Study Shows Chemotherapy Induces Cellular Aging, Which Promotes Side Effects, Cancer Relapse | UAMS Winthrop P. Rockefeller Cancer Institute

Jan. 17, 2017 | Chemotherapy for cancer causes a pro-inflammatory stress response that promotes adverse side effects and cancer relapse, says a research team that includes the University of Arkansas for Medical Sciences (UAMS).

Daohong Zhou, M.D., associate director for basic research in the UAMS Winthrop P. Rockefeller Cancer Institute, is a co-author of the study published Dec. 22 in Cancer Discovery.

While chemotherapy is often a life-saving treatment for some cancer patients, it affects both healthy cells and malignant cells throughout the body, often causing debilitating side effects, including fatigue.

The study shows that chemotherapy induces cellular senescence — or cellular aging — in normal tissues, which triggers a pro-inflammatory stress response and promotes the adverse effects of chemotherapy as well as fatigue and cancer relapse and metastasis. Eliminating the senescent cells in mice prevented the side effects and cancer relapse and metastasis.

“One of the side effects of chemotherapy is bone marrow suppression, which can lead to reduction in blood cell production and contribute to chemotherapy-induced fatigue,” said Zhou, also a professor of pharmaceutical sciences and deputy director of the Division of Radiation Health in the UAMS College of Pharmacy’s Department of Pharmaceutical Sciences. “Eliminating senescent cells can promote bone marrow recovery after chemotherapy.”

Judith Campisi, Ph.D., of the Buck Institute for Research on Aging, was the senior scientist on the study, which highlights the dual nature of cellular senescence — it permanently stops stressed cells from dividing, but also contributes to aging and late-life cancers.

“We are excited about the potential applications of this work,” said Campisi. “It would be a huge benefit if we could reduce the risk of cancer relapse and metastasis in patients. We also think it would be great to mitigate the other side effects of chemotherapy, the fear of which sometimes keep patients from seeking treatment.”

The research was led by Marco Demaria, Ph.D., a former postdoctoral scientist in the Campisi lab. The research utilized transgenic mice that permit tracking and eliminating senescent cells. Results showed that eliminating chemotherapy-induced senescent cells reduced several short-and long-term effects of treatment, including bone marrow suppression, toxicity to the heart, cancer recurrence and metastasis, and physical activity and strength. Common chemotherapy drugs Doxorubicin, Paclitaxel, Temozolomide and Cisplatin were used to treat the mice.
Demaria, who is now a principle investigator at the European Institute for the Biology of Aging at the University of Groningen in the Netherlands, said some of the most striking results involved running speed – an indicator of fatigue in mice.

Eliminating senescent cells was sufficient to almost entirely rescue remedy the decline in physical activity in the treated mice, Damaria said. “Normally, mice spend 40 percent of their time running. After chemotherapy that activity dropped to 10 percent. When we knocked out the senescent cells the mice returned to normal running.”
“Fatigue, which can be long-lasting, is a big deal for patients on chemotherapy,” said Norman E. Sharpless, M.D., director of the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill and a co-author of the study. “Years later they often say that was the worst part of the treatment.”
In addition, Sharpless looked at blood markers of cellular senescence in 89 women with breast cancer before they underwent chemotherapy aimed at curing their disease. Women who went into chemotherapy with the most senescent cells experienced the most debilitating fatigue after treatment, he said.

Other co-authors from Zhou’s lab at UAMS include Mr. Jianhui Chang and Dr. Lijian Shao.
Citation: Cellular senescence promotes adverse effects of chemotherapy and cancer relapse DOI: 10.1158/2159-8290.CD-16-0241
The work was supported by grants from the American Italian Cancer Foundation and the National Institutes of Health grants AG009909, AG017242, AG041122 and CA122023
Campisi and Zhou are co-founders of Unity Biotechnology, which is developing drugs to eliminate senescent cells. Sharpless and Demaria have equity in the company. Sharpless is a founder and has a financial interest in HealthSpan Diagnostics. Mitin is an employee of HealthSpan Diagnostics. All other authors declare no financial interests.

Sept. 1, 2016 | The family of the late William E. “Bill” Clark has given $300,000 to establish a distinguished endowed chair in honor of J. Thomas May in which world-renowned radiation effects expert Martin Hauer-Jensen, M.D., Ph.D., was invested Aug. 29 at the University of Arkansas for Medical Sciences (UAMS).

Hauer-Jensen, a professor of pharmaceutical sciences, surgery and pathology, is director of the Division of Radiation Health in the UAMS College of Pharmacy.

A distinguished endowed chair is the highest academic honor a university can bestow on its faculty and is established with gifts of $1.5 million or more to support the educational, research and clinical activities of the chairholder. Those named to a chair are among the most highly regarded scientists, physicians and professors in their fields of expertise.

The J. Thomas May Distinguished Endowed Chair in Oncology was funded by the family of Clark, who was chairman and CEO of CDI Contractors in Little Rock, to honor his friend May, former CEO of Simmons First National Corp.

“The Clarks’ generous gift ensures that UAMS can continue providing the highest quality oncology physicians and researchers in Arkansas. Bill Clark and Tommy May share a legacy of dedicated service,” said UAMS Chancellor Dan Rahn, M.D. “Their friendship is a wonderful testimony to the importance of relationships and the power of two friends sharing a common goal to improve the future of health care for others.”

An endowed chair was established in 2006 with $1 million from Bill and Margaret Clark. Bill Clark died of cancer one year later. The initial investment grew by $200,000 over the last decade. In June, Margaret Clark, and her son, William E. Clark II, chairman of the UAMS Foundation Fund Board, gave another $300,000 to elevate the chair to a distinguished endowed chair. It is the first distinguished endowed chair for a faculty member of the UAMS College of Pharmacy.

“We thank the Clark family from the bottom of our hearts for this additional gift. This will benefit our oncology program from now on into the future,” said Peter Emanuel, M.D., executive director of the UAMS Winthrop P. Rockefeller Cancer Institute.

Bill Clark, a former member of the UAMS Foundation Fund Board, became friends with May when the two served together for nine years on the University of Arkansas Board of Trustees. “It was a friendship like I’d never seen before,” Margaret Clark has said.

A resident of Pine Bluff, May has an extensive background in civic and community service, for which he has received numerous awards, and served on the UAMS Department of Psychiatry capital campaign steering committee. He holds an honorary doctorate of law from the University of Arkansas at Pine Bluff.

In addition to Rahn, Emanuel and William E. Clark II, speakers at the ceremony included Stephanie Gardner, Pharm.D., Ed.D., UAMS provost and chief academic officer; Keith M. Olsen, Pharm.D., dean of the College of Pharmacy; and James W. Hardin, Ph.D., chief scientific and administrative officer for SunEcoEnergy Inc., who formerly worked with Hauer-Jensen at the UAMS Cancer Institute. University of Arkansas System President Donald Bobbitt, Ph.D., was also in attendance.

Hauer-Jensen was presented with a commemorative medallion by Rahn and Olsen.

“I thank the Clark family and Tommy May for making this distinguished endowed chair possible, and Peter Emanuel for organizing it. I am looking forward to working with Dean Olsen to enhance the competitiveness of the Division of Radiation Health,” Hauer-Jensen said.

“None of this would be possible without my family,” he continued. “I’ve had many long nights, many business trips, and many weekends that I could not be with them, and I give them my sincere, heartfelt thanks.”

Gardner, who was dean of the College of Pharmacy when Hauer-Jensen was recruited, praised his leadership and his work mentoring a new generation of researchers. “I have been looking forward to this day for almost a decade,” Gardner said. “Martin’s strong leadership and vision are what draw people to this division. He’s not just an internationally recognized scientist; he’s a visionary, a mentor, a leader, and a coach.”

Hauer-Jensen is an internationally recognized authority on normal tissue radiation responses. His research focuses on determining mechanisms of injury and developing strategies to prevent adverse effects after radiation therapy in cancer patients, to make radiation therapy for cancer safer and more effective.

He joined the UAMS faculty in 1990 to launch a career in academic surgery. In 2008, Hauer-Jensen moved from the College of Medicine to the College of Pharmacy and was appointed associate dean for research and director of the newly formed Division of Radiation Health in the Department of Pharmaceutical Sciences.

Hauer-Jensen is president of the Radiation Research Society and serves on numerous national and international advisory boards, review panels and editorial boards.

At UAMS, he co-leads the Host Response and Radiation Sciences program at the Winthrop P. Rockefeller Cancer Institute. He has been chair of the Radiation Study Section of the National Institutes of Health, a consultant on radiological emergencies to the World Health Organization, and a member of the National Council on Radiation Protection and Measurements.

He has published more than 250 scientific papers and has received peer reviewed research funding for more than 20 years. He is the recipient of the coveted MERIT Award from the National Cancer Institute.