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1 big problem with many possible solutions

Washington, DC -- For women with hormone receptor-positive breast cancers, treatment after initial surgery is straightforward: a daily dose of an anti-hormone drug will block the tumor from fuel needed for growth, and keep the breast cancer at bay. The treatments work like gangbusters at first, but after time, many tumors become resistant to therapy. With no other treatment options, the cancer grows again and eventually spreads.

Teams of scientists from Georgetown Lombardi Comprehensive Cancer Center are studying multiple ways to address this problem. Findings from their most recent research are being presented this week at the AACR 101st Annual Meeting 2010 in Washington, DC. (Embargoes listed with each abstract summary that follows).

"In our lab, we're working on two approaches for overcoming breast cancers that are treatment resistant," says Robert Clarke, PhD, DSc, a professor of oncology and physiology & biophysics at Lombardi, and interim director of GUMC's Biomedical Graduate Research Organization. "We're after what works, even if means taking the longer road. So, while it can be easier to find new combinations of existing drugs as a short term approach, if we need to identify new targets and new drugs to get the best outcome for patients in the long term, then that's what we should be doing." Clarke was recently awarded a $7.5 million NCI grant to lead one of 11 Centers for Cancer Systems Biology addressing cancer resistance.

A third and provocative approach is being studied in the lab of V. Craig Jordan, OBE, PhD, DSc, scientific director and vice chairman of the department of oncology at Lombardi. "We believe we can trigger the treatment-resistant breast cancer cells to become vulnerable to existing treatments once again," he says. This is the underlying theory of a clinical study for women with treatment resistant, hormone receptor-positive tumors. "We are giving these women a 'splash' of estrogen to trick the cells into going back to their old way of growing before they learned to evade current therapies."

The American Cancer Society estimates that in 2009, 192,000 women were diagnosed with invasive breast cancer, and approximately 70 percent of these cases were considered to be estrogen receptor-positive (ER+), meaning that estrogen and its receptor drive the disease.


XBP1 and the unfolded protein response in antiestrogen resistance in breast cancer (Abstract #2919)

EMBARGO: Monday, April 19, 2010; 3:25 pm ET

Author's summary: "About 70 percent of breast cancer patients have tumors that are positive for a protein called estrogen receptor α (ER +) and these patients are often given endocrine therapy (that blocks function of estrogen). Our previous work has shown that breast cancer cells that are resistant to endocrine therapy produce a protein called X-Box Binding Protein 1 (XBP1). Under certain pathological conditions, the normal protein folding process in the endoplasmic reticulum is disrupted resulting in a "stress" condition can initiate the unfolded protein response (UPR). UPR functions to restore the normal functioning of the endoplasmic reticulum. XBP1 is an important component of the UPR and our work shows that breast cancer cells that are resistant to endocrine therapeutic drugs may be using the UPR pathway to prolong survival." Ayesha N. Shajahan

Ayesha Shajahan is a recipient of a 2010 AACR-Sanofi-Aventis Scholar-in-Training Award.

Authors: Ayesha N. Shajahan, Rebecca B. Riggins, Alan Zwart, F. Edward Hickman and Robert Clarke. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Minisymposium Steroid Receptor Targets and Preclinical Therapies in Cancer; 3:25 pm ET in Room 103

ERK/MAPK regulation of ERR in Tamoxifen-resistant breast cancer (Abstract #4595)
The role of COUP transcription factors in Tamoxifen resistant breast cancer cells (Abstract #4600)

EMBARGO: Tuesday, April 20; 2:00 pm ET (embargo is for both abstracts)

Authors' Summary: "More than 134,000 women, fully 70 percent of all women diagnosed with breast cancer in the United States in 2009, have a breast tumor that expresses estrogen receptor alpha (ER). While ER is often considered to be a marker for good prognosis and an indication that these women are excellent candidates for treatment with either an aromatase inhibitor or an antiestrogen such as tamoxifen, all too often their breast cancer can recur or become resistant to these types of anti-hormonal therapy. Our research focuses on how ER-positive breast tumors become resistant to tamoxifen, with the hope that what we learn today can be used to improve the effectiveness of anti-hormonal therapy and extend the lives of women with breast cancer.

"One potentially exciting approach to reversing or preventing resistance to tamoxifen and other anti-hormonal therapies is by targeting a family of proteins known as orphan nuclear receptors. They are known as 'orphans' because naturally-occurring small molecules or peptides that activate or inhibit these receptors have not been identified. We have previously shown that one of these orphans, estrogen-related receptor gamma, is very highly expressed in breast cancer cells and in breast tumors that are resistant to tamoxifen.

"The first of our current studies (#4595) has explored whether the ability of estrogen-related receptor gamma to make breast cancer resistant to tamoxifen is regulated by a protein kinase called ERK. We have found that the function of estrogen-related receptor gamma in breast cancer cells is strongly enhanced by ERK, and that the inhibition of this kinase blocks the activity of estrogen-related receptor gamma while making breast cancer cells more responsive to tamoxifen. Now that there are inhibitors of the ERK pathway in phase I and II clinical trials, we hope to define estrogen-related receptor gamma as a robust biomarker that could be used to identify patients for whom a combination of tamoxifen and an ERK pathway inhibitor would be very beneficial.

"Our second study (#4600) has focused on two lesser-known orphan nuclear receptors, the COUP transcription factors. While other research groups have previously studied the COUP proteins in breast cancer, findings from some of these studies have not been consistent. COUPs may interact with ER and be regulated by tamoxifen and the protein kinase ERK. We aim to resolve these issues in order to better understand the role of these orphan nuclear receptors in tamoxifen resistant breast cancer." Rebecca B. Riggins, Mary M. Mazzotta and Omar Maniya

Authors of 4595: Mary M. Mazzotta, Minetta C. Liu, Robert Clarke, and Rebecca B. Riggins. Georgetown Lombardi Comprehensive Cancer Center.

Authors of 4600: Omar Maniya, Alan Zwart, Li Chen, Jianhua Xuan, Robert Clarke, and Rebecca B. Riggins. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Tuesday, April 20, 2:00-5:00pm, Hall A-C, Poster Section 29: 4595 Board 6; 4600 Board 11

Caveolin-1 inhibits survivin and increases sensitivity to paclitaxel in breast cancer cells (Abstract # 2547)

EMBARGO: Monday, April 19, 2010; 2:00 pm

Author's Summary: "Paclitaxel is part of a family of chemotherapeutic drugs known as taxanes and it is commonly used to treat breast cancer patients. Resistance to paclitaxel, however, remains a problem. We have shown that caveolin-1 (CAV1), a structural protein, is a key determinant of paclitaxel sensitivity in MCF-7 breast cancer cells. My research focuses on CAV1 and its possible role in promoting cell death in response to paclitaxel by inhibiting the function of a pro-survival protein called survivin. The upregulation of survivin is associated with cancer and we show that while overexpression of CAV1 down-regulates survivin, over-expression of survivin down-regulates CAV1 in MCF-7 cells. Findings from this research can help researchers and clinicians to evaluate whether CAV1 expression in breast tumors can help predict the responsiveness of these tumors to taxanes." Nadia Jafar

Authors: Nadia Jafar, Ayesha N. Shajahan, Robert Clarke. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Monday, April 19, 2:00 5:00 pm; Exhibit Hall A-C, Poster Section 23, Board 4

Paradoxical actions of a c-Src inhibitor on estradiol-induced apoptosis in long-term estrogen deprivation breast cancer cells (Abstract #609)

EMBARGO: Sunday, April 18, 2010; 2:00 pm ET

Author's Summary: "We have demonstrated that physiological estrogen could induce apoptosis in long term estrogen-deprived MCF-7 breast cancer cells which mimics as resistance to aromatase inhibitors in clinical. Inorder to increase the therapeutic potential, c-Src inhibitor was combined with estrogen to treat this endocrine resistance breast cancer cells. Contrary to our original ideas, this combination actually retarded apoptosis and the resulting cell line (MCF-7:PF) was unique, as they grew vigorously in culture with physiological levels of estrogen. These data illustrate that caution must be exercised when considering the evaluation of c-Src inhibitors in clinical trial following the development of acquired resistance to aromatase inhibitors." Ping Fan

Authors: Ping Fan, Helen R. Kim, V. Craig Jordan. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Sunday, April 18, 2:00 pm 5:00 pm ET; Exhibit Hall A-C, Poster Section 23, Board 6

Selective inhibitor of STAT1 sensitizes breast cancer cells to radiation therapy. (Abstract #489)

EMBARGO: Sunday, April 18, 2:00 pm ET

Author's Summary: "About 70 percent of breast cancer patients with progressive disease are resistant to conventional cancer treatments such as adjuvant chemotherapy and/or radiation therapy. Recently, the STAT1 signaling pathway has been identified as a predictive marker of poor outcome in breast cancer patients and as a factor responsible for radiation and chemotherapy resistance. We have recently developed a selective inhibitor of STAT1 that directly binds to the STAT1 and inhibits STAT1 transcriptional activity. The inhibitor kills breast cancer cells at nanomolar concentrations and further sensitize breast cancer cells to ionizing radiation, but does not effect survival of normal mammary epithelial cells. Our data suggest that a novel inhibitor of STAT1 decreases radiation resistance of breast cancer cells through downregulation of pro-survival genes and inhibition of DNA repair.

"Inhibition of STAT1 signaling appears to be a promising strategy in overcoming radiation resistance and can be used as an effective treatment of metastatic breast cancer when combined with conventional therapies." Olga A. Timofeeval

Authors: Olga A. Timofeeva1, Nadya Tarasova2, Honghe Wang2, Alan Perantoni2, Anatoly Dritschilo1. Georgetown Lombardi Comprehensive Cancer Center; 2National Cancer Institute

Presentation: Sunday, April 18, 2:00pm -5:00pm, Exhibit Hall A-C, Poster Section 18, Board 5

The role of autophagy in taxane resistant breast cancer models(Abstract #4857)

EMBARGO: Wednesday, April 21; 8:00 am ET

"Treatment with the taxanes (Paclitaxel or Docetaxel) is often the therapy of choice for women with advanced breast cancer. However, some tumors develop resistance during the course of treatment, which is a major concern for both patients and physicians. We hypothesize that changes in cell death are responsible for taxane resistance in breast cancers and have found that treatment of breast cancer cells with inhibitors of a certain type of cell death. Namely, Autophagy resensitizes cells to taxane chemotherapy treatment. Ultimately our studies may not only improve our understanding of taxane resistance at the bench, but may also provide the framework for formulation of novel therapies that may improve the success of taxane therapy in women with breast cancer in the clinic." - Nesrin Rechache

Authors: Nesrin S. Rechache, Rebecca B. Riggins, Ayesha N. Shajahan, Alan Zwart, Robert Clarke. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Wednesday, Apr 21, 2010, 8:00 am -11:00 am; Exhibit Hall A-C, Poster Section 1, Board 27

XBP1 regulated function of c-MYC and BCL2 in antiestrogen resistance in breast cancer (abstract #4601)

EMBARGO: Tuesday, April 20, 2010; 2:00 pm ET

Author's summary: "Breast cancer patients with tumors that are positive for a protein called estrogen receptor are good candidates for endocrine therapy. However, a large number of these patients who initially respond to endocrine therapy may develop resistance to the drugs. In our project, we plan to understand one aspect of how breast cancer cells become resistance by producing more-than-normal levels of a protein called X-box binding protein 1 (XBP1). We hypothesize that XBP1 may be regulating breast cancer cell growth by controlling the function of pro-survival proteins called c-MYC and BCL2."

Authors: Lauren McDaniel, Ayesha N. Shajahan and Robert Clarke. Georgetown Lombardi Comprehensive Cancer Center.

Presentation: Tuesday, Apr 20, 2010 2:00 pm - 5:00 pm; Exhibit Hall A-C, Poster Section 29, Board 12


Contact: Karen Mallet
Georgetown University Medical Center

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