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2007




Development of Targeted Therapy Strategies for Breast Cancer
Posted October 8, 2007
Gabriel N. Hortobagyi, Ph.D, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Fiscal Year 2001 Department of Defense Breast Cancer Research Program (BCRP) Center of Excellence (COE) awardee Dr. Gabriel Hortobagyi, along with a team of scientists and a consumer advocate from the University of Texas M. D. Anderson Cancer Center, the University of California - Irvine, and the University of California - Davis, have joined forces to focus efforts on developing new therapeutic targets and improved strategies for diagnosing and treating breast cancer. Specifically, the team of COE investigators is targeting the phosphatase and tensin homolog (PTEN)/PI3K pathway and the BRCA1/2 DNA repair pathway to identify molecules for therapeutic targeting in breast cancer patients. They are also evaluating whether the pro-apoptotic genes Bik and Bok are suitable targets for systemic gene therapy, and they are developing new mouse models of breast cancer to test the efficacy of novel therapeutics and facilitate their rapid progression into clinical trials. In keeping with the BCRP's goal of promoting the active involvement of consumer advocates, this COE includes integral consumer input highlighting the consumer perspective for the scientists in the group and helping to maintain the translational focus of the entire program. The COE is supported by a web-based communication system that facilitates interaction between laboratory personnel, investigators, clinicians, and consumer advocates. This approach affords access to the latest developments and research results from the COE and offers opportunities for consumers to participate in clinical trials and other related research activities.

In vitro and in vivo studies conducted by COE investigators have identified inhibitors of AKT, mTOR, and PI3 kinase as potentially clinically relevant breast cancer therapeutics. An inhibitor of the pleckstrin homology domain of AKT, perifosine, effectively blocks PI3K signaling and significantly reduces tumor formation in mutant and wildtype PTEN orthotopic breast carcinoma xenograft mouse models. Perifosine will soon enter a Phase I clinical trial in patients with advanced breast cancer. The mTOR inhibitor RAD001 is being tested in two Phase I clinical trials, one of which will target breast cancer cells in patients with trastuzumab-refractory breast cancer. Similarly, the PI3K inhibitor LY294002 prodrug, SF1126, was shown to be effective against the PI3K signaling pathway. Preliminary analyses indicate that reverse protein lysates assays could be used to evaluate specific markers in the PI3K pathway to determine individual patient therapeutic prognostic response to therapy. In other inhibitor studies, two phenylsulfonyl indolyl isoquinolines, IBR1 and IBR2, were shown to successfully disrupt BRCA2-Rad51 interactions in the DNA repair pathway regulated by BRCA1 and BRCA2. This finding has led to the development and testing of second-generation small-molecule compounds that could be used clinically to inhibit cell proliferation and target Rad51 interactions.

In addition to the use of targeted inhibitors, the COE investigators also have developed a liposome-mediated systemic gene therapy to express apoptosis-inducing BikDD, which will soon be tested in a Phase I clinical trial for advanced breast cancer. Furthermore, to improve upon current in vivo gene delivery methods, COE investigators have engineered specialized expression vectors with cancer-specific promoters, a two-step transcriptional activation system, and post-translational regulatory elements that are capable of expressing therapeutic genes by several hundred-fold in breast cancer cells only. Successful testing of these expression vectors in animal models will move these vectors into clinical trials where they will be used to drive breast cancer-specific expression of therapeutic genes such as BikDD.

Finally, COE investigators have developed a breast cancer mouse model in which BRCA1 and p53 genes are conditionally inactivated in the mammary gland. This mouse model mimics the majority of human BRCA1 breast cancers and exhibits significant alterations in mammary gland morphology, increased mammary epithelial cell proliferation, and upregulation of the progesterone receptor. The investigators have demonstrated that treatment of these BRCA1/p53 conditional knockout mice with the anti-progesterone mifepristone significantly delayed the onset of mammary tumor development, reduced mammary gland morphological dysfunction, and retarded mammary epithelial cell and hyperplastic foci progression to tumors. Additionally, specific combinations of chemotherapeutic agents are being tested to assess their efficacy in reducing tumor growth using these mouse models.

As a result of the success of this COE Award, the M.D. Anderson Cancer Center has received a Specialized Program of Research Excellence (SPORE) grant for breast cancer by the National Cancer Institute.

Publications:

Bartholomeusz G, Wu Y, Ali-Seyed M, et al. 2006. Nuclear translocation of the pro-apoptotic Bcl-2 family member Bok induces apoptosis. Mol Carcinogen 45:73-83.

Day C-P, Rau K-M, Qiu L, et al. 2006. Mutant Bik expression mediated by the enhanced minimal topoisomerase II-alpha promoter selectively suppressed breast tumor in animal model. Cancer Gene Ther 13:706-719.

Bartholomeusz G, Wu Y, Ali-Seyed M, et al. 2005. Nuclear translocation of the pro-apoptotic Bcl-2 family member Bok induces apoptosis. Mol Carcinog.

Sellappan S, Grijalva R, Zhou X, et al. 2004. Lineage infidelity of MDA-MB-435 cells: Expression of melanocyte proteins in a breast cancer cell line. Cancer Res 64:3479-3485.

Cheng KW, Lahad JP, Kuo W-L, et al. 2004. The Rab 25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10:1251-1256.

Dong J, Peng J, Zhang H, et al. 2005. The role of glycogen synthase kinase 3b in rapamycin mediated cell cycle regulation and chemosensitivity. Cancer Res 65:1961-1972.

Kohn EC, Y Lu, H Wang, et al. Targeted Therapeutics in Breast Cancer: Challenges to Success. In Diseases of the Breast, Marc Lippman, ed.

Mondesire WH, W Jian, H Zhang, et al., 2004. Targeting mTOR synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin. Cancer Res., 10(20):7031-42.

Noh WC, WH Mondesire, J Peng, et al., 2004. Determinants of rapamycin sensitivity in breast cancer cells. Clin. Cancer Res. 10:1013-1023.

Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, Tsurutani J, Dennis PA, Mills GB, Arteaga CL. 2003. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene 22:2812-2822.

Lin HR, Ting NS, Qin J, Lee WH. 2003. M-phase specific phosphorylation of BRCA2 by Polo-like kinase 1 correlates with the dissociation of the BRCA2-P/CAF complex. Journal of Biochemistry 278:35979-35987.

Kohn EC, Lu Y, Wang H, Yu Q, Yu S, Hall H, Smith DL, Meric-Bernstam F, Hortobagyi GN, Mills GB. 2004. Molecular therapeutics: Promise and challenges. Seminars in Oncology 31:39-53.

Li YM, Wen Y, Zhou BP, Kuo HP, Ding Q, Hung MC. 2003. Enhancement of Bik antitumor effect by Bik mutants. Cancer Research 63:7630-3

Links:

Public and Technical Abstracts: Development of Targeted Therapy Strategies for Breast Cancer

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Center of Excellence in Molecular Targeting of Breast Cancer Metastasis
Posted October 8, 2007
Saraswati Sukumar, Ph.D., The Center for the Prevention and Therapy of Metastatic Breast Cancer, The Johns Hopkins University, Baltimore, Maryland

Fiscal Year 2003 Department of Defense (DOD) Breast Cancer Research Program (BCRP) Center of Excellence (COE) Awardee Dr. Saraswati Sukumar, of Johns Hopkins University, is leading a team of scientists and consumer advocates from The Johns Hopkins University, University of Maryland, University of Texas M. D. Anderson Cancer Center, and Genzyme Oncology to collaboratively develop novel therapies to effectively prevent and treat metastatic breast cancer. COE investigators are combining their expertise in genetics, biochemistry, molecular, and cellular biology to better understand the nature of metastatic breast cancer cells and their surrounding tumor environment. By combining information from gene and protein expression analyses of specific cell types in metastatic tumors, they aim to identify pathways that contribute to metastasis and to discover new molecular targets for use in imaging, immunotherapy, drug therapy, and various combination therapies for breast cancer.

Using a phage display technique to screen immunoglobulins from breast cancer patient serum, COE investigators have made significant progress in identifying multiple tumor cell surface homing peptides, such as GRP78, that have potential for use in imaging, drug discovery, and immunotherapy. In other work, through differential gene expression profile analysis, COE investigators found that malignant breast epithelial cells overexpress homeobox B7 protein (HOXB7), and they also associated HOXB7 overexpression with tamoxifen resistance in estrogen receptor-positive cells. Current FDA-approved (fulvestrant, letrozole) and newly developed (vaccine, pharmacophore mimics) therapeutic agents are being evaluated for their effectiveness as HOXB7 inhibitors. In addition, the COE investigators are developing novel, noninvasive techniques and reagents that will provide better ways to monitor the effectiveness of targeted therapies and also contribute to an increased understanding of metastatic disease. Database resources and a central Communication Core facilitate the sharing of information and reagents among scientists and enable feedback from consumer advocates, thus allowing for faster research progress.

Central to the COE's mission and goals is the role of consumer advocates in communicating the Center's activities and research findings to those affected by breast cancer, other consumer advocates, and the wider scientific community. In addition, consumers partner with investigators to assess the Center's progress and make recommendations to achieve the Center's objectives, resolve issues, and advocate for those affected by breast cancer. Consumer advocates also are involved in the review and analysis of scientific data, prioritizing molecular targets for designing new therapies, selecting drugs for combination therapies, and designing instruments for educational outreach and clinical trials. As a result of their participation in a recent national meeting of the DOD BCRP Centers of Excellence, consumer advocates initiated a study to analyze the Rapid Autopsy Tissue Donation Program (RATDP), a key component of this COE, which is currently administered by scientists in the Tissue and Pathology Resource Core. The goals of the analysis are to determine the impact of RATDP autopsies on families, identify barriers that prohibit participation/donation, and obtain data to design new recruitment instruments for the program.

Publications:

Hajitou A, Trepel M, Lilley CE, et al. 2006. A hybrid vector for ligand-directed tumor targeting and molecular imaging. Cell 125(2):385-398.

Kolonin MG, Sun J, Do KA, et al. 2006. Synchronous selection of homing peptides for multiple tissues by in vivo phage display. FASEB J (7):979-981.

Kolonin MG, Bover L, Sun J, et al. 2006. Ligand-directed surface profiling of human cancer cells with combinatorial peptide libraries. Cancer Res 66(1):34-40.

Davidson NE and Sukumar S. 2005. Of Snail, mice, and women. Cancer Cell 8: 173-174.

Murata S, Kominsky SL, Vali M, et al. 2006. Ductal access for prevention and therapy of mammary tumors. Cancer Res 66(2):638-645.

Liang X, Lau QC, Salto-Tellez M, et al. 2006. Mutational hotspot in exon 20 of PIK3CA in breast cancer among Singapore Chinese. Cancer Biol Ther 5(5) [Epub ahead of print]

Lau QC, Raja E, Salto-Tellez E, et al. 2006. RUNX3 is frequently inactivated by dual mechanisms in breast carcinoma: Protein mislocalization and promoter hypermethylation. Cancer Res 66:6512-6520.

Wu X, Chen H, Parker B, et al. 2006. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial mesenchymal transition. Cancer Res 61:9527-9534.

Murata S, Ladle BH, Kim PS, et al. 2006. OX40 costimulation synergizes with GM-CSF whole cell vaccination to overcome established tolerance to an endogenous tumor antigen. J Immunol 176:974-983.

Murata S, Kominsky SL, Vali M, et al. 2006. Ductal access for prevention and therapy of mammary tumors. Cancer Res 66:638-645.

Emens LA. 2006. Trastuzumab: Molecularly targeted therapy for early and metastatic HER-2/neupositive breast cancer. Johns Hopkins Scientific Advances in Medicine 6:353-363.

Emens LA, Reilly RT, and Jaffee EM. 2005. Cancer vaccines in combination with multimodality therapy. Cancer Treat Res 123:227-245.

Emens LA. 2005. Towards a therapeutic breast cancer vaccine: The next steps. Expert Rev Vaccines 4:831-841.

Emens LA, Reilly RT, and Jaffee EM. 2005. Manipulating immunologic checkpoints to maximize antitumor immunity. In: Immunotherapy of Cancer (Nora Disis, Ed.). Humana Press 331-353.

Macedo LF, Guo Z, Tilghman SL, et al. 2006. Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Res 66(15):7775-7782.

Brodie A, Jelovac D, Sabnis G, et al. 2005. Model systems: mechanisms involved in the loss of sensitivity to letrozole. J Steroid Biochem Mol Biol 95(1-5):41-48.

Jelovac D, Macedo L, Goloubeva OG, et al. 2005. Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model. Cancer Res 65(12):5439-5444.

Jelovac D, Sabnis G, Long BJ, et al. 2005. Activation of mitogenactivated protein kinase in xenografts and cells during prolonged treatment with aromatase inhibitor letrozole. Cancer Res 65(12):5380-5389.

Sabnis GJ, Jelovac D, Long B, et al. 2005. The role of growth factor receptor pathways in human breast cancer cells adapted to long-term estrogen deprivation. Cancer Res 65(9):3903-3910.

Brodie A, Jelovac D, Macedo L, et al. 2005. Therapeutic observations in MCF-7 aromatase xenografts. Clin Cancer Res 11(2 Pt 2):884s-888s.

Glunde K, Ackerstaff E, Mori N, et al. 2006. Choline phospholipid metabolism in cancer: consequences for molecular pharmaceutical interventions. Mol Pharm 3(5):496-506.

Glunde K, Jie C, Bhujwalla ZM. 2005. Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia 8(9):758-771.

Li C, Greenwood TR, Bhujwalla ZM, et al. 2006. Synthesis and characterization of glucosaminebound near-infrared probes for optical imaging. Org Lett 8(17):3623-3626.

Pathak AP, Artemov D, Neeman M, et al. 2006. Bhujwalla ZM. Lymph node metastasis in breast cancer xenografts is associated with increased regions of extravascular drain, lymphatic vessel area, and invasive phenotype. Cancer Res 66(10):5151-5158.

Gimi B, Mori N, Ackerstaff E, et al. 2006. Noninvasive MRI of endothelial cell response to human breast cancer cells. Neoplasia 8(3):207-213.

Gimi B, Leong T, Gu Z, et al. 2005. Self-assembled three-dimensional radio frequency (RF) shielded containers for cell encapsulation. Biomed Microdevices 7(4):341-345.

Glunde K, Raman V, Mori N, et al. 2005. RNA interference-mediated choline kinase suppression in breast cancer cells induces differentiation and reduces proliferation. Cancer Res 65(23):11034-11043.

Mironchik Y, Winnard PT Jr, Vesuna F, et al. 2005. Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res 65(23):10801-10809.

Glunde K, Foss CA, Takagi T, et al. 2005. Synthesis of 6'-O-lissamine-rhodamine Bglucosamine as a novel probe for fluorescence imaging of lysosomes in breast tumors. Bioconjug Chem 16(4):843-851.

Pathak AP, Artemov D, Ward BD, et al. 2005. Characterizing extravascular fluid transport of macromolecules in the tumor interstitium by magnetic resonance imaging. Cancer Res 65(4):1425-32.

Pathak AP, Bhujwalla ZM, Pepper MS. 2004. Visualizing function in the tumor-associated lymphatic system. Lymphat Res Biol 2(4):165-72.

Jacobs MA, Barker PB, Argani P, et al. 2005. Combined dynamic contrast enhanced breast MR and proton spectroscopic imaging: A feasibility study. J Magn Reson Imaging 21(1):23-28.

Links:

Public and Technical Abstracts: Center of Excellence in Molecular Targeting of Breast Cancer Metastasis

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