Molecular Oncology

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.

A Test for Brain Tumors
In 2001, Institute researchers used leading-edge, gene-chip analysis to discover a new cancer biomarker: laminin-411 (formerly known as laminin-8). Human gliomas excessively produce laminin-411, which plays an important role in the ability of tumor cells to spread and grow (Cancer Res. 2001, 61:5601-5610). This biomarker was later analyzed in a number of human gliomas and showed a significant correlation with glial tumor grade, time to recurrence and patients' survival times (Cancer, 2004 101:604-612, Front Biosci. 2006, 11:81-88).

This test is being used to evaluate the biological behavior of gliomas in order to better plan individualized therapeutic treatment and follow-up regimens for each patient.

Ongoing Implications for Tumor Development
Brain tumor progression was associated with overexpression of a major cancer blood vessels structural protein, laminin-411 (former laminin-8). The overproduction of the same "tumorogenic protein" was detected during penetration of vascular BMs that occurs when tumors grow and spread to other parts of the body, forming metastasis into the brain (e.g., breast tumor metastasis in the brain). Abnormal interactions between cancer cells and laminin are major traits of malignant disorders.

Published data from the Institute showed that laminin-411 is mainly expressed in vascular BMs of an especially aggressive form of brain tumor (glioblastoma multiforme). The other isoform of laminin-421 (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. After laminin-411 was inhibited, glioma cells were less invasive and animals with brain tumors survived longer (Mol.Cancer Ther, 2003, 2:985-994; Angiogenesis 2006 9:183-191, Nanomedicine, 2008, 3:247-265, PNAS, USA 2010 107:18143-18148).

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. Researchers at Cedars-Sinai and biochemists at the University of Regensburg in Germany have developed a novel cancer-treatment delivery system based on nanomedicine technology. This technology 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 the Institute, 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. The new delivery technology 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 currently studying Polycefin's effects on malignant brain tumor (glioma) cells and breast cancer cells.

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