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Having a go at HER2
COLD SPRING HARBOR, N.Y.—HER2-positive breast cancer is one of the more common types of breast cancer, affecting one in four patients, and is characterized by the overexpression of a signaling protein known as HER2. While treatments do exist—the current standard-of-care treatment for HER2-positive breast cancer is the blockbuster drug Herceptin—the prognosis is worse than for other breast cancer patients, particularly since many patients develop a resistance to Herceptin within a year.
A recent study out of Cold Spring Harbor Laboratory (CSHL), however, might be the first step to new treatments for this cancer subtype. CSHL Prof. Nicholas Tonks led a multi-institutional team in the discovery of a means by which to inhibit PTP1B, a protein whose expression is upregulated in HER2-positive breast cancer. PTP1B was found to play a critical role in the development of tumors with aberrant HER2 signaling, implying that the protein may represent a therapeutic target for treatment.
In this work, mice modeling HER2-positive breast cancer were treated with MSI-1436 (trodusquemine), a drug candidate of Ohr Pharmaceutical Inc., which proved to inhibit signaling by both PTP1B and HER2 proteins. Dr. Navasona Krishnan, a postdoctoral investigator in the Tonks lab and lead author on the paper, noted that “The result was an extensive inhibition of tumor growth and prevention of metastasis to the lung in HER2-positive animal models of breast cancer.”
While their work has shown that “PTP1B plays a positive role in promoting signaling by HER2, the precise mechanism remains to be defined,” says Tonks, though the team is investigating a number of substrates that “would inhibit HER2 signaling when they are in a phosphorylated state.” Tonks adds that it is possible that other targets of PTP1B are related to its role in HER2 signaling.
Tonks originally discovered PTP1B roughly 25 years ago. The enzyme is one of a superfamily of 105 known as protein tyrosine phosphatases (PTPs), which remove phosphate groups from amino acids known as tyrosines in other proteins; this addition and removal of phosphates is one of the primary means by which signals are transferred between proteins. PTP1B has been investigated for many years for its potential in diabetes and obesity, being an antagonist of both insulin signaling and leptin (the hormone that regulates appetite) signaling.
Unfortunately, the charge of PTP1B’s active site has proven a roadblock in terms of developing potential inhibitors. This recent paper, however, details an alternative binding site, known as an allosteric site, that doesn’t feature the same biochemical difficulties seen with the main catalytic site. The allosteric site is the target of trodusquemine.
Tonks’ lab, he notes, has been focusing its efforts on “defining the structure, regulation and mechanism of action of PTP1B,” in hopes that a more detailed understanding of the enzyme will enable the development of inhibitors capable of bypassing the issues of PTP1B’s catalytic site.
“Industry has applied standard approaches to generating active site-directed inhibitors of PTP1B, which resulted in potent, reversible and selective inhibitors,” Tonks explains. “However, due to the properties of the PTP1B active site, these are highly charged and, therefore, limited in their drug development potential … The current study that led to characterization of an allosteric inhibitor of PTP1B, which is being driven by my colleague Nava Krishnan and has been conducted over the last five years, targets a regulatory segment of the phosphatase that is remote from the active site. Our goal is to validate this approach to inhibition of PTP1B to open up new therapeutic strategies in cancer and other major diseases.”
Tonks says the team will continue to pursue two paths for this research: to characterize derivatives of MSI-1436 “that may present improved characteristics relative to the parent molecule”—particularly derivatives that may offer better oral bioavailability— and to explore whether combinations of Herceptin and MSI-1436 can extend the time before patients develop resistance to treatment. They will also investigate whether MSI-1436 could overcome a Herceptin-resistant state, Tonks adds.
Early-stage trials for trodusquemine are set to begin later this year under collaboration between CSHL and clinicians at the Monter Cancer Center of North Shore-Long Island Jewish Hospital. Tonks and CSHL both have interests in DepYmed Inc., a joint venture of Ohr Pharmaceutical and CSHL that seeks to develop trodusquemine and related analogs.
The paper, “Targeting the disordered C terminus of PTP1B with an allosteric inhibitor,” appeared online May 18 in Nature Chemical Biology. Funding for this research came from the National Institutes of Health, Cold Spring Harbor Laboratory Cancer Center, the American Diabetes Association, Brown University Research Seed Fund and Agence Nationale de Researche.