[Federal Register Volume 74, Number 77 (Thursday, April 23, 2009)]
[Notices]
[Pages 18585-18586]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-9344]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Public Teleconference Regarding Licensing and Collaborative 
Research Opportunities for: A Double-Barreled Attack: Azatoxins, A New 
Hope for Treating Cancer

AGENCY: National Institutes of Health, Public Health Service, HHS.

ACTION: Notice.

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Technology Summary

    This technology describes a novel class of Topoisomerase II (top2) 
inhibitors that are useful in treating cancer. Drugs that inhibit the 
top2 enzyme are among the most active anticancer agents discovered. 
However, many of the currently available inhibitors produce toxic side 
effects, have poor pharmacokinetics, or eventually become ineffective 
because malignant cells readily acquire resistance. Therefore, there is 
a need for developing new top2 inhibitor drugs that will overcome these 
limitations.
    Azatoxin and its derivatives, which are derived by combining two 
parent compounds etoposide and ellipticine, are the first compounds 
rationally designed as inhibitors of top2. Azatoxins are also potent 
inhibitors of tubulin polymerization. These two anti-cancer activities 
can be successfully separated by synthesizing azatoxin derivatives to 
yield compounds which can be pharmacologically advantageous against 
tumor proliferation. The azatoxin platform represents an unexploited 
class of top2 inhibitors that could be developed into especially potent 
chemotherapeutics.

Competitive Advantage of Our Technology

    Currently, several top2 inhibitors are approved for clinical use; 
however, they produce serious side effects. Etoposide, for example, 
causes problems with myelosuppression, drug resistance, and has poor 
bioavailability. Moreover, it appears to have carcinogenic properties 
as it has been linked to the development of acute myelogenous 
leukemia--an effect also observed with mitoxantrone. Anthracyclines, 
like doxorubicin, have the same limitations as etoposide, but they also 
possess cardiotoxic effects. Azatoxins have the potential to be 
developed into chemotherapeutics that outperform these currently used 
top2 inhibitors.
    Azatoxins have been substantially characterized through years of 
pre-clinical research demonstrating that

[[Page 18586]]

they possess properties from both of its parental compounds, etoposide 
and ellipticine. They act by stabilizing the top2-DNA cleavage complex, 
like etoposide does, instead of inhibiting top2 catalytic activity, the 
mechanism by which ellipticine acts. With regard to DNA cleavage 
activity, azatoxins show similar activity to etoposide. In addition to 
acting as a top2 inhibitor, azatoxin is also a potent inhibitor of 
tubulin polymerization.
    The anti-cancer activity of azatoxins has been validated by cell 
line screening. The Developmental Therapeutics Program (DTP) of the 
National Cancer Institute (NCI) has tested azatoxins in its tumor cell 
panel and established their effectiveness against disseminated leukemia 
and localized tumors, such as non-small cell lung and colon cancer. 
These results are very encouraging showing that certain azatoxin 
derivatives are 100 times more active than etoposide, which is the 
common top2 inhibitor used in chemotherapy. Azatoxins are a novel class 
of potent top2 and/or tubulin inhibitors that could outperform current 
chemotherapeutic agents.

Technology Description

    Topoisomerase enzymes are critical for normal cell division because 
they prevent tangles and knots from forming during DNA replication by 
cleaving and religating DNA. Several compounds have been discovered 
that block topoisomerases and stop its ability to religate DNA 
resulting in an increased number of double strand DNA breaks that kill 
the cell. These inhibitors are especially effective against rapidly 
dividing malignant cells that express high levels of top2, which 
represents a main reason these top2 enzymes have become an important 
therapeutic target. The problem is that currently used drugs are 
limited by their toxicity, insolubility, and their susceptibility to 
induce drug resistance.
    In an effort to produce top2 inhibitors with increased therapeutic 
efficiency, well established top2 inhibitors were compared by molecular 
modeling to produce a composite top2 inhibitor pharmacophore of the 
diverse inhibitors. Based on this model, azatoxin was designed as an 
analogue hybrid of etoposide and ellipticine. Subsequently, several 
modifications of azatoxin have been synthesized to generate 
derivatives, such as anilinoazatoxins, which have improved 
pharmacological profiles.

Market

    Despite further discoveries leading to a greater understanding and 
treating of cancer, it continues to be a burden to the public health. 
After heart disease, cancer is the most common cause of death in the 
United States. In 2008, it was estimated that about 565,650 Americans 
were expected to die of cancer. Although, the incidence of cancer has 
been dropping over the years, it was estimated that over 1.4 million 
Americans would be diagnosed with cancer in 2008.
    Cancer is not only a health burden but also a financial burden to 
the country. The NIH estimated the overall cost of cancer in 2007 to be 
$219.2 billion dollars with $89 billion attributable to direct medical 
costs. It is expected that cancer will continue to be a public health 
problem for the foreseeable future which prompts the need for the 
development of new therapeutics.
    Chemotherapy is still the standard approach for treating cancers 
even though there were high expectations that targeted therapeutics 
would become the preferred drugs in cancer treatment. Current 
topoisomerase inhibitors have demonstrated to be effective chemotherapy 
drugs and they continue being developed for use in combination therapy 
with targeted therapeutics. However, top2 inhibitors need to be 
improved in order to overcome their limitations. A next-generation top2 
inhibitor like azatoxins has potential in meeting this need.

Patent Estate

    The National Institutes of Health holds a substantial portfolio of 
patents in U.S., Europe, Canada, and Australia which claim compositions 
of azatoxin and its derivatives, pharmaceutical formulations, and 
methods of use for chemotherapy.
    The portfolio includes the following issued patents:
    I. United States Patent No. 5,622,960 entitled ``Topoisomerase II 
inhibitors and therapeutic uses therefor'' issued April 22, 1997 (HHS 
Ref. No. E-119-1992/1-US-01).
    II. United States Patent No. 5,747,520 entitled ``Topoisomerase II 
inhibitors and therapeutic uses therefor'' issued May 5, 1998 (HHS Ref. 
No. E-119-1992/1-US-17).
    III. European Patent No. 0665846 entitled ``Topoisomerase II 
inhibitors and therapeutic uses therefor'' issued July 29, 1998 (HHS 
Ref. No. E-119-1992/1-EP-10) validated in Austria, Belgium, Denmark, 
France, Germany, Great Britain, Ireland, Italy, Luxembourg, 
Switzerland, and The Netherlands.
    IV. Canadian Patent No. 2147608 entitled ``Topoisomerase II 
inhibitors and therapeutic uses therefor'' issued December 12, 2006 
(HHS Ref. No. E-119-1992/1-CA-06).
    V. Australian Patent No. 676511 entitled ``Topoisomerase II 
inhibitors and therapeutic uses therefor'' issued June 13, 1997 (HHS 
Ref. No. E-119-1992/1-AU-04).

Next Step: Teleconference

    There will be a teleconference where the principal investigator, 
Dr. Yves Pommier, will explain this technology. Licensing and 
collaborative research opportunities will also be discussed. If you are 
interested in participating in this teleconference please call or e-
mail Samuel Bish; (301) 435-5282; [email protected]. The NIH Office 
of Technology Transfer (OTT) will then e-mail you the date, time, and 
number for the teleconference.

    Dated: April 16, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. E9-9344 Filed 4-22-09; 8:45 am]
BILLING CODE 4140-01-P