A gene target for drug resistance, a triple-drug cocktail for triple negative breast cancer, and patients’ risk for carpal tunnel syndrome are among study highlights scheduled to be presented by Johns Hopkins Kimmel Cancer Center scientists during the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium, held Dec. 8-12. 

For more information or to interview the presenters contact Vanessa Wasta at 410-955-1287 or [email protected].

Vodcast from Breast Cancer Program Co-Directors Vered Stearns and Sara Sukumar

Vodcast from Johns Hopkins Medicine's Vice Dean for Research Chi Dang

HOXB7 GENE PROMOTES TAMOXIFEN RESISTANCE
(Presentation # PD05-10)

Many postmenopausal women with early-stage breast cancers who initially respond well to tamoxifen become resistant to the drug over time and develop recurrent tumors. Johns Hopkins Kimmel Cancer Center researchers have found that a gene called HOXB7 may be the culprit in tamoxifen resistance.

Taken by mouth, tamoxifen is used at every stage of breast cancer to treat existing tumors and prevent new ones from developing. The drug works only in women whose tumor cells have a protein, called the estrogen receptor, which binds to the estrogen hormone. Tamoxifen binds to this estrogen receptor and blocks estrogen’s effect on fueling cancer cells.

In experiments on cancer cells, the scientists found that when the HOXB7 gene is overexpressed, as occurs in many breast cancers, tumors cells became resistant to tamoxifen. Overexpression of HOXB7 results in proteins that interact with a series of other estrogen-activated genes and proteins, including the HER2 gene, known to make breast cancers aggressive. When the scientists knocked out the HOXB7 gene in one group of breast cancer cells, HER2 activation decreased and the cells became more responsive to tamoxifen. The scientists then showed how the HOXB7-HER2 interaction works.

“HOXB7 appears crucial in orchestrating estrogen receptors, HER2 and other receptors that promote aggressive tumor growth in breast cancer cells,” says senior author Saraswati Sukumar, PhD, professor of oncology and co-director of the Breast Cancer Program at Johns Hopkins. “Dialing down expression of the HOXB7 gene could stave off tamoxifen resistance.”

Though it’s not yet evident how to shut down HOXB7, Sukumar says that oncologists could potentially use the drug Herceptin to kill tumors in patients whose HER2 expression increases.

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TRIO OF DRUGS MAY COMBAT “TRIPLE NEGATIVE” BREAST CANCER
(Presentation # PD01-05)

Working with cell cultures and mouse models, researchers at the Johns Hopkins Kimmel Cancer Center have tested a cocktail of three drugs that holds promise for treating so-called triple negative breast cancers.

Women with such cancers lack all three hormone receptors – estrogen, progesterone and human epidermal growth factor 2 (HER2).  Currently, treatments for triple negative breast cancers are limited to surgery, chemotherapy and radiation, which provide some improvements but overall poor prognoses.

In the new study, Johns Hopkins scientists began with a drug called Entinostat, which blocks an enzyme that unfolds DNA, providing regulatory molecules access to genes within and also reactivates a gene called retinoic acid receptor-beta (RAR?).  Then, they added a drug called All Trans Retinoic Acid (ATRA), related to Vitamin A, which binds a protein made by the reactivated RAR? gene. Together, the ATRA drug and RAR? gene act as a brake on cancer cell growth.  The scientists completed the drug cocktail with conventional chemotherapy using either low doses of doxorubicin or paclitaxel.

According to the scientists, each of the three drugs used alone may have some effect on killing tumors cells, but combining them tips the scale in favor of killing more cells.

Tests on laboratory-cultured cells showed that the triple combo therapy halted the growth of multiple triple negative breast cancer cell lines more effectively than any one of the treatments alone. The combined therapy also rejuvenated the expression of RAR?, and strongly inhibited tumor growth in three-quarters of mice engrafted with breast tumor cells.

The researchers are discussing potential clinical trials of the combo therapy, which they hope to start in the next year, says Nguyen K. Nguyen, a graduate student in the Cellular and Molecular Medicine Program at Johns Hopkins.

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SIMPLE FINGERTIP TEST MAY IDENTIFY BREAST CANCER PATIENTS AT RISK FOR CARPAL TUNNEL SYNDROME
(Presentation # P2-14-09)

As many as half of postmenopausal women taking aromatase inhibitor drugs for breast cancer complain of bothersome musculoskeletal symptoms, including carpal tunnel syndrome (CTS).  Now, a new study by Johns Hopkins Kimmel Cancer Center researchers shows that a simple test that measures a woman’s ability to feel two metal points pressed against her fingertips may help evaluate the risk for developing CTS.

CTS, most often associated with computer keyboard typing, is caused by bone growth in the wrist, compressing nerves and causing radiating arm pain and weak, numb hands and wrists.

For the study, researchers gathered and analyzed information on 104 women participating in a clinical trial of aromatase inhibitors exemestane and letrozole between September 2008 and June 2009. They recorded symptoms of pain and numbness common to carpal tunnel syndrome and also used a discriminator, a metal instrument with two sliding prongs used to measure tactile sensitivity. The instrument recorded the shortest distance between the prongs where the women could feel two pressure points versus one, called a two-point discrimination score. The tests were repeated three and six months later.

The percentage of women with carpal tunnel syndrome increased from 11 percent at baseline to 16 percent within six months of aromatase inhibitor treatment. The average two-point discrimination scores worsened from 3.4 mm to 4 mm within three months, particularly among overweight women.

“Our results show that the two-point discrimination score worsens in some women receiving aromatase inhibitor therapy, providing a potential way to measure risk for carpal tunnel syndrome,” says lead author Aditya Bardia, M.D., M.P.H., a clinical fellow at the Johns Hopkins Kimmel Cancer Center

Larger studies are needed to confirm the findings before they can be incorporated into clinical practice, he adds.

If further studies confirm the findings, patients at risk for carpal tunnel syndrome could be referred to a rheumatologist for therapy during early stages of the syndrome before surgery is necessary, or could have their medication regimen switched, says senior author Vered Stearns, M.D., associate professor and co-director of the Breast Cancer Program at Johns Hopkins.

On the Web:
www.hopkinskimmelcancercenter.org
San Antonio Breast Cancer Symposium: http://www.sabcs.org/

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