The US Food & Drug Administration has announced the approval of 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, Memorial Sloan-Kettering Cancer Center, and Southern Research Institute led to clinical trials on related compounds conducted by Memorial Sloan-Kettering Cancer Center starting in the 1980s. Pralatrexate was ultimately identified as a viable clinical candidate and was licensed to Allos Therapeutics for further development in 2002.
Francis M Sirotnak, 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, 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, and William Colwell, 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 is a relative of an older chemotherapy drug called methotrexate, which was found to be effective only in limited forms of leukaemia and lymphomas. In the 1950s, scientists at SRI International focused on developing related drugs that would be more effective against tumour cells.
"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 in cancer, infectious diseases and CNS disorders; and advanced engineering research in materials, systems development, environment and energy.
Silicon Valley-based SRI International is one of the world's leading independent research and technology development organizations.