Scientific and Technical Aerospace Reports Volume 39 April 6, 2001

strides in detection, diagnosis, and treatment. The Molecular Medicine graduate training program at Yale was recently developed
to address these issues. This program was developed to offer an interdisciplinary course of study that will foster an integrated view
of disease, built upon a rigorous foundation of basic sciences. The emphasis on disease mechanisms and translational research
is unique to Molecular Medicine, and distinguishes it from other pre-doctoral programs at Yale. The Predoctoral Training Program
in Breast Cancer Research will recruit individuals interested in careers in breast cancer research to the Molecular Medicine Program,
provide specialist training in breast cancer-specific areas, and integrate their training experience with basic scientists and
clinicians investigating breast cancer at Yale.
DTIC
Mammary Glands; Cancer; Education; Diagnosis
20010025746 New York Univ. Medical Center, New York, NY USA
Factors Modulating Estrogen Receptor Activity Final Report, 1 Jan. 1996-30 Jun. 2000
Garabedian, Michael; Jul. 2000; 64p; In English
Contract(s)/Grant(s): DAMD17-96-1-6032
Report No.(s): AD-A385859; No Copyright; Avail: CASI; A04, Hardcopy; A01, Microfiche
Our goal to elucidate the molecular mechanisms of transcriptional regulation by the estrogen receptor alpha (ER) in breast
cancer. ER is a hormone-dependent transcription factor involved in the regulation of both normal and malignant breast cell growth
by controlling target genes and signaling pathways involved in cellular proliferation. ER signal transduction and transcriptional
regulation is modulated by accessory proteins and through phosphorylation. The N-terminus of ER contains a transcriptional
activation function, AF-1, that is phosphorylated at four major sites in cultured mammalian cells. Several kinases have been identified
that phosphorylate ER in vitro at the identified sites. of these, we have shown that the cyclin A/ cyclin-dependent kinase 2
complex (cyclinA/Cdk2) phosphorylate serine 104 (S104) and serine 106 (S106) and that the phosphorylation of these sites is
important for ER function: serine to alanine mutations of S104 and S106 decrease ER transcriptional activation. In addition, we
have identified the hsp90 associated cochaperone p23 as an important regulator of the ER signaling pathway. Finally, results from
our lab have established the Rho GTPases as novel modulators of ER transcriptional activation.
DTIC
Hormones; Estrogens; Cancer
20010025758 Johns Hopkins Univ., Baltimore, MD USA
Oncolytic Gene Therapy for Prostate Cancer Annual Report, 1 Sep. 1998-31 Aug. 1999
Simons, Jonathan W.; Sep. 1999; 41p; In English
Contract(s)/Grant(s): DAMD17-98-1-8475
Report No.(s): AD-A385895; No Copyright; Avail: CASI; A03, Hardcopy; A01, Microfiche
The overall purpose of this award has been to study the molecular pharmacology of replication restricted adenoviral vectors
for prostate cancer gene therapy. The scope of the research is to identify relevant transcription units, which are prostate and cancer
selective for the creation of potent oncolytic adenoviral vectors for ultimate translation to human clinical trials. Major findings
of this award have been several. First, we have developed a first generation vector, CN706, which is prostate selective for PSA
based on regulation of the ElA gene by the prostate specific enhancer promotor PSE from the PSA gene. Second, our DOD award
research studies show antineoplastic action by killing by apoptosis. These vectors kill hormone refractory prostate cancer clones,
which can be synergized by ionizing radiation at doses, which are clinically administered. We also have found these vectors have
preclinical efficacy when given intravenously. Second, we have identified a new transcription unit, and the HIF gene as potent
constructs and targets for improved gene therapy killing of hypoxic prostate cancer cells in vitro and in vivo. Our studies show
that HIF is expressed as a gene therapy target in prostate cancer, but not normal prostate cells in humans and transgenic models.
Basic research and creation of HIF PSA chimeric Ad S vectors has disclosed HIF is an important transcription target for oncolytic
vectors. These new discoveries are currently being exploited in the creation of second generation vectors. The molecular pharmacology
of oncolytic vectors suggests this is a new antineoplastic modality for hormone refractory prostate cancer.
DTIC
Clinical Medicine; Genes; Pharmacology; Prostate Gland
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