A candidate for HER2

NEW YORK—DepYmed Inc., a joint venture of Ohr Pharmaceutical Inc. and Cold Spring Harbor Laboratory (CSHL), announced recently the validation of Trodusquemine as a therapeutic candidate for HER2-positive breast cancer. The results were published online May 20 in Nature Chemical Biology.

Trodusquemine (or MSI-1436) is the company’s inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B), which Ohr notes is “a well-recognized target for a range of therapy areas.”

The company further notes on its website that “the primary challenge in developing PTP1B inhibitors has been safety, with issues stemming from a lack of selectivity for PTB1B versus other tyrosine phosphatases and a focus on inhibition of the enzyme at its active site.” The molecule has also been shown to be able to cross the blood-brain barrier, “and thus may be centrally active as well, opening a new range of potential indications.” According to Ohr, the drug has been well tolerated in dose escalation and dose ranging clinical studies so far.

As DepYmed notes, HER2-positive breast cancer is a malignancy that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In approximately one-quarter of all 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.

Although Herceptin (trastuzumab) is a first-line treatment for many women with HER2-positive breast cancer, most recipients develop resistance to the drug within a year, DepYmed notes. Thus, the search for therapies that can act alone or in combination with Herceptin to enhance patient outcomes has been a major oncology focus for many companies.

In the Nature Chemical Biology paper “Targeting the Disordered C Terminus of PTP1B With an Allosteric Inhibitor,” a multi-institution team led by Dr. Nicholas Tonks of CSHL reported that it was able to inhibit PTP1B, expression of which is upregulated in HER2-positive breast cancer, and the team provided what DepYmed calls “compelling evidence of PTP1B as a therapeutic target in HER2-positive breast cancer.”

PTP1B is also a well-characterized target for such major diseases as diabetes and obesity, but 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,” Tonks observes, and in the approach described by him and his team, Trodusquemine has been identified as a selective, allosteric inhibitor of PTP1B that exerts its effects outside the active site of the enzyme.

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 reportedly 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 CEO 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.”

A Phase 1 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.