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Translational Profiling Suggests How to Judge, Use Cancer Drug

By Anette Breindl
Science Editor

By focusing on protein translation, scientists have gained surprising insights into the control of prostate cancer metastasis, linking it to dysregulation of the protein kinase mTOR.

The work, senior author Davide Ruggero told BioWorld Today, gives new insights into how mTOR functions.

But more generally, the paper, which appeared in the Feb. 23, 2012, issue of Nature, showed that basic scientific studies can continue to inform the use of experimental drugs – in this case, Intellikine Inc.'s INK128 – even after they have entered clinical trials. "Once a drug is in the clinic, the research needs to carry on," said Ruggero, associate professor at the University of California, San Francisco.

mTOR is a protein that senses nutrient availability, and it controls cell growth according to whether cells are, at a given moment, in an environment of plenty or scarcity.

mTOR itself "has not been described as an oncogene yet, and I don't think it ever will be," senior co-author Christian Rommel told BioWorld Today. "But a lot of upstream oncogenes and/or tumor suppressors really hammer on this node," because when mTOR goes out of control, so does cell growth – which is, of course, exactly what a cancer cell needs.

Rommel is chief scientific officer of La Jolla, Calif.-based based Intellikine, which was acquired late last year by Takeda Pharmaceutical Co. Ltd. (See BioWorld Today, Dec. 22, 2011.)

In the clinic, mTOR has been targeted by two different classes of compounds: so-called ATP site inhibitors and allosteric inhibitors.

Preclinically, ATP site inhibitors appear to work better than allosteric inhibitors. The reasons for that are partly clear – and partly not. (See BioWorld Today, Feb. 20, 2009.)

In the work now published in Nature, the scientists used ribosome profiling, a new method that specifically pulls out mRNAs that are being transcribed by the cell's translation machinery, the ribosome, at any given moment.

"The concept is not new, but the method is," Ruggero said. And Rommel added that, by looking only at mRNAs that are being actively translated, "you remove a lot of uncertainties" about whether changes in mRNA levels carry through to proteins.

In their studies, the team focused on prostate cancer, because mTOR signaling is dysregulated in almost all advanced prostate cancers. They profiled prostate cancer cell lines and tested the effects of treating them with both allosteric and ATP-site inhibitors, with the goal of finding "a differential fingerprint of the ribosome output," Rommel said.

With that approach, the team was able to classify the genes being transcribed into several classes. Some were rather unsurprising. For example, clusters of genes involved in ribosome biogenesis and cancer metabolism were pretty safe bets for a protein that senses nutrients to control cell metabolism and growth.

But another class of proteins was more surprising: The team found that several genes that are "crucial" for metastasis were dysregulated in prostate cancer cells – and that they were differentially affected by different types of mTOR inhibitors. Those mTOR inhibitors that target the protein's ATP binding site, such as INK128, affected the translation of metastasis mRNAs, while allosteric inhibitors did not.

When mice with mTOR pathway-driven prostate cancer were treated with INK128, invasion and metastasis was "profoundly" decreased, the authors wrote. On the average, treated animals had only half as many metastatic lymph nodes as controls.

Rommel said the results have, or at least could have, practical implications for clinical trials.

For one thing, the work adds to the body of evidence that blocking mTOR in cancer will work best in combination with other approaches – and "guides us what kind of combination to apply." If INK128 affects metastasis without killing cells, the best strategy is to "find a combination agent that focuses on harming the cancer cells intrinsically," he said.

The company is testing INK128 in combination with the cytotoxic chemotherapy paclitaxel, as well as on its own in solid and hematological cancers.

A combination with an angiogenesis-targeting drug might also allow the strengths of both approaches to complement each other. Angiogenesis blockers clearly are effective against primary tumors, but research has implied that they might actually increase the risk of metastasis. (See BioWorld Today, March 4, 2009.)

Also, mTOR inhibitors such as INK128 do not kill cells; they block growth and specifically affect metastasis – basically "putting the tumor to sleep" and keeping it at bay, at least for a while, Rommel said.

Clinical trial readouts to judge a drug's success could be focused on metastases, in addition to looking at shrinkage of the primary tumor itself. The understanding of how INK128 works will not affect the endpoint, Rommel specified, "because the endpoint needs to be survival." But looking at issues like metastatic burden can show early on in a trial whether a drug shows promise.

So far, the latter strategy has been harder to implement than one might think, in part because although clinicians are eager for more science-based approaches to medicine, turning science and clinical trials into a two-way street is still in its infancy.

For scientific insight into experimental drugs to actually make a difference in clinical trials, "you have to have a receptor for [those insights] on the other end," Rommel said. Finding such receptors initially was something of a challenge, he added. "But we are getting there."