‘Homing’ in on side effect-free therapies

New tumor-homing peptide from Sanford-Burnham shrinks tumors with lower dosage, no apparent side effects

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LA JOLLA, Calif.—Standard anti-cancer therapies likechemotherapy have long been a mixed blessing. No one can deny theireffectiveness or their results, but the sometimes-harsh side effects—such asnausea, weakened immune systems and risk of developing secondary cancers—stackup against chemotherapy's benefits rather quickly. Researchers continue to tryand develop new ways of increasing the effectiveness of cancer drugs whileminimizing the toll they take on the rest of a patient's body.
And scientists at Sanford-Burnham Medical Research Institutemay have found one such method.
A team of researchers led by Dr. Michiko Fukudaexperimented with coupling a cancer drug to a small protein specificallyattracted to the blood vessels that feed tumors, known as IF7. When tested in amouse model with human colon cancer, IF7 was seen to carry the drug directly totumors, suppressing growth at a low dosage with no apparent side effects. Theresults of the study were published the week of Nov. 21 in the Proceedings of the National Academy ofSciences.
"We can cure terminal stage mice with very large tumorswithout any side effects simply by giving them this drug coupled with IF7,"Fukuda, a professor in Sanford-Burnham's National Cancer Institute-designatedCancer Center and corresponding author of the study, said in a news release.
In the study, entitled "Targeted drug delivery to tumorvasculature by a carbohydrate mimetic peptide," the Sanford-Burnham teamcoupled IF7 with a fluorescent probe, then administered it to mice with humancolon tumors. The probe was shown to light up the tumors within minutes. Theythen coupled IF7 with SN-38, an anti-cancer drug, and engineered the tumors toglow, allowing them to see that tumors in the mice that received IF7 shrankdramatically, while remaining unchanged in mock-treated mice. Thanks to thetargeting ability of IF7, only one-seventh the amount of SN-38 used in aprevious study to treat mouse tumors was used in this study, and blood testsshowed no signs of side effects in the treated mice.
Fukuda says that in termsof dosage reductions (compared to current treatments), "Our study with mousecolon tumor models showed 1/4.6 reduction to large tumors, and 1/36.8 reductionto 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 cellularprocesses, including tumor formation and metastasis. Working with IF7 and otherpeptides, collections of short proteins, allowed the researchers to work aroundthe difficulties related to synthesizing carbohydrates in the lab in pursuit offinding something capable of mimicking carbohydrates and inhibitingcarbohydrate-dependent metastasis.
The peptide works by binding annexin 1, acarbohydrate-binding protein found in high levels on the surfaces of bloodvessels that nourish tumors. Fukuda notes that, "Dr. Jan Schnitzer's groupworked on this issue extensively. Their study showed annexin 1 is specificallyexpressed on endothelial cell surface in many tumor types, not limited tocertain kinds," implying that IF7 could be effective in the treatment ofseveral types of cancer. 
"In our previous studies on carbohydrate mimetic peptides,we identified 10 phage clones each displaying unique carbohydrate mimeticpeptide," says Fukuda. "One of the peptides designated as I-peptide bound to afragment of annexin 1 in the lung.  Phageclone displaying IF7 sequence was the only clone [that] preferentially targetstumor over lung in vivo in themouse."
Dr. Minoru Fukuda, a professor in Sanford-Burnham'sCancer Center and co-author of the study, noted in a news release that,"Although we tested colon tumors in this study, theoretically any tumor thatinduces expression of annexin 1 in blood vessels would work with this system—itjust depends on what kind of drug it's paired with."
The National Cancer Institute, the U.S. Department of Defense andSusan G. Komen for the Cure funded this study. Co-authors include, in additionto Michiko Fukuda and Minoru Fukuda, Shingo Hatakeyama, Toshiaki K. Shibata,Tomoya O. Akama, Naoaki Tamura, Shuk-Man Wong, Andrey A. Bobkov and YutakaTakano of Sanford-Burnham; Kazuhiro Sugihara, of Hamamatsu University School ofMedicine; Jun Nakayama of Shinshu University Graduate School of Medicine; andChikara Ohyama of Hirosaki University School of Medicine.

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