On May 27, 2014 DepYmed Inc., a joint venture of Ohr Pharmaceutical, Inc. (Nasdaq:OHRP) and Cold Spring Harbor Laboratory, reported the validation of Trodusquemine (MSI-1436) as a therapeutic candidate for HER2-positive breast cancer (Press release, Ohr Pharmaceutical, MAR 27, 2014, View Source [SID:1234512310]). Trodusquemine is the Company’s inhibitor of the enzyme PTP1B (protein tyrosine phosphatase 1B). The results were published online on May 20, 2014 in Nature Chemical Biology.
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HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In approximately 1 out of every 4 breast cancers, tumor cells make an excess of HER2 due to a gene amplification. HER2-positive breast cancers tend to be aggressive and the prognosis for patients is poor. The drug Herceptin (trastuzumab) is a first-line treatment for many women with HER2-positive breast cancer, but in most cases resistance develops within a year. It is anticipated that alternative therapies which act either alone or in combination with Herceptin may enhance patient outcomes.
In a paper entitled "Targeting the Disordered C Terminus of PTP1B With an Allosteric Inhibitor" a multi-institution team led by Professor Nicholas Tonks of Cold Spring Harbor Laboratory reports that it has found a means of inhibiting PTP1B, expression of which is upregulated in HER2-positive breast cancer. They provide compelling evidence of PTB1B as a therapeutic target in HER2-positive breast cancer.
PTB1B is a well-characterized target for several major diseases, including diabetes and obesity. However, it has been a challenging target for therapeutic development due to the chemical properties of the enzyme at its active site. "Novel approaches are required to exploit this important target fully," Dr. Tonks observes. In the approach reported in the newly published paper, Trodusquemine has been identified as a selective, allosteric inhibitor of PTP1B that exerts its effects outside the active site of the enzyme.
Dr. Tonks and his team tested Trodusquemine in several mouse models of HER2-dependent breast cancer. They showed that in animals treated with Trodusquemine, there was extensive inhibition of tumor burden and prevention of metastasis to the lung. They also demonstrated that it was inhibition of PTP1B that antagonized signaling by HER2 proteins in the treated animals.
"We are pleased with the publication of this important paper on Trodusquemine in breast cancer," said Dr. Irach Taraporewala, President and Chief Executive Officer of Ohr Pharmaceutical. "These results build on data from earlier studies showing PTP1B to be a tumor promoter and suggest it may be a viable therapeutic target in HER2-positive breast cancer. This form of breast cancer is very aggressive and difficult to treat. Many women ultimately build up a resistance to current treatments, so it is important to identify additional therapeutic agents for intervention."
In other studies, Trodusquemine has been shown to cross the blood-brain barrier, which enhances its potential applications. It has been well tolerated in dose-escalation clinical studies completed to date in over 65 patients. Novel analogs of Trodusquemine have also been identified that are potent inhibitors of PTP1B and have potential delivery route advantages.
A Phase I clinical trial evaluating Trodusquemine in HER2-positive breast cancer patients is planned for later this year and will be conducted at North Shore-Long Island Jewish Hospital.