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Method of Rapidly Identifying Inhibitors of Topoisomerase DNA Religation (S00014.pdf)

Inventors
Frederic Bushman and Young Hwang

Applications
Infection, Oncology, Antibacterials, Antifungal, Antiviral, Drug Discovery and Development
High throughput screen for compounds that modulate topoisomerase activity

Topoisomerases play a central role in nucleic acid metabolism and are important in a variety of biological processes related to cell division, DNA replication, chromosome structure and gene expression. Compounds that act as effective cellular inhibitors of topoisomerases are expected to act as cytotoxic agents through the disruption of the normal cell division process. Such compounds can be effective and selective antibacterial, antifungal and antiviral agents. And because cell division is an important characteristic of cancers and other proliferative diseases, agents that inhibit topoisomerases are also useful as antineoplastic agents. The invention provides methods for identifying topoisomerase activity modulators in both solid and liquid phase formats. High throughput screening methods, compositions, kits and integrated systems for performing the assays are provided. The invention represents an improvement over existing technology in several ways. Through the use of different nucleic acid substrates, the assays can be adapted to screen for inhibitors of numerous different classes of topoisomerase enzymes and assay multiple different topoisomerase enzymes in a single reaction, thus enhancing throughput. The assays can be run in a parallel fashion such that multiple different topoisomerase enzymes and/or modulators are assayed simultaneously. The assays can be performed in the liquid or solid phase and each of the formats is readily amenable for automation and high throughput screening. Further, the assays are are extremely sensitive relative to previous assay formats and only minimal quantities of reagents are required..

References
Nucleic Acids Res 28(24):4884-92 (December 2000)

Patent Status:

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Compounds Useful for the Modulation of Processes Mediated by Nuclear Hormone Receptors, Methods for the Identification and Use of Such Compounds (S97012.pdf)

Inventors
Ronald Evans and Laszlo Nagy

Applications
Oncology, Drug Discovery and Development
Compositions for treatment of cancer, comprised of a ligand for a member of the steroid/thyroid hormone superfamily of receptors and a histone deacetylase inhibitor

It has been discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. It has further been discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors. The invention includes compositions for the treatment of cancer, which are made up of a ligand for a member of the steroid/thyroid hormone superfamily of receptors and a histone deacetylase inhibitor. Preferred ligands are ligands for retinoid receptors (e.g., all-trans retinoic acid, 9-cis retinoic acid), ligands for thyroid hormone receptors or ligands for vitamin D3 receptor. Preferred inhibitors included histone deacetylase inhibitors (e.g., Trichostatin A, Trapoxin), and chromatin remodeling machinery inhibitors..

References
Cell 1997 May 2;89(3):373-80
Nature 1998 Feb 19;391(6669):811-4
Published PCT application WO98/48825

Patent Status:

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Treatment of Disease States which Result from Neoplastic Cell Proliferation Using PPAR-gamma Activators and Compositions Useful Therefor (S96024A.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Oncology, Drug Discovery and Development
Administration of PPAR-gamma agonists, optionally in combination with RXR specific agonists, can block neoplastic cell proliferation

Neoplastic cell proliferation is the underlying cause of a wide variety of diseases, e.g., breast cancer, leukemia, colon cancer, prostate cancer. Traditional approaches to treatment of neoplastic cell proliferation include surgery, chemotherapy and radiotherapy. Induction of terminal differentiation represents a promising alternative to conventional methods of treatment for certain malignancies. It has been discovered that PPAR-gamma is expressed consistently in tissues associated with a variety of disease states which result from neoplastic cell proliferation. Maximal activation of PPAR-gamma with exogenous ligand promotes terminal differentiation of primary cells which are otherwise subject to neoplastic cell proliferation. Thus, cells undergoing neoplastic cell proliferation can be induced to differentiate, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent agents for induction of differentiation of cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of cells subject to neoplastic cell proliferation with a PPAR-gamma-selective ligand, in combination with an RXR-specific ligand, results in an additive stimulation of differentiation. The invention includes compounds and compositions which could be useful for the treatment of breast cancer, leukemia, colon cancer and prostate cancer..

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:

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Treatment of Liposarcomas Using a Combination of Thiazolidinediones and Retinoid X Receptor Selective Agonists (S96023A.pdf)

Inventors
Ron Evans, Peter Tontonoz, and Barry Forman

Applications
Oncology, Drug Discovery and Development
Compositions useful for the treatment of liposarcomas

Liposarcoma is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group. Localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. The development of effective, noninvasive methods for treating liposarcomas would represent a significant advancement in the therapeutic arts. It has been discovered that PPAR-gamma is expressed consistently in each of the major histologic types of human liposarcoma. Maximal activation of PPAR-gamma with exogenous ligand (a thiazolidinedione or derivative thereof) promotes terminal differentiation of primary human liposarcoma cells, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent adipogenic agents in cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of liposarcoma cells with a thiazolidinedionyl moiety (a PPAR-gamma-selective class of compounds) and an RXR-specific ligand results in an additive stimulation of differentiation. The invention includes compositions useful for the treatment of liposarcomas..

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:

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Transcription Factor Regulating FGF-2 and Variants Thereof (S98015.pdf)

Inventors
Fred H. Gage and Tetsuya Ueba

Applications
Oncology, Diagnostic, Drug Discovery
Genes which encode polypeptides that are FGF-2 regulators of transcription

This invention is based on the discovery of genes which encode polypeptides that are FGF-2 regulators of transcription (RFT). RFT-A, a negative regulator of transcription and RFT-A' and RFT-B, positive regulators of FGF-2 transcription are provided. The invention also relates to methods for diagnosis of prognosis for a subject having or at risk of having a disorder associated with FGF-2 and for treatment of cell proliferative disorders associated with FGF-2, such as neoplasia, atrocytoma, glioma, glioblastoma, medulloblastoma, colon cancer, lung cancer, renal cancer, leukemia, testicular cancer, breast cancer, prostate cancer, endometrial cancer and neuroblastoma. Screening methods for identifying a compound which affects RFT-A polypeptide or a variant of RFT-A polypeptide and for identifying proteins that bind to RFT-A polypeptide or a variant of RFT-A are also provided..

References
J Biol Chem 274(15): 10382-7 (April 1999)

Patent Status:

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Gonadotrophin Releasing Hormone (GnRH) Analogs (S96027.pdf)

Inventors
Jean Rivier, John Porter, Steven Koerber, Carl Hoeger

Applications
Drug Development, Oncology, Fertility
Potent GnRH antagonists with significantly increased duration of action, useful for applications including fertility regulation, endometriosis, hormone-dependent tumors, and precocious puberty.

GnRH is a hypothalamic decapeptide that stimulates the secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These hormones modulate the levels of testosterone and estrogen in the body. The amino acid sequence of GnRH was discovered in 1971, and spawned the development of GnRH agonists and antagonists with many scientific and pharmaceutical perspectives. Certain advantages of antagonists are that they require a shorter administration period and pituitary suppression is immediately reversible after withdrawal of the antagonist. A breakthrough made at the Salk Institute was the discovery that acylated 4-aminophenylalanines in the L- and D-configurations at positions 5 and 6 respectively and an isopropyl-lysine at position 8 along with other established modifications at positions 1, 2, 3 and 10 yielded potent GnRH analogs with significantly increased duration of action. These antagonists are useful as fertility regulators (in vitro fertilization) and for the treatment of pathological conditions such as precocious puberty, hirsutism, acne, hormone dependent neoplasia, uterine myoma, amenorrhea, dysmenorrhea, endometriosis, PMS, ovarian and mammary cystic diseases, such as PCO, and hormone-dependent tumors, including malignant and benign prostatic, mammary, ovarian and testicular tumors..

References
J. Med. Chem. 1995, 38, 2649-2662
J Med Chem. 2000, 43(5):807-18

Patent Status:
U.S. Patent 5,352,796 issued Oct. 4, 1994 entitled Amino Acids Useful in Making GnRH Analogs
U.S. Patent 5,744,450 issued April 28, 1998 entitled GnRH Analogs

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Melanin-Concentrating Hormones (S48600.pdf)

Inventors
Joan Vaughan, Wolfgang Fischer, Jean Rivier, Jean-Louis Nahon, Francoise Presse, Wylie Vale

Applications
CNS, Oncology, Drug Discovery and Development
MCH as a therapeutic for suppression of melanoma-proliferation by topical application of melanin-concentrating hormones, or as a target for molecules acting on MCH

The invention relates to mammalian melanin-concentrating hormone (MCH), MCH precursors (NEI and NGE) and DNA encoding same. Mammalian MCH is useful to treat humans and other mammals to lighten skin color, by local or topical application. It is also useful to suppress the proliferation of certain skin tumor cells, such as melanomas, when suitably applied by topical application or the like. It is also found that mammalian MCH can be used to modulate the secretion of ACTH in humans and other mammals and thus can be used to modify the effects of stress, by systemically administering an effective amount of mammalian MCH..

References
Endocrinology 125: 1660-1665 (1989) and 130: 1024-1029 (1992)
Neuroscience Lett. 136: 145-149 (1992)

Patent Status:
U.S. Patent No. 5,449,766 issued September 12, 1995 (S55511)

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Corticotropin Releasing Factor-Binding Protein (CRF-BP) (S54426.pdf)

Inventors
Wylie Vale, Ellen Potter, Dominic Behan, Wolfgang Fischer, Elizabeth Linton, and Philip Lowry

Applications
CNS, Cardiovascular, Oncology, Obesity, Drug Discovery and Development
Proteins capable of binding and modulating the biological effect of CRF

The invention relates to CRF-BPs which are capable of binding to and modulating the biological effect of CRF and which have therapeutic applications. These CRF-BPs can be administered therapeutically to bind to and inactivate CRF thereby reducing high ACTH levels in mammals caused by excess CRF and can be used to treat Cushing's Disease, and the like. These CRF-BPs are also useful in combating pituitary tumors that produce CRF. Moreover, they can be used to reduce pituitary ACTH secretion and hence reduce cortisol levels under any condition in which they are abnormally high, such as during chronic stress or in patients afflicted with anorexia nervosa or alcoholism. CRF-BP or fragments thereof and/or antibodies to the proteins may be employed in diagnostic assays to determine the levels of CRF, CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. The DNA or subsequence thereof can be used as probes for genetic material in certain assays. The anti-CRF-BP antibodies are also useful to purify the CRF-BP protein and to modulate the biological effect of the CRF-BPs proteins. CRF-BPs can also be employed to screen for inhibitors which may be used to treat obesity and Alzheimer's disease..

References
Nature 349:423-426 (January 1991)
Genomics 16:63-68 (1993)

Patent Status:
U.S. Patent No. 5,733,790 issued March 31, 1998
U.S. Patent No. 5,910,428 issued June 8, 1999
Numerous Foreigns

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S54426
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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New Tumor Mouse Models Using Lentiviral Vectors (S07006B.pdf)

Inventors
Tomotoshi Marumoto, Inder Mohan Verma, Yasushi Soda, Yifeng Xia

Applications
Oncology, CNS, Transgenic Animals
Methods, compositions and systems for modeling tumorigenesis and generating tumor cells that are representative of human tumors in model animals.

Incidence rates of primary CNS lymphoma in patients over age 60 have increased nearly 10-fold in the past two decades, and a form of primitive neuroectodermal tumor is the most frequent CNS tumor in children. Regardless of treatment, the prognosis of these and similar brain tumors is dismal. Primary reasons for the lack of therapeutic advances include insufficient knowledge about lymphomagenesis, the identity of the appropriate tumor cells to target, and the absence of good animal models. Current tumor models typically employ a shotgun approach that generates random or unrepresentative tumors, or manipulates every cell, causing them to undergo tumorigenesis en masse. Most of these model systems have been used for drug testing and for studying molecular mechanisms of oncogenesis. Unfortunately, because they are also based on the activation of oncogenes or inactivation of suppressors in the immature cells of the fetus or neonatal mice, most do not faithfully mimic human tumors in adults. In order to recapitulate what actually happens in the tumor in humans, it is necessary to induce oncogenic events in adult mice in a cell-type-specific manner. For example, tumors more typically initiate by activating oncogenes or inactivating suppressor genes in single cells, then progress to a malignant phenotype by accumulation of additional mutations. Furthermore, current models do not take into account the role of the normal cells surrounding a mutated cell in tumor progression. Scientists at the Salk Institute have developed a novel way to induce oncogenic event(s) in adult mice in a cell-type-specific manner using lentiviral vectors that are able to infect non-dividing cells in most organs in adult mice. In proof-of-principle experiments, an animal model intra-cranially transplanted with patients' lymphoma cells is the first to reproduce the necessary microenvironment for the generation of primary CNS lymphomas. The resulting tumor cells showed very similar histological characteristics to human glioblastomas, were able to survive in culture, and formed neurosphere-like structures. As few as 100 cells could regenerate a robust glioma, indicating the presence of tumor stem/initiating cells that could be the target of therapy. Similar technology can be applied to any organ, such as pancreas, breast, and prostate, and tumor models based on this approach could be excellent candidates to use for drug screening. .

References
None to date

Patent Status:
U.S. Patent Filed 3/5/2007

License Terms:
Non-Exclusive Licenses available by field of use

Reference_Number: S07006B
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu