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OHSU Team Develops Assay to Help Pick Tyrosine Kinase Inhibitors Against AML

The Oregon Health & Science University Cancer Institute is in the early stages of developing an RNAi-based diagnostic designed to help doctors choose what tyrosine kinase inhibitors will work best for certain cases of acute myeloid leukemia.
The assay, developed by OHSU researchers with technology licensed from MolecularMD, “rapidly delivers the information [and] has the capability of telling researchers which actual proteins from the tyrosine kinase family are contributing to an individual patient's cancer,” OHSU said in a statement issued last month.  
According to the OHSU researchers, the assay, called RAPID, for RNAi Assisted Protein Target Identification, can yield results in four days compared with months to years to yield similar information when using other kinds of technologies, such as high-throughput sequencing or proteomic analysis, to personalize AML treatments.
High-throughput sequencing and proteomic analyses “are very expensive and time-consuming, and they give enormous amounts of data that still need to be evaluated in a functional manner,” OHSU researcher Jeffrey Tyner told Pharmacogenomics Reporter in a late December e-mail.
By comparison, “RNAi seemed an ideal platform for this because it allows you to knock down the expression of individual genes,” Tyner explained.
The OHSU team used its library of siRNA molecules to silence the expression of the tyrosine kinase family of genes to determine which genes were important for the viability of the AML cells, which could in turn help oncologists better choose tyrosine kinase inhibitors.
The assay “gives us the opportunity to begin with the functional evaluation and work backwards to uncover the genetic lesions” that determines how a patient responds to a tyrosine kinase inhibitor.
In developing the assay, the researchers initially took a large-scale DNA sequencing approach that sought to uncover new mutations linked to AML drug response. They did not have much success with this approach. Eventually, OHSU researchers decided to work backwards by looking for known mutations underlying drug response by employing an assay that could “functionally screen cells and give us some idea based on what [drug] killed cells and what [drug] didn't kill cells.”
According to Tyner, knowing which proteins are driving a cancer will allow doctors to better pick a treatment. With this research, “it may be possible to identify mechanisms as to why certain leukemias respond well to therapy and why others may not,” Tyner said.
He said the assay will need to be validated on more patient samples before it can be commercialized most likely as a CLIA test. Tyner said that OHSU had no current plans to take that assay through the FDA, but it may be a consideration in the future.

“RNAi seemed an ideal platform for this because it allows you to knock down the expression of individual genes."

In patients with AML, abnormal cells rapidly spread and accumulate in the bone marrow, hindering the production of normal blood cells. AML is the most common cause of acute leukemia in adults, and an individual’s risk of developing the disease increases with age.
Published studies have most frequently associated internal tandem duplications in the juxtamembrane region of the receptor tyrosine kinase FLT3 with AML. According to the American Society for Clinical Oncologists, studies have also shown that mutations in C- Kit, a tyrosine kinase and transmembrane receptor for stem cell factor, can contribute to AML pathophysiology and have been associated with shorter survival and higher risk of recurrence following standard AML therapy.
While AML is commonly treated with traditional high-dose chemotherapeutic regimens, studies have observed responses in AML patients following treatment with TK inhibitors such as imatinib (Gleevec).
Whether the OHSU assay can actually determine the appropriate treatment regimen for AML patients has yet to be determined. OHSU currently has ongoing studies with the assay to confirm its validity and utility against the disease. Results from these studies are critical to determining if a diagnostic is commercialized for the indication, Tyner said.
OHSU is currently in the process of publishing the research that led to the development of the test. Following publication, OHSU will be able to talk in more detail about the test based on MolecularMD’s technology, Tyner said. He hopes to publish the first papers about the AML diagnostic OHSU is developing in the next four to six months.
MolecularMD states on its website that its current R&D focus, “in collaboration with recognized global leaders, is the development and commercialization of a world-class BCR-ABL RNA quantitation service for chronic myelogenous leukemia patients being treated by imatinib, bone marrow transplantation, and related therapeutics.”
The company offers screening for mutations in ABL. “For these tests, RNA is extracted from blood and cDNA is prepared,” the company describes on its website. The cDNA is then analyzed for T315I through FRET in four business days, and for the ABL Kinase through direct DNA sequencing in four to eight business days.
Tyner noted that ahead of developing an assay, the more immediate focus for his team is to compile a database of cancer-causing genetic mutations. Ultimately, Tyner hopes that this research will yield an assay similar to RAPID that “does become broadly available and clinically useful.”

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