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FDA approves pralatrexate for treatment of peripheral T-cell lymphoma.

The United States Food & Drug Administration approved pralatrexate for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). Research on drugs of this class began in the 1950s at SRI International. A subsequent scientific collaboration among SRI International (Menlo Park, CA), Memorial Sloan-Kettering Cancer Center (MSKCC)(New York, NY), and Southern Research Institute (Brimingham, AL) led to clinical trials on related compounds conducted by Memorial Sloan-Kettering Cancer Center starting in the 1980s. Pralatrexate was identified as a viable clinical candidate and was licensed to Allos Therapeutics for further development in 2002.

Francis M. Sirotnak, Ph.D., one of the inventors of pralatrexate and a molecular pharmacologist and Memorial Sloan-Kettering Cancer Center Member Emeritus said, "In the laboratory and in clinical trials at Sloan-Kettering, we were able to demonstrate that this was a therapeutically active drug. After many years of research and drug development, it is very rewarding to see this work come to fruition."

"Investigators at Southern Research Institute, SRI International, and Memorial Sloan-Kettering Cancer Center worked together under the auspices of the National Cancer Institute for many years," said Robert Piper, Ph.D. of Southern Research Institute. "We prepared and tested many compounds before finally identifying a substance that gave favorable results. We are very glad our compound will help alleviate human suffering and extend lives."

"We are pleased that our long-term medicinal chemistry program in the area of antifolate therapeutic agents has resulted in development of a clinically effective drug for treatment of certain types of human cancer," stated Joseph DeGraw, Ph.D., and William Colwell, Ph.D., both formerly of SRI International. "This was achieved through SRI's long-standing collaboration with the chemistry and molecular therapeutics investigators at Southern Research Institute and Memorial Sloan-Kettering Cancer Center."

Pralatrexate has shown enhanced efficacy with less toxicity than other therapeutic regimens and is being studied against several forms of cancer, including peripheral T-cell lymphoma and non-small-cell lung cancer.

The drug is a selective antifolate designed to accumulate preferentially in cancer cells. Based on preclinical studies, Allos believes that pralatrexate selectively enters cells expressing RFC-1, a protein that is over expressed on certain cancer cells compared to normal cells. Once inside cancer cells, pralatrexate is efficiently polyglutamylated, which leads to high intracellular drug retention.

Polyglutamylated pralatrexate essentially becomes "trapped" inside cancer cells, making it less susceptible to efflux-based drug resistance. Acting on the folate pathway, pralatrexate interferes with DNA synthesis and triggers cancer cell death.

Pralatrexate was first prepared at SRI International by Dr. Joseph DeGraw and Dr. William Colwell, two of the scientists in the tripartite agreement among SRI International, Southern Research Institute and Memorial Sloan-Kettering Cancer Center.

Pralatrexate is a relative of an older chemotherapy drug called methotrexate, which was found to be effective only in limited forms of leukemia and lymphomas. In the 1950s, scientists at SRI International focused on developing related drugs that would be more effective against tumor cells. Their first major discovery in this search was a modification of methotrexate that was a powerful enzyme inhibitor, but more easily absorbed through the walls of tumor cells.

In the late 1970s, Dr. Francis M. Sirotnak at MSKCC began to investigate improvements to methotrexate. He and his colleagues initially did research to understand what makes methotrexate effective against certain cancers.

"We discovered that natural folate is brought into and metabolized in a tumor cell via a plasma membrane transporter, and that this is the same route of entry that tumor cells use to bring in methotrexate," explained Dr. Sirotnak. Studies provided the collaborators with the information they needed to exploit this feature of cancer cells and to develop an antifolate that would be more effectively transported into the cells via RFC-1. "We wanted to design a drug with greater therapeutic selectivity--an agent that would interfere with DNA synthesis would be more efficiently internalized into tumors, and would be more toxic to cancer cells than to normal cells," said Dr. Sirotnak. "We finally identified pralatrexate as a viable clinical candidate in the mid-1990s."

Dr. Robert Piper at Southern Research Institute synthesized the key starting material (a bromomethyl compound) used to prepare the pralatrexate intermediates and later synthesized the multigram quantities of high-purity pralatrexate used in preclinical investigations and described in a patent application.

The identification of the compound and the ensuing studies led to multiple issued patents that are jointly owned by SRI International, MSKCC, and Southern Research Institute and licensed to Allos.

Southern Research Institute is a nonprofit 501(c)3 scientific research organization that conducts preclinical drug discovery and development, and advanced engineering research in materials, systems development, environment and energy. Our more than 550 scientific and engineering team members support clients and partners in the pharmaceutical, biotechnology, defense, aerospace, environmental and energy industries. Southern Research is headquartered in Birmingham, Ala., with facilities in Wilsonville, Ala., Anniston, Ala., Frederick, Md., and Durham, NC and offices in New Orleans, La., Washington, DC and Kiev, Ukraine.

SRI International is one of the world's leading independent research and technology development organizations. SRI, which was founded by Stanford University as Stanford Research Institute in 1946 and became independent in 1970, has been meeting the strategic needs of clients and partners for more than 60 years. Perhaps best known for its invention of the computer mouse and interactive computing, SRI has also been responsible for major advances in networking and communications, robotics, drug discovery and development, advanced materials, atmospheric research, education research, economic development, national security, and more. The nonprofit institute performs sponsored research and development for government agencies, businesses, and foundations. SRI also licenses its technologies, forms strategic alliances, and creates spin-off companies. In 2008, SRI's consolidated revenues, including its wholly owned for-profit subsidiary, Sarnoff Corporation, were approximately $490 million.

SRI International


Memorial Sloan-Kettering


Southern Research Institute

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Publication:BIOTECH Patent News
Date:Aug 1, 2009
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