05-8287. Government-Owned Inventions; Availability for Licensing

AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

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.

ADDRESSES:

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: [phone]; fax: [phone]. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

Composition and Methods for Diagnosis and Treatment of Metastatic Disease

Xin Wei Wang and Anuradha Budhu (NCI).

U.S. Provisional Application filed 8 Mar 2005 (DHHS Reference No. E-127-2005/0-US-01).

Licensing Contact: Michelle A. Booden; 301/451-7337; [e-mail].

Liver cancer, particularly hepatocellular carcinoma (HCC), is a leading cause of cancer deaths worldwide. In spite of recent progress in therapeutic strategies, prognosis of patients with advanced HCC remains very poor. Although routine screening of individuals at risk for developing HCC may extend the life of some patients, many are still diagnosed with advanced HCC and have little chance of survival. A small subset of HCC patients qualifies for surgical intervention, but the consequent improvement in long-term survival is only modest. The extremely poor prognosis of HCC is largely the result of a high rate of recurrence after surgery or of intra-hepatic metastases that develop through invasion of the portal vein or spread to other parts of the liver; extra-hepatic metastases are less common.

The present invention describes tools to determine a unique gene expression profile present in either liver parenchyma through needle biopsy or blood that can aid diagnosis or prognosis of HCC patients with or without metastatic potential. This method also provides a signature-derived polymerase chain reaction or serological screening method to identify drug candidates to treat metastatic or recurrent HCC.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Aminoglycosides and Ribosome Inhibitors as Inhibitors of Tyrosyl-DNA-Phosphodiesterase

Drs. Yves Pommier and Zhi-Yong Liao (NCI).

DHHS Reference No. E-117-2005/0-US-01.

Licensing Contact: John Stansberry; 301/435-5236; [e-mail].

Cancer has long been a leading cause of mortality in the United States. DNA-damaging therapies, such as radiotherapy and chemotherapy, are the methods of choice for treating subjects with metastatic cancer or subjects with diffuse cancers such as leukemias. However, radiotherapy can cause substantial damage to normal tissue in the treatment field, resulting in scarring and, in severe cases, loss of function of the normal tissue. Although chemotherapy can provide a therapeutic benefit in many cancer subjects, it often fails to treat the disease because cancer cells may become resistant to the chemotherapeutic agent. To overcome these limitations additional antineoplastic strategies, such as enhancing the antineoplastic effect of existing therapies, are needed.

This invention discloses a method for enhancing an antineoplastic effect of a DNA-damaging therapy. The method includes administering to a subject having a neoplasm a therapeutically effective amount of the DNA-damaging therapy and a ribosome inhibitor that inhibits tyrosyl-DNA phosphodiesterase 1 (Tdp1) activity, wherein the ribosome inhibitor is administered in a sufficient amount to enhance the DNA-damaging therapy.

This disclosure also provides pharmaceutical compositions that include at least one chemotherapeutic agent and at least one ribosome inhibitor that inhibits Tdp1 activity, wherein the chemotherapeutic agent and the ribosome inhibitor are present in a therapeutically effective amount for the ribosome inhibitor to enhance an antineoplastic effect of the chemotherapeutic agent.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Inhibition of Proteosome Function to Potentiate the Proapoptotic and Antitumor Activity of Cytokines

Jon Wigginton et al. (NCI).

U.S. Provisional Patent Application filed 23 Mar 2005 (DHHS Reference No. E-072-2005/0-US-01).

Licensing Contact: Michelle A. Booden; 301/451-7337; [e-mail].

Protein degradation via the ubiquitin-proteosome pathway is an important regulator of cell cycle progression and survival. Thus, inhibitors of this pathway can be directly cytotoxic and can sensitize several tumor cell types to cytotoxic chemotherapy and radiation.

Neuroblastoma is the most common extracranial solid tumor in children, and the development of clinical resistance to cytotoxic therapies is a major therapeutic obstacle in these patients. Several apoptosis abnormalities, which result from decreased expression of pro-apoptotic proteins, are associated with increased resistance to standard therapeutic interventions. In addition, neuroblastoma cells also show increased expression of several pro-survival proteins such as Bcl-2, FLIP, and AKT. Preclinical models suggest that IFN-gamma/TNF-alpha cytokines including IL-2, IL-12 and IL-18 among others may have potent antitumor efficacy in several preclinical models, and that these regimens may act by inducing an adaptive cell-mediated immune response. Although some single agent cytokine regimens have achieved modest efficacy in the clinical setting, the utility of some approaches has been limited overall by side effects that can be associated with high-dose cytokine therapy.

The present invention describes a method for combining ubiquitin-proteosome inhibitors with various cytokines to overcome mechanisms of tumor self-defense and sensitize both tumor and/or endothelial cell populations to apoptosis. These combination approaches may not only offer the prospect for improved therapeutic efficacy, but achieve these effects at lower, more clinically tolerable doses than can be achieved utilizing either respective agent alone. It is anticipated that this therapeutic intervention could be directed towards multiple human carcinomas, and potentiate the efficacy of multiple different cytokines both in the setting of oncology and infectious disease applications.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Methods for Inhibiting or Treating Cancer

Ernest Hamel (NCI), et al.

U.S. Provisional Application No. 60/616,347 filed 05 Oct 2004 (DHHS Ref. No. E-323-2004/0-US-01).

Licensing Contact: Thomas P. Clouse; 301/435-4076; [e-mail].

This invention describes novel arylthioindole derivatives having enhanced interaction with tubulin and increased effectiveness in growth inhibition of MCF-7 breast cancer cells as well as other cell types. Antitubulin drugs have an established role in the treatment of cancer, parasitic diseases and inflammatory disorders. These new chemical compounds have the potential to result in more effective therapeutics for the treatment of neoplastic, inflammatory and parasitic diseases.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Regulation of ATG7 Beclin 1 Program of Autophagic Cell Death by Caspase-8

Michael Lenardo and Yu Li (NIAID), et al.

U.S. Provisional Application No. 60/556,857 filed 30 May 2004 (DHHS Reference No. E-318-2004/0-US-01).

Licensing Contact: Mojdeh Bahar; 301/435-2950; [e-mail].

The invention discloses the role of autophagy in regulation cell death. Further it teaches a method of inducing autophagic cell death by administering a caspase inhibitor. The invention also discloses that autophagic cell death can be induced by caspase-8 inhibition and requires the genes ATG7 and Beclin 1.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Cancer Specific SPANX-N Markers

Natalay Kouprina et al. (NCI).

DHHS Reference No. E-212-2004/0-US-01.

Licensing Contact: Mojdeh Bahar; 301/435-2950; [e-mail].

The invention provides SPANX-N polypeptides, nucleic acids and antibodies that could be useful for detecting and treating prostate or other cancers. The SPANX-N genes are a family of related genes that are expressed in normal testis and in tumor cells in humans including melanoma, bladder carcinomas and myelomas. The SPANX cancer/testis antigens thus represent good candidates for diagnosis or treatment of several cancers.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Methods for Inhibiting or Treating Cancer

Srividya Swaminathan, Shyam Sharan (NCI).

U.S. Provisional Application No. 60/588,918 filed 16 Jul 2004 (DHHS Reference No. E-160-2004/0-US-01).

Licensing Contact: Thomas P. Clouse; 301/435-4076; [e-mail].

This invention describes a novel role for BRCA2 in the repair of O⁶-alkylguanine adducts and provides evidence that after treatment with O⁶-benzylguanine, tumor cells with intact BRCA2, are susceptible to ionizing radiations. In this invention the essential and novel function of BRCA2 in the repair of O⁶-methylguanine is described and demonstrated. BRCA2 physically interacts with alkylated-AGT and undergoes repair-associated degradation. Treatment with O⁶-benzylguanine renders cell radiation hypersensitive due to degradation of BRCA2. Radio-sensitization of tumors by O⁶-benzylguanine should have a significant impact on cancer therapeutics. The elucidation of the mechanism of action for the chemotherapeutic agent O⁶-benzylguanine relative to BRCA2 may potentially improve the success rate of treating BRCA2 expressing tumors.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Chinese Hamster Ovary Cells Resistant to Colcemid With Altered beta-Tubulin

Michael M. Gottesman and Fernando R. Cabral (NCI).

DHHS Reference No. E-156-2004/0—Research Tool.

Licensing Contact: Thomas P. Clouse; 301/435-4076; [e-mail].

The invention is Chinese hamster ovary cells (CHO) resistant to colcemid with altered beta-tubulin. These mutants establish the essential role of tubulin in forming mitotic spindles and identify beta-tubulin as the target for colcemid toxicity.

Cloning and Characterization of an Avian Adeno-Associated Virus and Uses Thereof

Ioannis Bossis (NIDCR).

U.S. Provisional Application No. 60/472,066 filed 19 May 2003 (DHHS Reference No. E-105-2003/0-US-01); PCT Application No. PCT/US04/15534 filed 18 May 2004, which published as WO 2005/017101 A2 on 24 Feb 2005 (DHHS Reference No. E-105-2003/0-PCT-02).

Licensing Contact: Jesse S. Kindra; 301/435-5559; [e-mail].

Currently, adeno-associated virus (AAV) represents the gene therapy vehicle of choice because it has many advantages over current strategies for therapeutic gene insertion. AAV is less pathogenic than other virus types; stably integrates into dividing and non-dividing cells; integrates at a consistent site in the host genome; and shows good specificity towards various cell types for targeted gene delivery.

To date, eight AAV isolates have been isolated and characterized, but new serotypes derived from other animal species may add to the specificity and repertoire of current AAV gene therapy techniques.

This invention describes vectors derived from an avian AAV. These vectors have innate properties related to their origin that may confer them with a unique cellular specificity in targeted human gene therapy. Therefore, vectors derived from this avian AAV are likely to find novel applications for gene therapy in humans and fowl.

This research has been described, in part, in Bossis and Chiorini (2003) J. Virol. (77)12:6799-6810.

Identification of Novel Birt-Hogg-Dubé (BHD) Gene

Laura S. Schmidt (NCI).

U.S. Patent Application No. 10/514,744 filed 16 Nov 2004 (DHHS Reference No. E-190-2002/2-US-02).

Licensing Contact: John Stansberry; 301/435-5236; [e-mail].

Birt-Hogg-Dubé (BHD) syndrome is an inherited autosomal dominant neoplasia syndrome characterized by benign hair follicle tumors and is associated with a higher risk for developing renal cancer, spontaneous pneumothorax and /or lung cysts.

The present invention describes identification of the BHD syndrome associated germline mutations in a novel human gene, herein called BHD gene. This gene encodes for the protein, folliculin, functions of which remain currently unknown.

This discovery makes possible the development of a diagnostic method for BHD syndrome using a simple blood test. The test is particularly useful in detecting BHD mutations in asymptomatic carriers within BHD families.

Patients with kidney tumors can be evaluated for BHD gene mutations using a similar genetic diagnostic test, which will allow for a more accurate diagnosis of a kidney cancer and improved patient prognosis. The BHD encoding sequence is the third gene found to be responsible for inherited kidney cancer, and mutation testing allows for a correct diagnosis and initiation of the proper treatment, which is different for each of the types of kidney cancer caused by the three genes. Since BHD is the first gene found to be associated with chromophobe renal cancer or renal oncocytoma, this invention will enable the development of specific treatments or therapies for these particular histologic types of kidney cancer.

Methods of using BHD encoding sequence also allows for a differential genetic diagnosis of spontaneous pneumothorax, or collapsed lung. Since collapsed lung can be caused by several factors, a BHD diagnostic test allows a physician to determine predisposition to and possible recurrence of additional spontaneous pneumothoraces due to mutation(s) in the BHD gene.

The discovery should also lead to the development of novel pharmaceutical products and methods for treating BHD skin lesions using creams containing the BHD gene product, folliculin. Such products and methods of treatment are expected to reduce the size and appearance of the benign hair follicle tumors.

The disclosed technology will provide new and exciting methodologies to correctly diagnose BHD syndrome and should lead to the development of novel pharmaceutical reagents for treatment of BHD skin lesions as well as other skin diseases.

This research is also described in: MB Warren et al., Mod Pathol. (2004 Aug) 17(8):998-1011; ML Nickerson et al., Cancer Cell (2002 Aug) 2(2):157-164; B Zbar et al., Cancer Epidem. Bio. Prev. (2002 Apr) 11(4):393-400; LS Schmidt et al., Am. J. Hum. Genet. (2001 Oct) 69(4):876-882; Toro et al., Arch. Dermatol. (1999 Oct) 135(10): 1195-1202.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Compositions Of Transforming Growth Factor Beta (TGF-beta) Which Promotes Wound Healing and Methods for Their Use

Michael Sporn et al. (NCI).

U.S. Patent No. 5,104,977, granted April 14, 1992, entitled “Purified Transforming Growth Factor Beta” (DHHS Ref. No. E-070-1982/2-US-05);

U.S. Patent No. 5,656,587, granted August 12, 1997, entitled “Promotion Of Cell Proliferation By Use Of Transforming Growth Factor Beta (TGF-Beta)” (DHHS Ref. No. E-070-1982/2-US-07); and

U.S. Patent No. 5,705,477, granted January 6, 1998, entitled “Compositions Of Transforming Growth Factor Beta (TGF-Beta) Which Promotes Wound Healing And Methods For Their Use” (DHHS Ref. No. E-070-1982/2-US-08).

Licensing Contact: Jesse S. Kindra; 301/435-5559; [e-mail].

There is a continuing need for the promotion of rapid cell proliferation at the site of wounds, burns, diabetic and decubitus ulcers, and other traumata. Prior to this invention, a number of “growth factors” were known to promote the rapid growth of cells. None of these growth factors, however, had been found to be pharmaceutically acceptable agents for the acceleration of wound healing.

This invention relates to compositions of Transforming Growth Factor beta (TGF-beta) which promote repair of tissue, particularly fibroblast cells, in animals and human beings. This invention also relates to a method of treating wounds by the topical or systemic administration of the compositions. The discovery of this invention initiated a worldwide field of research aimed at the characterization and development of TGF-beta in wound healing and disease. It is now known that TGF-beta's role in wound healing is complex. Its diverse effects on the many individual participating cell types in a wound are integrated into a specific temporal sequence of events within a defined tissue architecture. In addition to its many roles in wound healing, TGF-beta is also implicated in the pathogenesis of diseases such as autoimmune disease, fibrosis, and cancer.

Current research in TGF-beta biology is leading to the development of novel wound healing and disease therapies related to the growth factor and its signaling pathways.

Dated: April 18, 2005.

Steven M. Ferguson,

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.