Drug-chemo combo destroys challenging breast cancer stem cells

Gregg Semenza

Gregg Semenza

Researchers affiliated with Johns Hopkins Physical Sciences-Oncology Center (PS-OC) have shown that combining chemotherapy with an agent that blocks a certain cancer survival protein holds the key to fighting one of the the toughest forms of breast cancer.

Only 20 percent of patients with what are known as “triple-negative” breast cancer cells respond to chemotherapy. PS-OC associate director and Johns Hopkins professor of  medicine Gregg Semenza demonstrated in a recent study that chemotherapy actually enhances triple-negative cancer stem cell survival by switching on proteins called hypoxia-inducible factors (HIF). But when combined with currently available and FDA-approved HIF-inhibiting drugs, such as digoxin, Semenza said, chemotherapy shrank tumors.

Mice with implanted triple-negative breast cancer stem cells were treated with a combination therapy comprised of the HIF-inhibiting drug plus the chemotherapeutic drug paclitaxel. That combo treatment decreased tumor size by 30 percent more than treatment with chemotherapy. Furthermore, Semenza’s study showed that combining digoxin with the a different chemotherapeutic agent called gemcitabine “brought tumor volumes to zero within three weeks and prevented the immediate relapse at the end of treatment that was seen in mice treated with gemcitabine alone,” a press release on the study stated. Clinical trials will be needed to verify these results.

Debangshu Samanta, Ph.D., a postdoctoral fellow in the Semenza lab, was the lead author on this research published online in the Proceedings of the National Academy of Sciences. Additional authors include Daniele Gilkes, Pallavi Chaturvedi and Lisha Xiang of the Johns Hopkins University School of Medicine.

Read the PNAS article here.

Visit the PS-OC website here.

For all press inquiries regarding INBT, its faculty and programs, contact INBT’s science writer Mary Spiro, mspiro@jhu.edu or 410-516-4802.

 

Molecular culprit linked to breast cancer spread

Johns Hopkins researchers have uncovered a protein “partner” commonly used by breast cancer cells to unlock genes needed for spreading the disease around the body. A report on the discovery, published Nov. 5 on the website of the Proceedings of the National Academy of Sciences, details how some tumors get the tools they need to metastasize.

“We’ve identified a protein that wasn’t known before to be involved in breast cancer progression,” says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Medicine at the Johns Hopkins University School of Medicine and director of the Vascular Program at the university’s Institute for Cell Engineering. “The protein JMJD2C is the key that opens up a whole suite of genes needed for tumors to grow and metastasize, so it represents a potential target for cancer drug development.” Semenza also is associate director of the Johns Hopkins Physical Sciences-Oncology Center.

Semenza and his colleagues made their finding when they traced the activity of HIF-1, a protein known to switch on hundreds of genes involved in development, red blood cell production, and metabolism in normal cells. Previous studies had shown that HIF-1 could also be hijacked to switch on genes needed to make breast tumors more malignant.

Would-be tumor cells face a host of challenges as they make the transition from working with their host to working against it, such as the need to evade the immune system and to produce more cancer cells, explains Weibo Luo, Ph.D., an instructor in the Institute for Cell Engineering and Department of Biological Chemistry who led the project. All of these efforts require switching on the right genes for the job.

To learn more about how HIF-1 works, the researchers tested a range of human proteins to see whether they would interact with HIF-1. They then sifted through the 200 resulting hits, looking for proteins involved in chemical changes to sections of DNA that determine whether or not the genes they contain are available for use. “In order for HIF-1 to switch genes on, they have to be available, but many of the genes HIF-1 activates are normally locked down in mature cells,” explains Luo. “So we thought HIF-1 must have a partner that can do the unlocking.”

That partner turned out to be JMJD2C, Luo says. Delving deeper, the researchers found that HIF-1 switches on the JMJD2C gene, stimulating production of the protein. HIF-1’s presence also enables JMJD2C to bind to DNA at other HIF-1 target genes, and then loosen those DNA sections, enabling more HIF-1 to bind to the same sites and activate the target genes.

To test the implications of their discovery, the research team injected mice with breast cancer cells in which the JMJD2C protein was not produced. Tumors with depleted JMJD2C were much less likely to grow and metastasize to the lungs, confirming the protein’s role in breast cancer progression, says Luo.

“Active HIF proteins have been found in many types of tumors, so the implications of this finding go beyond breast cancer,” says Luo. “JMJD2C is both an important piece of the puzzle of how tumors metastasize, and a potential target for anti-cancer therapy.”

Other authors of the research report are Ryan Chang, Jun Zhong, Ph.D., and Akhilesh Pandey, M.D., Ph.D., all of the Johns Hopkins University School of Medicine.

This work was supported by grants from the National Heart, Lung, and Blood Institute (contracts N01-HV28180 and HHS-N268201000032C), and by funds from the Johns Hopkins Institute for Cell Engineering.

On the Web:

Johns Hopkins Physical Sciences-Oncology Center: http://psoc.inbt.jhu.edu/

Link to article: http://www.pnas.org/content/early/2012/10/31/1217394109.abstract

Semenza lab: http://www.hopkinsmedicine.org/institute_cell_engineering/experts/gregg_semenza.html

Q&A with Semenza: http://www.hopkinsmedicine.org/institute_cell_engineering/experts/meet_scientists/gregg_semenza.html

Original press release by Shawna WilliamsCatherine Kolf and Vanessa McMains

 

 

EOC leader Gregg Semenza wins Canada Gairdner Award

Gregg Semenza

Gregg Semenza, associate director of Johns Hopkins Engineering in Oncology Center (EOC), has been named among seven 2010 winners of Canada’s international prize for medical research–the Canada Gairdner Award. The award is among the most prestigious for medical research and comes with a $100,000 cash prize.

The Canada Gairdner Award recognized Semenza for his work on how cells respond to oxygen availability in the body. He was the first to identify and describe hypoxia-inducible factor-1 (HIF-1), which switches genes on or off in response to oxygen levels.

Semenza leads a research project related to this topic for EOC with Sharon Gerecht, an assistant professor of chemical and biomolecular engineering. Their work focuses on analyzing the makeup and physical properties of the extracellular matrix, the three-dimensional scaffold in which cells live.

“Normal cells live in a flexible scaffold, but cancer cells create a rigid scaffold that they climb through to invade normal tissue,” Semenza said. “We will study how this change occurs and how it is affected by the amount of oxygen to which cancer cells are exposed. Our studies have shown that cancer cells are deprived of oxygen, which incites them to more aggressively invade the surrounding normal tissues where oxygen is more plentiful. Hypoxia-inducible factor 1 controls the responses of cancer cells to low oxygen, and we have recently identified drugs that block the action of HIF-1 and inhibit tumor growth in experimental cancer models.”

Semenza is the C. Michael Armstrong Professor in Medicine and founding director of the Vascular Biology program at  Johns Hopkins Institute for Cell Engineering at the School of Medicine. He also is a member of the McKusick-Nathans Institute of Genetic Medicine, is an affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, and has ties to the Department of Biological Chemistry and the Sidney Kimmel Comprehensive Cancer Center, both at the Johns Hopkins School of Medicine.

The Johns Hopkins Engineering in Oncology Center, launched October 2009, is one of 12 funded by the National Cancer Institute to bring a new cadre of theoretical physicists, mathematicians, chemists and engineers to the study of cancer. During the five-year initiative, the NCI’s Physical Sciences-Oncology Centers (PS-OC) will take new, nontraditional approaches to cancer research by studying the physical laws and principles of cancer; evolution and evolutionary theory of cancer; information coding, decoding, transfer and translation in cancer; and ways to deconvolute cancer’s complexity.

Read more about Gregg Semenza winning the Canada Gairdner Award in the Johns Hopkins Gazette story by Audrey Huang here.

Johns Hopkins Engineering in Oncology Center