NASA Scientific and Technical Aerospace Reports

20040111682 Burnham Inst., La Jolla, CA
Targeting Breast Cancer Vasculature
Ruoslahti, Erkki I.; Mar. 2004; 46 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0315
Report No.(s): AD-A425815; No Copyright; Avail: CASI; A03, Hardcopy
The main problems with current cancer therapies, including those for breast cancer, are that they are only partially
effective and highly toxic. We work on a strategy that enhances the efficacy of anti-tumor therapies, while simultaneously
decreasing the side effects. Our target is the vasculature of tumors. Tumor cells depend on blood supply and the tumor
vasculature is accessible through the blood stream. An added advantage is that the vasculature is composed of normal cell,
which are unlikely to develop resistance to treatments. We identify tumor-specific vascular markers by screening
phage-displayed peptide libraries in mice bearing breast cancer xenografts or endogenous transgenic breast cancers. When the
libraries are intravenously injected into the mice, the phage that have specific affinity for tumor vasculature home to the
tumors. These peptides can then be used to carry drugs and other therapeutics into tumors. The receptors for the peptides are
potential drug targets. During the past year, the main findings are: (1) The discovery of a novel protein, which we have named
metadherin, as a breast cancer cell surface protein that mediates the binding of the tumor cells to the lung vasculature,
facilitating metastasis. (2) The identification of cell surface nucleolin as the receptor for a previously identified tumor-homing
peptide, and (3) the as yet unpublished observation that antibodies to nucleolin have an anti-angiogenic activity in vitro and
in vivo. These finding 5 ma lead to new ways 5 of combating metastasis and inhibiting tumor growth.
DTIC
Blood Circulation; Cancer; Mammary Glands; Toxic Diseases
20040111685 Virginia Univ., Charlottesville, VA
Studies of a Ras Antagonist in Breast Cancer
Santen, Richard J.; May 2004; 13 pp.; In English
Contract(s)/Grant(s): DAMD17-02-1-0609
Report No.(s): AD-A425819; No Copyright; Avail: CASI; A03, Hardcopy
Deprivation of estrogen, called Endocrine Therapy (ET), is commonly used to treat women with estrogen receptor (ER)
positive breast cancer. Resistance to ET occurs in a many women after about 18 months of treatment. Upregulation of growth
factor pathways mediated by the 21 kDa Ras GTPase protein may contribute to resistance to ET. A novel Ras antagonist,
farnesylthiosalicylate (FTS), causes Ras downregulation with concomitant abrogation of growth factor pathways. We tested
the ability of FTS, which was complexed to a cyclodextrin moiety for solubility, to reduce the growth of ER positive breast
cancer cells that were resistant to ET. FTS prevented growth of ER positive breast cancer cells by increasing apoptosis and
reducing proliferation. Accompanying loss of cell growth was a significant reduction in the response to estrogen. The loss of
estrogen response may have been due to an observed loss of ER protein in response FTS treatment. FTS might be causing
reduced cell growth in part by increasing turnover of the ER in ER positive breast cancer cells. FTS was additive with
Doxorubicin in vitro. We suggest that the FTS should enter preclinical trials against ER positive breast cancer.
DTIC
Cancer; Endocrine Glands; Mammary Glands
20040111689 Tel-Aviv Univ., Ramat-Aviv, Tel-Aviv
Analysis of the Secreted Novel Breast-Cancer- Associated MUC1/Zs Cytokine
Wreschner, Daniel H.; Jun. 2003; 32 pp.; In English; Original contains color illustrations
Contract(s)/Grant(s): DAMD17-00-1-0451
Report No.(s): AD-A425838; No Copyright; Avail: CASI; A03, Hardcopy
We report a novel small protein derived from the MUC1 gene by alternative splicing that does not contain the MUC1
tandem repeat array. This protein termed MUCl/Zs (=MUCl/ZD) retains the same N-terminal MUC1 sequences as all MUC1
protein isoforms, that comprises the signal peptide and a subsequent stretch of thirty amino acids. The MUCl/ZD C- terminal
43 amino acids are novel and result from a reading frameshift engendered by a splicing event. Expression of MUCl/ZD was
demonstrated by immunohistochemistry, immunoblotting, immunoprecipitation and an ELISA assay, using MUCl/ZD specific
polyclonal and monoclonal antibodies. MUC1/ZD protein was expressed in cancerous tissues and epithelial cells comprising
skin tissue- its expression did not parallel the mucinous MUC1 protein. MUC1/ZD protein is expressed in tissues as an
oligomeric complex composed of disulfide-linked MUC1 /ZD monomers. Limited homology between the novel MUC1/ZD
C-terminal 43 amino acids and the N-terminal region of CD14, an innate immunity protein, prompted investigations as to
whether MUCl/ZD binds to bacteria. Using transfectants expressing the MUC1/ZD protein we demonstrated that MUCl/ZD
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