Treatment makes chemo more effective, less toxic, mouse study shows
Breast cancer that spreads often infiltrates bone, causing fractures and intense pain. In such cases, chemotherapy is ineffective because the environment of the bone protects the tumor, even as the drug has toxic side effects elsewhere in the body.
Seeking new treatments for metastatic breast cancer, researchers have designed nanoparticles (shown in magenta) that carry chemotherapy and are targeted directly to tumors that have spread to bone.
Now, scientists at Washington University School of Medicine in St. Louis have developed a nanoparticle that can deliver chemotherapy directly to tumor cells that have spread to bone. In mice implanted with human breast cancer and exposed to circulating cancer cells likely to take up residence in bone, the researchers showed the treatment kills tumor cells and reduces bone destruction while sparing healthy cells from side effects.
The study is available online in the journal Cancer Research.
“For women with breast cancer that has spread, 70 percent of those patients develop metastasis to the bone,” said senior author Katherine N. Weilbaecher, MD, a professor of medicine. “Bone metastases destroy the bone, causing fractures and pain. If the tumors reach the spine, it can cause paralysis. There is no cure once breast cancer reaches the bone, so there is a tremendous need to develop new therapies for these patients.”
In the study, the researchers showed that breast cancer cells that spread to bone carry molecules on their surface that are a bit like Velcro, helping tumor cells stick to the bone. These adhesion molecules also sit on the surface of cells responsible for bone remodeling, called osteoclasts.
“In healthy bones, osteoclasts chew away old, worn out bone, and osteoblasts come in and build new bone,” said Weilbaecher, who treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “But in cancer that spreads to bone, tumors take over osteoclasts and essentially dig holes in the bone to make more room for the tumor to grow.”
Weilbaecher said she and her colleagues were surprised to find that the same adhesive molecule on the surface of osteoclasts also is present in high levels on the surface of the breast tumors that spread to bone. The research showed that the molecule — called integrin αvβ3 — was absent from the surfaces of the original breast tumor and from tumors that spread to other organs, including the liver and the lung. The researchers confirmed that this pattern also was true in biopsies of human breast tumors that had spread to different organs.
A collaboration with co-senior author Gregory M. Lanza, MD, PhD, a professor of medicine and of biomedical engineering, then led to the design of a nanoparticle that combines the bone-adhesion molecules with a form of the cancer drug docetaxel, which is used to treat breast cancer as well as other tumors. The adhesive molecules allow the nanoparticle to penetrate the otherwise protective environment of the bone matrix in a way that, in essence, mimics the spreading of the tumor cells themselves. The result is a delivery method that keeps the chemotherapy drug contained in the nanoparticle until the adhesion molecules make contact with the tumor cell, fusing the nanoparticle with the cell surface and releasing the drug directly into the cancer cell.
“When we gave these nanoparticles to mice that had metastases, the treatment dramatically reduced the bone tumors,” Weilbaecher said. “There was less bone destruction, fewer fractures, less tumor. The straight chemo didn’t work very well, even at much higher doses, and it caused problems with liver function and other toxic side effects, which is our experience with patients. But if we can deliver the chemo directly into the tumor cells with these nanoparticles that are using the same adhesive molecules that the cancer cell uses, then we are killing the tumor and sparing healthy cells.”
This work was supported the National Institutes of Health (NIH), grant numbers CA154737, CA100730, CA097250, HL122471, HL112518, HL113392, HHSN26820140042C, P30CA091842, CA143057, CA69158, 5T32GM007067-39, T32AR060719, 5T32CA113275-07 and GM07200; the St. Louis Men’s Group Against Cancer; Siteman Cancer Center; the Washington University Center for Cellular Imaging, supported by Washington University School of Medicine, the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital, grant number CDI-CORE-2015-505; the National Institute for Neurological Disorders and Stroke, grant number NS086741; The Foundation for Barnes-Jewish Hospital. Technical support was provided by the Washington University Musculoskeletal Research Center, grant number P30AR057235; the Hope Center Alafi Neuroimaging Lab, shared instrumentation grant S10 RR027552; the Molecular Imaging Center at Washington University, grant number P50 CA094056; and the St. Louis Breast Tissue Registry funded by the Department of Surgery at Washington University School of Medicine in St. Louis.
Ross MH, Esser AK, Fox GC, Schmieder AH, Yang X, Cui G, Pan D, Su X, Xu Y, Novack DV, Walsh T, Colditz GA, Lukaszewicz GH, Cordell E, Novack J, Fitzpatrick JAJ, Waning DL, Mohammad KS, Guise TA, Lanza GM, Weilbaecher KN. Bone-induced expression of integrin β3 on breast cancer metastases enables targeted nanotherapy. Cancer Research. Aug. 30, 2017.Washington University School of Medicine
’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish
and St. Louis Children’s
hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation, currently ranked seventh in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare
.Siteman Cancer Center
, ranked among the top cancer treatment centers by U.S. News & World Report, also is one of only a few cancer centers to receive the highest rating of the National Cancer Institute (NCI) – “exceptional.” Comprising the cancer research, prevention and treatment programs of Barnes-Jewish Hospital
and Washington University School of Medicine
in St. Louis, Siteman treats adults at five locations and partners with St. Louis Children’s Hospital
in the treatment of pediatric patients. Siteman is Missouri’s only NCI-designated Comprehensive Cancer Center and the state’s only member of the National Comprehensive Cancer Network. Through the Siteman Cancer Network
, Siteman Cancer Center works with regional medical centers to improve the health and well-being of people and communities by expanding access to cancer prevention and control strategies, clinical studies and genomic and genetic testing, all aimed at reducing the burden of cancer.