Possible therapy for tamoxifen-resistant breast cancer identified

A study by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) has discovered how tamoxifen-resistant breast-cancer cells grow and proliferate. It also suggests that an experimental agent might offer a novel targeted therapy for tamoxifen-resistant breast cancer.

Like a second door that opens after the first door closes, a signaling pathway called hedgehog (Hhg) can promote the growth of breast-cancer cells after tamoxifen shuts down the pathway activated by the hormone estrogen. A second signaling pathway, called PI3K/AKT, is also involved.

Activation of the Hhg pathway renders tamoxifen treatment ineffective and enables the tumor to resume its growth and progression. As part of the study, the researchers analyzed over 300 human tumors and found that the tumors with an activated Hhg pathway had a worse prognosis.

Finally, the researchers showed that an experimental drug called vismodegib, which blocks the Hhg pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. The drug is in clinical trials testing for other types of cancer.

Currently, chemotherapy is used to treat hormone-resistant breast cancers, but this is associated with significant side effects. This study has identified targeted therapies that could be an alternative to chemotherapy for these resistant tumors.

The study is published in the journal Cancer Research.

"Our findings suggest that we can target this pathway in patients with estrogen-receptor breast cancers who have failed tamoxifen therapy," says first author Dr. Bhuvaneswari Ramaswamy, a medical oncologist specializing in breast cancer at the OSUCCC - James.

"We describe a link between the hedgehog signaling pathway, which promotes tamoxifen resistance, and the PI3K/AKT pathway," says principal investigator Sarmila Majumder, research assistant professor in molecular and cellular biochemistry at the OSUCCC - James. "Targeting the hedgehog pathway alone or in combination with the PI3K/AKT pathway could be a novel therapeutic option for treating tamoxifen-resistant breast cancer."

Ramaswamy, an assistant professor of internal medicine at Ohio State, emphasizes that novel options are needed for these patients.

"A combined targeted therapy using both hedgehog and PI3K inhibitors could lead to a novel treatment for endocrine-resistant tumors in the future without use of chemotherapy," she says. "And these agents we have identified are all in clinical development for other kinds of cancer."

Approximately 230,000 new cases of breast cancer are expected in the United States in 2012, and almost 40,000 Americans will die from the disease. More than two-thirds of breast cancer cases show high levels of the estrogen receptor (ER). Doctors use the drug tamoxifen to treat these ER-positive tumors, and Ramaswamy notes that the drug has improved the disease-free survival of people with ER-positive breast cancer by 50 percent.

"But 30 to 40 percent of patients taking tamoxifen become resistant to it after about five years," she says. Currently, there are very limited options for these patients and most end up receiving chemotherapy.

Key findings for this study include:
Tamoxifen-resistant breast cancer depends on the Hhg pathway for cell growth;
The PI3K/AKT pathway protects key Hhg signaling proteins from degradation, which promotes activation of the Hhg pathway. Analysis of 315 invasive breast cancers showed that high levels of the protein GLI1, an important Hhg marker, was correlated with poorer disease-free survival and overall survival.

"Our next step is to organize a clinical trial to evaluate vismodegib in patients with tamoxifen-resistant breast cancer," Ramaswamy says.

Funding from the NIH/National Cancer Institute (grants CA137567 and CA133250) and a Pelotonia Idea grant supported this research.

Other Ohio State researchers involved in this study were Yuanzhi Lu, Kun-yu Teng, Gerard Nuovo, Xiaobai Li and Charles L. Shapiro.

The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only seven centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 210-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.

Most Popular Now

Pfizer receives positive FDA Advisory Committee vo…

Pfizer Inc. (NYSE: PFE) announced that the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted that avail...

Engineered bacteria find tumors, then alert the au…

Combining discoveries in cancer immunology with sophisticated genetic engineering, Columbia University researchers have created a sort of "bacterial suicide squad" that ...

First nasal monoclonal antibody treatment for COVI…

A pilot trial by investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, tested the nasal administration of the ...

US FDA Advisory Committee votes to support effecti…

GSK plc (LSE/NYSE: GSK) announced that the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted that the avail...

"Semantic similarity" leads to novel dru…

The words that researchers use to describe their results can be harnessed to discover potential new treatments for Parkinson's disease, according to a new study published...

Tumour cells' response to chemotherapy is driven b…

Cancer cells have an innate randomness in their ability to respond to chemotherapy, which is another tool in their arsenal of resisting treatment, new research led by the...

Pfizer's ZAVZPRET™ (zavegepant) migraine nasal spr…

Pfizer Inc. (NYSE: PFE) today announced the U.S. Food and Drug Administration (FDA) has approved ZAVZPRET™ (zavegepant), the first and only calcitonin gene-related peptid...

Nanosatellite shows the way to RNA medicine of the…

The RNA molecule is commonly recognized as messenger between DNA and protein, but it can also be folded into intricate molecular machines. An example of a naturally occur...

Gene and cell therapies to combat pancreatic cance…

Pancreatic cancer is an incurable form of cancer, and gene therapies are currently in clinical testing to treat this deadly disease. A comprehensive review of the gene an...

Pfizer invests $43 billion to battle cancer

Pfizer Inc. (NYSE: PFE) and Seagen Inc. (Nasdaq: SGEN) today announced that they have entered into a definitive merger agreement under which Pfizer will acquire Seagen, a...

Scientists reveal a potential new approach to trea…

Scientists at the National Institutes of Health and Massachusetts General Hospital in Boston have uncovered a potential new approach against liver cancer that could lead ...

Digital twin opens way to effective treatment of i…

Inflammatory diseases like rheumatoid arthritis have complex disease mechanisms that can differ from patient to patient with the same diagnosis. This means that currently...