a vulnerability that is being exploited in the clinic. Years of antihormonal therapy alters the cellular response mechanism to estrogen. Normally, estrogen Is classified as a survival signal in breast cancer, but in sensitive anti hormone-resistant cells, estrogen induces apoptosis. When resistant cells are killed, antihormonal therapy is once again effective. This new targeted approach to the treatment of metastatic breast cancer could open the door to novel approaches to treatment with drug combinations.

Estrogen is a potent stimulus for growth in its target organs: the uterus, vagina, and some estrogen receptor-positive breast cancers. However, estrogen is also able to control menopausal symptoms and maintain bone density in postmenopausal women. Until recently, there was also believed to be a link between estrogen and the prevention of cardiovascular disease. For these reasons, hormone replacement therapy (HRT) with an orally active estrogen and progesterone has been used routinely for more than 50 years to maintain physiologic homeostasis after menopause. Not surprisingly, HRT increases the risk of developing breast cancer. The link between estrogen and breast cancer growth served as the incentive to develop long-term tamoxifen therapy and, subsequently, the aromatase inhibitors (AIs) as successful "anti-estrogenic" treatments. Unfortunately, the consequence of exhaustive therapy is drug resistance. Laboratory studies have defined the evolution of tumor drug resistance to tamoxifen, raloxifene (used for breast and osteoporosis chemoprevention), and the AIs. Remarkably, the long-term exposure of breast cancers to antihormonal therapy also exposes a vulnerability that is being exploited in the clinic. Years of antihormonal therapy alters the cellular response mechanism to estrogen. Normally, estrogen is classified as a survival signal in breast cancer, but in sensitive antihormone-resistant cells, estrogen induces apoptosis. When resistant cells are killed, antihormonal therapy is once again effective. This new targeted approach to the treatment of metastatic breast cancer could open the door to novel approaches to treatment with drug combinations.

PURPOSE: Standard radiation for early breast cancer requires daily treatment for 6 to 7 weeks. This is an inconvenience to many women, and for some a barrier for breast conservation. We present the acute toxicity of a 4-week course of hypofractionated radiation. METHODS AND MATERIALS: A total of 75 patients completed radiation on a Phase II trial approved by the hospital institutional review board. Eligibility criteria were broad to include any patient normally eligible for standard radiation: age >/=18 years, invasive or in situ cancer, American Joint Committee on Cancer Stage 0 to II, breast-conserving surgery, and any systemic therapy not given concurrently. The median age was 52 years (range, 31-81 years). Of the patients, 15% had ductal carcinoma in situ, 67% T1, and 19% T2; 71% were N0, 17% N1, and 12% NX. Chemotherapy was given before radiation in 44%. Using photon intensity-modulated radiation therapy and incorporated electron beam boost, the whole breast received 45 Gy and the lumpectomy bed 56 Gy in 20 treatments over 4 weeks. RESULTS: The maximum acute skin toxicity by the end of treatment was Grade 0 in 9 patients (12%), Grade 1 in 49 (65%) and Grade 2 in 17 (23%). There was no Grade 3 or higher skin toxicity. After radiation, all Grade 2 toxicity had resolved by 6 weeks. Hematologic toxicity was Grade 0 in most patients except for Grade 1 neutropenia in 2 patients, and Grade 1 anemia in 11 patients. There were no significant differences in baseline vs. 6-week posttreatment patient-reported or physician-reported cosmetic scores. CONCLUSIONS: This 4-week course of postoperative radiation using intensity-modulated radiation therapy is feasible and is associated with acceptable acute skin toxicity and quality of life. Long-term follow-up data are needed. This radiation schedule may represent an alternative both to longer 6-week to 7-week standard whole-breast radiation and more radically shortened 1-week, partial-breast treatment schedules.

Fox Chase Cancer Center Partners (FCCCP) is a community hospital/academic partnership consisting of 25 hospitals in the Delaware Valley. Originally created in 1986, FCCCP promotes quality community cancer care through education, quality assurance, and access to clinical trial research. An important aspect of quality assurance is a yearly medical oncology audit that benchmarks quality indicators and guidelines and provides a roadmap for quality improvement initiatives in the community oncology clinical office setting. Each year, the FCCCP team and the Partner Medical Oncologists build disease site- and stage-specific indicators based on National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Concordance with multiple indicators is assessed on 20 charts from each community practice. A report for each FCCCP medical oncology practice summarizes documentation, screening recommendations, new drug use, and research trends in a particular disease site. Descriptive statistics reflect indicators met, number of new cases seen per year, number of disease site cases from tumor registry information, and clinical trial accrual total. Education and documentation tools are provided to physicians and oncology office nursing staff. The FCCCP Clinical Operations Team, consisting of medical oncologists and oncology-certified nurses, has conducted quality audits in medical oncology offices for 7 years using NCCN-derived indicators. Successful audits comprising gastric, colorectal, and breast cancer have been the focus of recent evaluations. For the 2005 stage II/III breast cancer evaluation, mean compliance per parameter was 88%, with 15 of 16 practices achieving mean compliance greater than 80%. A large-scale quality assurance audit in a community cancer partner network is feasible. Recent evaluation of localized breast cancer shows high compliance with guidelines and identifies areas for focused education. Partnership between academic and community oncologists produces a quality review process that is broadly applicable and adaptable to changing medical knowledge.

Purpose: We determined the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on hsp90 and its client proteins Her-2, AKT, and c-Raf, as well as evaluated the cytotoxic effects of cotreatment of SAHA with trastuzumab or docetaxel in human breast cancer BT-474 and SKBR-3 cells containing amplification of Her-2. Experimental Design:The cells were treated with SAHA (1.0-5.0 mu mol/L) and/or trastuzumab (5-40 mu g/mL) or docetaxel (5-20 nmol/L). Following this, apoptosis and the levels of p21(WAF1), P27(KIP1), AKT, c-Raf, and Her-2, as well as of the key regulators of apoptosis were determined. Synergistic interaction between drugs was evaluated by median dose-effect analysis. Results: Treatment with SAHA up-regulated p21(WAF1) and p27(KIP1) levels, increased the percentage of cells in G(2)-M phase of the cell cycle, as well as induced apoptosis in a dose-dependent manner. This was associated with up-regulation of the pro-death Bak and Bim, as well as with attenuation of the levels of Her-2 and XIAP, survivin, Bcl-2, and BCl-x(L) proteins. SAHA treatment induced acetylation of hsp90. This reduced the chaperone association of Her-2 with hsp90, promoting polyubiquitylation and degradation of Her-2. SAHA also attenuated the levels of c-Raf and AKT Cotreatment with SAHA significantly increased trastuzumab or docetaxel-induced apoptosis of BT-474 and SKBR-3 cells. Additionally, median dose-effect analysis revealed that cotreatment with SAHA and trastuzumab or docetaxel induced synergistic cytotoxic effects against the breast cancer cells. Conclusions: These preclinical findings support the development of SAHA in combination with docetaxel and/or trastuzumab against Her-2-amplified breast cancer.