National Institutes of Health, Public Health Service, HHS.
The inventions listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in accordance with 35 U.S.C. 207 to achieve expeditious commercialization of results of federally-funded research and development. Foreign patent applications are filed on selected inventions to extend market coverage for companies and may also be available for licensing.
Licensing information and copies of the U.S. patent applications listed below may be obtained by writing to the indicated licensing contact at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.
A Pharmacophore for Isatin-β-Thiosemicarbazone Compounds With MDR1-Inverse Activity
Description of Technology: One of the major hindrances to successful cancer chemotherapy is multi-drug resistance (MDR), which is frequently caused by the increased expression or activity of ABC transporter proteins. Research has generally been directed to overcoming MDR during cancer therapy by inhibiting the activity of ABC transporters. However, compounds that inhibit ABC transporter activity often elicit strong and undesirable side-effects, restricting their usefulness in therapy.
In an alternative approach to reducing the debilitating effects of MDR in cancer therapy, scientists at the National Cancer Institute identified a family of compounds whose antiproliferative effects were actually enhanced in cells with MDR. These compounds included NSC 73306, a specific compound that increased the chemosensitivity of cells that overexpress ABC transporters without inhibiting ABC transporter activity. This invention concerns new analogs of NSC 73306 with improved selectivity and solubility, and the use of the analogs as therapeutics.
Treatment of cancers associated with multi-drug resistance, either alone or in combination with other therapeutics.
Development of a pharmacophore for improved effectiveness in treating cancers associated with multi-drug resistance.
The agents capitalize on one of the most common drawbacks to cancer therapies (MDR) by using it as an advantage to treating cancer.
Increased specificity allows these analogs to be tailored to treating cancers associated with the overexpression and hyperactivity of particular ABC transporters.
Increased solubility allows greater access of the agent to tumor cells, increasing therapeutic effectiveness of the agents.
Benefits: Cancer is the second leading cause of death in United States and it is estimated that there will be approximately 600,000 deaths caused by cancer in 2007. Improving the quality of life and duration of life of cancer patients will depend on chemotherapies with increased effectiveness and reduced toxicity, thus this technology can contribute significantly to a social cause. Furthermore, small molecule cancer therapy technologies have a potential market of more than $2 billion.
Inventors: Matthew D. Hall et al. (NCI).Start Printed Page 11124
U.S. Patent Status: Provisional U.S. Application (HHS Reference No. E-017-2008/0-US-01).
Licensing Contact: David A. Lambertson, PhD; 301-435-4632; email@example.com.
Collaborative Research Opportunity: The National Cancer Institute's Laboratory of Cell Biology is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize for the clinic, compounds that demonstrate MDR1-inverse activity. Please contact John D. Hewes, PhD at 301-435-3121 or firstname.lastname@example.org for more information.
An Improved Non Viral System for Tumor Specific Suicide Gene Therapy
Description of Technology: Numerous tumor specific promoters have been identified and developed for targeted gene therapy. Survivin promoter activity is upregulated in 75% of tumors, however the activity is specific but low, resulting in sub-optimal suicide gene expression. Combination of survivin promoter with Bax, a proapoptotic gene, previously used in such therapy has demonstrated low efficacy.
Scientists at NCI have made a plasmid construct consisting of survivin promoter driven mutant form of bax that is constitutively active. This construct is more potent than the wild type bax, improving its efficacy several-fold, while, retaining specificity for tumors, as determined by in vitro and in vivo studies.
This new technology does not use CMV or SV-40 promoters, alleviating the need for modifications for commercialization.
Can be used with cationic liposomes or other DNA delivery systems.
Can be incorporated into adenoviral and lentiviral vectors.
Excludes viral promoters.
Can be modified easily to use other promoters/suicide genes.
Targeted Gene therapy
Market: In patients with advanced solid tumors or recurrences despite surgery, chemotherapy can provide quality survival. However, responses are usually partial, often disappointingly brief and unpredictable and coupled with side effects. These limitations of traditional cytotoxic chemotherapy make it necessary to explore other therapies such as targeted gene therapy. Viruses, while the carrier of choice in most gene therapy studies, present a variety of potential problems to the patient—toxicity, immune and inflammatory responses, and gene control and targeting issues. In addition, there is a fear that the viral vector may recover its ability to cause disease in the patient. Our new technology addresses some of the above issues making it a suitable agent for cancer and gene therapy.
Development Status: Early.
Inventors: Himanshu Garg and Robert P. Blumenthal (NCI).
Patent Status: HHS Reference No. E-245-2007/0—Research Tool. Patent protection is not being sought for this technology.
Licensing Status: Available for non-exclusive licensing.
Licensing Contact: John Stansberry, PhD; 301-435-5236; email@example.com.
Collaborative Research Opportunity: The National Cancer Institute Center for Cancer Research Nanobiology Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize tumor specific suicide gene therapy using survivin promoter driven mutant bax. Please contact John D. Hewes, PhD at 301-435-3121 or firstname.lastname@example.org for more information.
Eeyarestatins: Novel Deubiquitination Inhibitors for the Treatment of Drug-Resistant Cancers
Description of Technology: The ubiquitin-proteasome system has recently been recognized to play a central role in tumor biology. Bortezomib, an inhibitor of the chymotrypsin-like activity of the proteasome, has clinical activity in a variety of hematologic malignancies and is FDA approved for use in Multiple Myeloma and Mantle Cell Lymphoma.
The present invention for the first time describes that Eeyarestatins, a new class of small molecules, are potential anti-cancer agents. The compounds inhibit the deubiquitination of proteins by targeting the deubiquitination enzymes in the protein degradation pathway. More specifically, the inventors have demonstrated that the Eeyarestatins successfully kill different leukemia and lymphoma cell lines as well as leukemia cells isolated from patients with chronic lymphocytic leukemia by inducing the expression of Noxa, a pro-apoptotic member of the Bcl-2 protein family. Additionally, Eeyarestatins are active against cells that are resistant to Bortezomib and thus can be effective against drug-resistant tumors.
Eeyarestatins can be developed for the treatment of deubiquitination related disorders such as cancers and proliferative disorders.
Eeyarestatins can potentially have broader use against HIV and immune related disorders considering the role of deubiquitination in budding of retroviruses and immune regulation.
Eeyarestatins are active against cells that are resistant to Bortezomib.
In vitro data shows activity of Eeyarestatins against primary cells from patients with chronic lymphocytic leukemia. Clinical trials show that Bortezomib is inactive against patients suffering from chronic lymphocytic leukemia.
Market: The current cancer chemotherapeutic market is valued at $42 billion and expected to grow. Additionally, this compound has potential use in HIV and immune related disorders.
Development Status: In vitro studies are completed and in vivo animal model studies are planned.
Inventors: Adrian Wiestner (NHLBI), Yihong Ye (NIDDK), Qiuyan Wang (NIDDK), Helena Mora-Jensen (NHLBI)
Publication: Q Wang, L Li, Y Ye. Inhibition of p97-dependent protein degradation by Eeyarestatin I. J Biol Chem. 2008 Jan 16; Epub ahead of print, doi 10.1074/jbc.M708347200.
Patent Status: U.S. Provisional Application No. 60/961,202 filed 17 Jul 2007 (HHS Reference No. E-208-2007/0-US-01)
Licensing Status: Available for exclusive or non-exclusive licensing.
Licensing Contact: Surekha Vathyam; 301-435-4076; email@example.com.
Collaborative Research Opportunity: The National Institutes of Health laboratories of Dr. Adrian Wiestner (NHLBI) and Dr. Yihong Ye (NIDDK) are seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize Eeyarestatins. Please contact Dr. Wiestner (301-594-6855, firstname.lastname@example.org) or Dr. Ye (301-594-0845, email@example.com) for more information.
Synergistic Effect of TGF-Beta Blockade and Immunogenic Agents on Tumors
Description of Technology: Overcoming immune suppression in cancer patients is a major challenge for the success of cancer immunotherapy. TGF-β and its receptors are expressed in essentially all tissues, and they have been found to be important in many cellular processes including cell growth inhibition. The inhibition of TGF-β Start Printed Page 11125signaling has been shown to have an inhibitory effect on tumor growth. However, TGF-β also has immunosuppressive properties.
Cancer vaccines are one of many therapies available for treatment and prevention. In particular, vaccines that elicit immune responses have been used to treat or control tumor growth that has evaded immunosurveillance. However, these vaccines have demonstrated limited success.
Available for licensing is a method for synergistically affecting tumor growth involving the administration of an agent that blocks the TGF-β signaling pathway, in combination with an immunogenic agent. The agent that blocks the TGF-β signaling pathway may inhibit the immunosuppressive effects of TGF-β, while the immunogenic agent is believed to enhance an immune response. Surprisingly, the combination of such elements produces a synergistic effect. The administration of the 1D11.16 anti-TGF-β antibody in combination with the human papilloma virus E7(49-57) peptide enhances tumor regression in an animal model. The administration of the 1D11.16 anti-TGF-β antibody in combination with irradiated CT26 cells enhances tumor regression in another mouse model. The investigators found that administering the combination of agents is more effective than the sum of their individual effects.
Applications: A method of cancer combination therapy based on immunotherapeutics.
Development Status: The invention is in the clinical stages of development.
Inventors: Masaki Terabe (NCI) et al.
1. PCT patent publication WO 2006/089251, August 24, 2006.
2. M Terabe et al. Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med. 2003 Dec 1;198(11):1741-1752.
Patent Status: U.S. Provisional Application No. 60/654,329 filed 17 Feb 2005 (HHS Reference No. E-019-2005/0-US-01); PCT Application No. PCT/US2006/005888 filed 16 Feb 2006 (HHS Reference No. E-019-2005/0-PCT-02); U.S. Patent Application No. 11/816,410 filed 15 Aug 2007 (HHS Reference No. E-019-2005/0-US-06)
Licensing Status: Available for exclusive and non-exclusive licensing.
Licensing Contact: Jennifer Wong; 301-435-4633; firstname.lastname@example.org.
Biologically Active Macrolides, Compositions and Uses Thereof
Description of Technology: The current invention embodies the identification of a novel class of potent vacuolar-type (H+)-ATPase-inhibitory compounds. Vacuolar-type (H+)-ATPases are present in many tissues and cells of the body and are involved in the maintenance of various physiological functions. The modification of these functions, via inhibition of vacuolar-type (H+)-ATPases, may represent an effective means of treating various disease states, including Alzheimer's disease, glaucoma, and osteoporosis. In addition, these inhibitors may also be of particular value for use against cancer, as vacuolar-type (H+)-ATPases have been implicated in processes relating to cellular proliferation, angiogenesis, tumor cell invasiveness, metastasis, and drug resistance.
Inventors: Michael R. Boyd (NCI), Kirk R. Gustafson (NCI), et al.
Patent Status: U.S. Patent No. 7,144,918 issued 05 Dec 2006 (HHS Reference No. E-203-2000/0-US-04); U.S. Patent Application No. 11/435,189 filed 16 May 2006 (HHS Reference No. E-203-2000/08-US-08)
Licensing Status: Available for exclusive and non-exclusive licensing.
Licensing Contact: Adaku Nwachukwu, J.D.; 301-435-5560; email@example.com.
Human p53 Mutations and a Genetic System in Yeast for Functional Identification of Human p53 Mutations
Description of Technology: The tumor suppressor gene p53, a key regulator of cellular mechanisms that maintain genome integrity, is the most commonly inactivated gene target associated with neoplastic transformation. p53 is mutated in about 50% of all human tumors and more than 80% of these mutations are missense, leading to single amino acid changes. This invention relates to human p53 mutants and identification methods using screening assays in the yeast Saccharomyces cerevisiae to functionally categorize expressed p53 mutant proteins at varying levels of expression towards several human target response sequences. Additionally, the invention relates to methods of detecting or generating novel human p53 mutations with properties that can include toxicity in yeast and growth suppression in human cells, enhanced or reduced transactivation relative to wildtype p53, altered promoter selectivity, and reactivation by mutation or chemical modification of common tumor mutations for the transactivation function of major p53 downstream genes. In particular, the inventors have discovered a V122A p53 mutation exhibits strong cell proliferation inhibition. This feature suggests that p53 alleles such as V122A might be valuable both for functional studies of p53-regulated cellular responses and possibly for p53 based cancer gene therapy.
Model to screen for small molecules or peptides that can modify p53 functions.
Pharmaceutical screen for p53 drug modifiers.
An estimated 1,444,920 new cancer diagnoses in the U.S. in 2007.
Cancer drug market is estimated to be $50 billion a year in 2010.
Development Status: The technology is currently in the pre-clinical stage of development.
Inventors: Michael A. Resnick and Alberto Inga (NIEHS)
1. A Jegga, A Inga, D Menendez, BJ Aronow, MA Resnick. Functional evolution of the p53 regulatory network through its target response elements. Proc Natl Acad Sci. USA. 2008 Jan 22;105(3):944-949.
2. MM Horvath, X Wang, MA Resnick, DA Bell. Divergent evolution of human p53 binding sites: cell cycle versus apoptosis. PLoS Genet. 2007 Jul;3(7):1284-1295.
3. D Menendez, A Inga, J Snipe,O Krysiak, G Schönfelder, MA Resnick. A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Mol Cell Biol. 2007 Apr;27(7):2590-2600.
4. P Monti, Y Ciribilli, J Jordan, P Menichini, DM Umbach, MA Resnick, L Luzzato, A Inga, G Fronza. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Can Res. 2006 Jul 1;13(13):3789-3795.
5. D Menendez, A Inga, J Jordan, MA Resnick. Changing the p53 master regulatory network: ELEMENTary, my dear Mr. Watson. Oncogene. 2007 Apr 2;26(15):2191-2201.
6. D Menendez, A Inga, J Jordan, MA Resnick. The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes. Mol Cell Biol. 2006 Mar;26(6):2297-2308.
7. DJ Tomso, A Inga, D Menendez, G Pittman, M Campbell, D Bell, MA Start Printed Page 11126Resnick. Functionally distinct polymorphic sequences in the human genome that are targets for p53 transactivation. Proc Natl Acad Sci USA. 2005 May 3;102(18):6431-6436.
8. MA Resnick and A Inga. Functional mutations in the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc Nat Acad Sci USA. 2003 Aug 19;100(17):9934-9939.
9. A Inga, F Storici, TA Darden, MA Resnick. Differential transactivation by the p53 transcription factor is highly dependent on p53 level and promoter target sequence. Mol Cell Biol. 2002 Dec;22(24):8612-8625, 2002.
U.S. Patent No. 7,256,260 issued 14 Aug 2007 (HHS Reference No. E-183-1999/0-US-07)
U.S. Patent Application No. 11/893,037 filed 14 Aug 2007 (HHS Reference No. E-183-1999/0-US-09)
European Patent Application No. 0094897.0 filed 28 July 2007, recently allowed (HHS Reference No. E-183-1999/0-EP-05)
Australian Patent No. 784293 issued 14 Aug 2007 (HHS Reference No. E-183-1999/0-AU-03)
Australian Patent Application No. 2006202361 filed 2 Jun 2006 (HHS Reference No. E-183-1999/0-AU-08)
Canadian Patent Application No. 2380631 filed 28 July 2000 (HHS Reference No. E-183-1999/0-CA-04)
Japanese Patent Application No. 2001-514117 filed 28 July 2000 (HHS Reference No. E-183-1999/0-JP-03)
Licensing Status: Available for exclusive or non-exclusive licensing.
Licensing Contact: Jennifer Wong; 301-435-4633; firstname.lastname@example.org.Start Signature
Dated: February 21, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.
[FR Doc. E8-3837 Filed 2-28-08; 8:45 am]
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