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Cardio Drug Promising for Treatment of Leukemias with Mutations Linked to ROCK Pathway

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By Molika Ashford

Researchers at the Indiana University School of Medicine have found that Rho kinase inhibitors like the cardiopulmonary drug fasudil could be an effective treatment for some types of leukemia, opening a new pharmacogenomic avenue for the drug and a new treatment option for acute leukemia patients.

Fasudil, a vasodilator that inhibits the action of Rho kinase, or ROCK, is marketed by Japan's Asahi Kasei Pharma. The drug has been prescribed to more than 200,000 patients in Japan as a treatment for stroke, according to Reuben Kapur, the lead researcher on the Indiana group's study, which was published last week in Cancer Cell.

Because of the available evidence of the drug's safety in humans, the possibility of gaining regulatory approval in the U.S. is relatively encouraging, Kapur told PGx Reporter this week.

The study by Kapur and colleagues suggests that fasudil and other ROCK inhibitors are effective at slowing the growth and proliferation of leukemia cells with activating KIT mutations, as well as other mutations associated with acute, difficult-to-treat disease, like FLT3 and BCR-ABL.

Though Kapur's work — in cell lines, human samples, and leukemic mice — is in its early stages, he said he has been in contact with a company that may help his research group move forward to a clinical trial of ROCK inhibitors as an anti-leukemic treatment. "Fasudil seems most logical since it has been used in humans already," Kapur said.

"Nothing has been finalized … But we have filed a patent with respect to Rho kinase inhibitors and myeloproliferative disease for certain types of leukemias, especially where there is presence of activating KIT mutations," he said. "Patients that have these mutations actually have no treatment currently available. No specific drugs to my knowledge are FDA approved."

As described in the paper, Kapur's team found that mutations in several proteins associated with difficult-to-treat leukemias result in hyperactivation of ROCK. The researchers then demonstrated the anti-leukemic action of ROCK inhibition in cell lines bearing oncogenic forms of these genes and in patient-derived blast cells. They then moved on to show that ROCK inhibitors prolonged the life of laboratory mice with myeloprolifeative disease.

Kapur said that the activating KIT mutations that result in excess ROCK are found in patients with mastocytosis that are resistant to Novartis's Gleevec (imatinib) and that the mutation is also associated with acute myeloid leukemia — "specifically in patients that have core-binding factor leukemias."

The team also found that the ROCK inhibitor stopped the growth and proliferation of cells expressing BCR-ABL and FLT3-ITD. Kapur said that more than 35 percent of patients with AML express FLT3-ITD.

Further investigations into the signaling that connects these mutations with ROCK hyperactivation led the group to move on to preclinical trials in mice using two different models of leukemia. These studies looked at leukemia mice with mutations in both KIT and FLT3-ITD and treated samples with fasudil and another ROCK inhibitor, H-1152.

For these studies, the group took oncogene-bearing cells, transplanted them into the mice, and then treated the mice with a range of doses of the ROCK inhibitors in different time frames to see if the treatment delayed the onset of disease.

In the leukemic mice, Kapur said, "we saw a substantial delay versus control," and fasudil "showed fairly robust inhibitory activity [and] worked really well in prolonging the life of the leukemic mice," Kapur said.

The success of Gleevec for the treatment of chronic myeloid leukemia has spurred the search for other signaling molecule targets that could provide less toxic and more efficacious therapies for other leukemias, including AML and systemic mastocytosis, the researchers reported in their paper. While KIT mutations in gastrointestinal tumors are sensitive to Gleevec, KIT mutations in AML and SM, like KITD814V, preclude "sufficient imatinib binding for tyrosine kinase inhibition," they wrote.

"Our results suggest that inhibition of constitutively active ROCK in KITD814V-bearing cells is a highly efficacious alternative approach for treating hematologic malignancies involving [this] mutation," the group wrote in their paper. ROCK inhibition also suppressed tumor growth in BCR-ABLt3151 mutant cells that were resistant to imatinib, they said.

Based on their observations in the Cancer Cell study, the team wrote, "targeting ROCK for treatment of hematologic malignancies due to activation mutations of KIT, FLT3, and BCR-ABL is likely to be a viable therapeutic option."

"We looked at over 20 [patient] samples and we found that almost all of them showed inhibitory effects using the ROCK inhibitor," Kapur said, adding that a few samples may not have had KIT mutations, but "they all appeared to be pretty sensitive to Rho kinase inhibitors."

"It is conceivable that the growth of all AML cells to some extent is repressed by ROCK inhibitors," the team wrote In their report.

Now, the researchers are looking at "the consequences of inhibiting ROCK in leukemia-initiating cells or leukemia stem cells" found in patients with CML." Discussions about moving toward a clinical trial of ROCK inhibitors to treat leukemia are "ongoing" and "preliminary," Kapur stressed.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at mashford [at] genomeweb [.] com.

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