important discovery --how her2+ breast cancer infiltrates the brain--prevention possi

[Lani]

bilities open up!! Note topoisomerase1 is NOT the same as topoisomerase 2, a gene on the same arm of chromosome 17 as the her2gene (and sometimes amplified with it)


Enzyme presents therapeutic target in breast cancer brain metastasis
[Baylor College of Medicine]
HOUSTON — (February 17, 2010) — The enzyme heparanase plays a critical role in the spread of breast cancer cells to the brain, and, as such, is a promising target for future treatment, said researchers from Baylor College of Medicine and the University of California - Los Angeles, in a report in the current issue of the American Association of Cancer Research journal Molecular Cancer Research.
Allows cells to enter circulation, increases proliferation
The activity of this enzyme, which degrades the extracellular matrix to allow cells to escape into the surrounding tissue and circulation, is associated with the activation of HER2/epidermal growth factor receptor, said Dr. Dario Marchetti, the senior author of the report that elucidates the enzyme's role in spreading cancer cells to the brain. The extracellular matrix is the tissue framework that holds cells together.
Marchetti's experiments show that after cells are treated with epidermal growth factor, heparanase moves to the cell's nucleolus, the site of ribosome production in the nucleus. In that structure, high levels of heparanase activate an enzyme called topoisomerase 1, which is essential for DNA replication and transcription (translation of the genetic message into protein). Heparanase-induced activation of topoisomerase 1 results in a significant increase of cell proliferation.
"This occurs only in metastatic breast cancer cells that have high levels of HER2 and target the brain," said Marchetti. "These findings help us to determine how heparanase works and how it affects the activity of topoisomerase 1 in the life cycle of these cells.
Treatment opportunity
"It also opens an entire treatment spectrum in terms of the clinical application of this enzyme as a promising drug target for the treatment of brain metastasis," said Marchetti.
In the future, he said, it will be important to determine how and where cellular location of heparanase affects its activity with regard to cell differentiation and growth.
"As we try to understand how heparanase goes into the cell's nucleus and/or nucleolus, we will also better understand its role in metastatic events," said Marchetti.
Others who took part in this work include Lixin Zhang and Julie Suyama, also of BCM, and Peggy Sullivan of the University of California - Los Angeles.
Funding for this work came from the National Institutes of Health.


ABSTRACT: Epidermal Growth Factor-Induced Heparanase Nucleolar Localization Augments DNA Topoisomerase I Activity in Brain Metastatic Breast Cancer
[Molecular Cancer Research]
Identification of molecular mechanisms responsible for brain metastatic breast cancer (BMBC) is imperative to develop novel therapies. However, current understanding of the molecular circuitry that governs BMBC dissemination remains fragmentary. Heparanase (HPSE) is the only functional mammalian endoglycosidase whose activity correlates with cancer metastasis, angiogenesis, and the reduced postoperative survival of cancer patients, making it an active target for anticancer therapeutics. We hypothesized that human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) activation promotes HPSE function in human BMBC. To address this, we examined HPSE content, activity, and intracellular trafficking in a HER2/EGFR-expressing BMBC model system and show that HPSE is present, functional, and correlates with HER2 status. Further, we showed that EGF induced nucleolar translocation of HPSE in these cells in a dose- and time-dependent manner upon activation of HER2/EGFR. Knockdowns of HER2/EGFR by small interference RNA abolished EGF-induced HPSE nucleolar translocalization. It was also noted that nucleolar HPSE modulates DNA topoisomerase I (Topo I), an enzyme that is highly present in nucleoli, essential for DNA replication and transcription in a variety of tumors, and inhibited by heparan sulfate. Evidence is provided that HPSE can regulate Topo I activity, which subsequently affects BMBC cell proliferation. Finally, we showed that the nucleolar presence of HPSE with Topo I colocalization is detected only in HER2-overexpressing BMBC patient specimens. Altogether, these findings support the notion that HPSE is a critical downstream target of HER2 mechanisms driving BMBC and is potentially relevant for BMBC therapeutic interventions.

[Rich66]

after cells are treated with epidermal growth factor, heparanase moves to the cell's nucleolus, the site of ribosome production in the nucleus. In that structure, high levels of heparanase activate an enzyme called topoisomerase 1, which is essential for DNA replication and transcription (translation of the genetic message into protein). Heparanase-induced activation of topoisomerase 1 results in a significant increase of cell proliferation.

So...EGF inhibitors like Lapatinib to stop things from the start? Or..Heparanese inhibitors?

Cancer Chemother Pharmacol. 2010 Mar;65(4):743-53. Epub 2009 Jul 25.
Population pharmacokinetic model of PI-88, a heparanase inhibitor.

Hudachek SF, Eckhardt SG, Hicks B, Gustafson DL.
Animal Cancer Center, Department of Clinical Sciences, Colorado State University, 1620 Campus Delivery, Fort Collins, CO 80523-1620, USA. susan.hudachek@colostate.edu
PURPOSE: The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer. METHODS: A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery. RESULTS: Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%). CONCLUSIONS: This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.

PMID: 19633850 [PubMed - indexed for MEDLINE]