Principal Investigator: Julia Y. Ljubimova, MD, PhD

Researchers at the Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute have discovered and analyzed genes that appear to be involved in the genesis and growth of brain tumors.

Some of the new genes and corresponding proteins, laminins, are the major components in basement membranes (BMs) which play a primary role in cell adhesion, polarity, migration and differentiation. During tumor development laminin 411 (former laminin-8) was observed during the development of cancer blood vessels, and during penetration of vascular BMs that occurs when tumors grow and spread to other parts of the body. Abnormal interactions between cancer cells and laminin are major traits of malignant disorders.

Published data from the institute¿s molecular oncology laboratory showed that laminin 411 is mainly expressed in vascular BMs of an especially aggressive form of brain tumor (glioblastoma multiforme). Another alpha 4 chain-containing laminin (laminin-9) is mainly expressed in the blood vessel walls of low-grade, less aggressive tumors and in normal brain. Acting on this finding, researchers blocked laminin 411 expression using a compound (antisense oligonucleotides) to significantly reduce the spread of human glioma cells by in cell culture.
Laminin 411 also appears to be a marker not only for highly invasive glial tumors, but also for invasive breast tumors. After evaluating tissue samples of human breast tissue of both high- and low-grade carcinomas and tissue samples of normal breast, researchers observed a clear tendency for laminin 411 to be overexpressed in highly invasive breast tumors.

Laminin 411 may prove crucial to tumor progression, spread and angiogenesis, the process of new blood vessel formation that allows tumors to develop the ability to spread. However there were no methods available to prevent synthesis of this complicated structural protein for human treatment. Therefore researchers in the Department of Neurosurgery at Cedars-Sinai Medical Center, working with biochemists at the University of Regensburg in Germany, are developing a novel cancer-treatment delivery system based on nanomedicine technology that appears to be safe and effective after several years of laboratory and animal studies.

The new drug called Polycefin is a molecular biopolymer engineered to interrupt the changes in blood vessels that allow tumors to develop. Its specific targets are genes coding for laminin-411, which influence the thin basement membrane, the structural component of the blood vessels. Polycefin may offer the first therapeutic approach aimed at blood vessel changes for multiple chain proteins such laminins and collagens.

Polycefin, which is 20 to 30 nanometers in size, acts as a drug itself but also can be engineered to transport other therapeutic molecules, possibly leading to the creation of highly potent, patient-specific treatment options. In laboratory work at Cedars-Sinai, researchers attached antisense oligonucleotides (short strands of genetic material that interrupt gene-encoded protein synthesis) and monoclonal antibodies (immune molecules that target specific antigens for tumor-specific targeting) to the Polycefin molecule for transport into tumor cells. Theoretically, the delivery by a single carrier molecule of multiple drugs could produce a simultaneous, synergistic effect that is not seen when drugs are delivered individually over time.

The platform of the drug is ultra-purified polymalic acid derived from the slime mold. It appears to be completely and harmlessly ¿digested¿ by the body after serving its purpose, leaving no residue behind. Furthermore, in laboratory and animal studies, Polycefin was able to cross the blood-tumor-brain barrier and accumulate in cancer cells, suggesting it may be used to target brain tumors without affecting normal surrounding tissue. Results of animal studies have documented increased length of survival following drug administration.

Cedars-Sinai researchers are studying Polycefin¿s effects on malignant brain tumor (glioma) cells and breast cancer cells.

Ljubimova JY, Fugita M, Khazenzon NM, Das A, Pikul BB, Newman D, Sekiguchi K, Sorokin LM, Sasaki T, Black KL. Association between laminin-8 and glial tumor grade, recurrence, and patient survival. Cancer 101:604-612, 2004.

Fujita M, Khazenzon NM, Shikha Bose S, Sekiguchi K, Sasaki T, Carter WG, Ljubimov AV, Black KL Ljubimova JY. Overexpression of â1 chain-containing laminins in capillary basement membranes of human breast cancer and its metastases. Breast Cancer Res 7:R411-R421, 2005.

Ljubimova JY, Fujita M, Khazenzon NM, Ljubimov AV, Black KL. Changes in laminin isoforms associated with brain tumor invasion and angiogenesis. Front Biosci 11:81-88, 2006.

Lee BS, Fujita M, Khazenzon NM, Wawrowsky KA, Wachsmann-Hogiu S, Farkas DL, Black KL, Ljubimova JY, Holler E. Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(β-L-malic acid) for drug delivery. Bioconjug. Chem. 17:317-326, 2006.

Ljubimova JY, Fujita M, Lee BS, Khazenzon NM, Wachsmann-Hogiu S, Farkas DL, Black KL, Holler E. Nanoconjugates of poly(malic acid) with functional modules for drug delivery. NSTI-Nanotech, 2:354-357, 2006.

Fujita M, Khazenzon NM, Ljubimov AV, Lee BS, Virtanen I, Holler E, Black KL, Ljubimova JY. Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Angiogenesis 9:183-191, 2006.

Ljubimova JY, Fujita M, Khazenzon NM, Lee BS, Wachsmann-Hogiu S, Farkas DL, Black KL, Holler E. (2007) Nanoconjugate based on polymalic acid for tumor targeting. Chem. Biol. Interact. v.162, in press.

Fujita M, Lee B-S, Khazenzon NM, Wawrowsky KA, Penichet M, Patil R, Ding H, Holler E, Black KL, Ljubimova JY Direct brain tumor targeting using combination of monoclonal antibodies attached to biopoly(β-L-malic acid). J. Controlled Release,122:356-363, 2007.

Fujita M, Khazenzon NM, Lee BS, Holler E, Black KL, Ljubimova JY. Development of Nanoconjugate with Different Monoclonal Antibodies to Inhibit Molecular Targets Important for Tumor Angiogenesis. Chapter 9: Cancer Diagnostics, Imaging & Treatment. NSTI-Nanotech, 2:760-762, 2007.

For an appointment, a second opinion or more information, please call 1-800-CEDARS-1 (1-800-233-2771) or e-mail us.