‘Homing’ in on side effect-free therapies
LA JOLLA, Calif.—Standard anti-cancer therapies like chemotherapy have long been a mixed blessing. No one can deny their effectiveness or their results, but the sometimes-harsh side effects—such as nausea, weakened immune systems and risk of developing secondary cancers—stack up against chemotherapy's benefits rather quickly. Researchers continue to try and develop new ways of increasing the effectiveness of cancer drugs while minimizing the toll they take on the rest of a patient's body.
And scientists at Sanford-Burnham Medical Research Institute may have found one such method.
A team of researchers led by Dr. Michiko Fukuda experimented with coupling a cancer drug to a small protein specifically attracted to the blood vessels that feed tumors, known as IF7. When tested in a mouse model with human colon cancer, IF7 was seen to carry the drug directly to tumors, suppressing growth at a low dosage with no apparent side effects. The results of the study were published the week of Nov. 21 in the Proceedings of the National Academy of Sciences.
"We can cure terminal stage mice with very large tumors without any side effects simply by giving them this drug coupled with IF7," Fukuda, a professor in Sanford-Burnham's National Cancer Institute-designated Cancer Center and corresponding author of the study, said in a news release.
In the study, entitled "Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide," the Sanford-Burnham team coupled IF7 with a fluorescent probe, then administered it to mice with human colon tumors. The probe was shown to light up the tumors within minutes. They then coupled IF7 with SN-38, an anti-cancer drug, and engineered the tumors to glow, allowing them to see that tumors in the mice that received IF7 shrank dramatically, while remaining unchanged in mock-treated mice. Thanks to the targeting ability of IF7, only one-seventh the amount of SN-38 used in a previous study to treat mouse tumors was used in this study, and blood tests showed no signs of side effects in the treated mice.
Fukuda says that in terms of dosage reductions (compared to current treatments), "Our study with mouse colon tumor models showed 1/4.6 reduction to large tumors, and 1/36.8 reduction to small tumors."
Every cell in the body is covered with carbohydrates, which, along with the proteins that bind them, are pivotal in a multitude of cellular processes, including tumor formation and metastasis. Working with IF7 and other peptides, collections of short proteins, allowed the researchers to work around the difficulties related to synthesizing carbohydrates in the lab in pursuit of finding something capable of mimicking carbohydrates and inhibiting carbohydrate-dependent metastasis.
The peptide works by binding annexin 1, a carbohydrate-binding protein found in high levels on the surfaces of blood vessels that nourish tumors. Fukuda notes that, "Dr. Jan Schnitzer's group worked on this issue extensively. Their study showed annexin 1 is specifically expressed on endothelial cell surface in many tumor types, not limited to certain kinds," implying that IF7 could be effective in the treatment of several types of cancer.
"In our previous studies on carbohydrate mimetic peptides, we identified 10 phage clones each displaying unique carbohydrate mimetic peptide," says Fukuda. "One of the peptides designated as I-peptide bound to a fragment of annexin 1 in the lung. Phage clone displaying IF7 sequence was the only clone [that] preferentially targets tumor over lung in vivo in the mouse."
Dr. Minoru Fukuda, a professor in Sanford-Burnham's Cancer Center and co-author of the study, noted in a news release that, "Although we tested colon tumors in this study, theoretically any tumor that induces expression of annexin 1 in blood vessels would work with this system—it just depends on what kind of drug it's paired with."
The National Cancer Institute, the U.S. Department of Defense and Susan G. Komen for the Cure funded this study. Co-authors include, in addition to Michiko Fukuda and Minoru Fukuda, Shingo Hatakeyama, Toshiaki K. Shibata, Tomoya O. Akama, Naoaki Tamura, Shuk-Man Wong, Andrey A. Bobkov and Yutaka Takano of Sanford-Burnham; Kazuhiro Sugihara, of Hamamatsu University School of Medicine; Jun Nakayama of Shinshu University Graduate School of Medicine; and Chikara Ohyama of Hirosaki University School of Medicine.