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Translating disease-related findings

Research from the laboratories of Blenis and others helped define a complex signaling system that integrates inputs from growth factors, oncogenes, tumor suppressors, nutrients (such as glucose and amino acids), and oxygen. By determining that PI3 kinase and Ras act upstream of S6 kinase, and mTOR is upstream of S6K, Blenis began the process of identifying new nodes for intervention in this major cancer pathway.

While John Blenis, PhD (HMS), a cell biologist and biochemist interested in cancer cell metabolism, works at the basic science level, he collaborates with pre-clinical researchers. These include Elizabeth Henske, MD, and David Kwiatkowski, MD, PhD (both BWH), who are making discoveries in mouse models that will be tested in clinical studies of diseases involving dysregulated mTOR signaling. One of those diseases is lymphangioleiomyomatosis (LAM), a rare disease affecting women of childbearing age. In LAM, cancer-like cells originating in the kidney migrate to the lungs in a way reminiscent of metastasis, where they cause disorderly growth of smooth muscle-like cells that leads to often-fatal lung disease.

Cancer Cell Biology Program Leaders Andrea McClatchey, PhD (MGH) and David Pellman, MD (DFCI) are encouraging such disease-specific translational research. “We’re increasingly emphasizing helping researchers find collaborations to take these findings into clinical research,” they say.

In this case, abnormal activation of mTOR signaling – one of Blenis’s specialties – initiates the aberrant cell growth in LAM. But because LAM develops only in women, there may be a hormonal link. To determine how mTOR and estrogen work together to cause this tumor-like metastatic disease, Blenis’s collaborators are taking the discoveries about mTOR and estrogen signaling and applying them to mouse models. They in turn are working with Frank McCormack, a physician-scientist at the University of Cincinnati who is conducting clinical trials on LAM. McCormack recently demonstrated a small but significant efficacy of a rapamycin analog (sirolimus) in treating LAM.

However, the goal is to cure the disease, so Blenis and his collaborators plan to identify combination therapeutic approaches with rapamycin analogs or inhibitors of glutamine metabolism.

“Our collaborative group is dedicated to translating our basic research discoveries into novel therapies,” Blenis says. “Everything we do on glutamine metabolism is directly relevant to LAM, and because mTOR is improperly regulated in such a high percentage of tumors, we anticipate that our studies will translate to other cancers as well. We’re interested in all cancers that have activated mTOR signaling and determining their requirement for glutamine.”