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Mirna Data Points to Synergy between EGFR Inhibitor, microRNA Mimic in Lung Cancer

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Mirna Therapeutics this week announced the publication of in vitro data showing that microRNA-34a is able to sensitize both non-small cell lung cancer (NSCLC) cells and hepatocellular carcinoma cells to the approved lung cancer therapy Tarceva (erlotinib), and that the two work synergistically together.

In light of the findings, the company is considering expanding the development program for MRX34 — a synthetic version of miR-34a currently in phase I testing for primary liver cancer or advanced metastatic cancer with liver involvement — to include combination therapy studies, Mirna President and CEO Paul Lammers told Gene Silencing News.

Research has shown that miR-34a plays a key role in the p53 tumor-suppressor pathway, while Mirna's own work also suggests that miR-34a represses the expression of more than 20 oncogenes and inhibits processes required for cancer cell viability, cancer stemness, metastasis, and chemoresistance.

In preclinical testing, MRX34 has also shown the ability to inhibit liver tumor growth and cut tumor burden in mouse models of the disease.

When MRX34 moved into phase I in mid-2013, Lammers said that the company was examining the potential of combining MRX34 and various standard-of-care cancer therapies including chemotherapy, radiation therapy, and targeted therapies such as Tarceva. He also cited data implicating miR-34a in NSCLC

Those efforts have now yielded these latest data, which appeared last week in PLoS One.

Tarceva, which inhibits epidermal growth factor receptor (EGFR), is approved for treating advanced-stage NSCLC and certain other cancers. While it has shown to be effective in patients with mutations in the EGFR gene, a large portion of NSCLC patients are resistant to treatment, due to an amplification and overexpression of receptor kinase MET and its ligand HGF, increased expression of the receptor kinase AXL and its ligand GAS6, and other factors.

Due to data showing that miR-34a directly represses both MET and AXL, Mirna researchers hypothesized that their drug candidate might help sensitize cancer cells to Tarceva.

According to Andreas Bader, director of analytical and external research at Mirna and senior author of the PLoS One paper, cancer resistance is generally categorized as either primary or acquired. The former refers to cancers that are naturally resistant to a treatment while the latter refers to cancers that are sensitive to a particular drug but develop resistance after continued exposure.

To examine the effects of miR-34a on acquired resistance, Bader and his colleagues treated NSCLC cells to increasing concentrations of Tarceva until they showed no signs of growth inhibition — an effect tied to an upregulation of MET and HGF. Upon introduction of the miRNA, however, the cells once again responded to the EGFR inhibitor.

"This was very striking because these resistant cells could grow at an erlotinib concentration that is equivalent to IC90," with IC50 values exceeding 25 micromolar, Bader noted. "But when we added a very tiny amount of miR-34, we could drop the IC50 requirement for erlotinib back down to below 0.1 micromolar, and that was very similar to IC50 value of the parental cell line."

In terms of primary resistance, the scientists examined NSCLC cells in which Tarcerva naturally produced an IC50 value of 11 micromolar, and found that an approximately four-fold lower dose of the drug was needed to slow cell growth following miR-34a treatment.

Notably, both effects were shown to be miR-34a-specific as the addition of a negative control miRNA did not improve the activity of Tarceva.

The Mirna researchers next turned to see whether the addition of miR-34a could work synergistically with Tarceva — an effort that Bader explained required the use of an algorithm designed to help measure reciprocal interaction between two drugs.

"Essentially, you establish dose-response curves for each drug alone and in combination," he said. "The algorithm figures out … whether [the effect of both drugs] is synergistic or additive."

The algorithm allows for the measurement of dose requirements for any given effect level, such as 80 percent growth inhibition, for example. If a combination of drugs reduces the dose of each needed to achieve a particular effect, you are observing synergy.

In their experiments, the scientists observed synergy across a range of different dose levels and drug ratios, reducing IC50 dose requirements for erlotinib and miR-34a by up to 46-fold and 13-fold, respectively," they wrote in their paper.

"Maximal synergy was detected at dosages that provide a high level of cancer cell inhibition beyond the one that is induced by the single agents alone and, thus, is of clinical relevance," they added.

Interestingly, the Mirna group was also able to see a synergistic effect with a combination of Tarceva and miR-34a in liver cancer cells — something they tested given that the EGFR inhibitor has proven moderately effective alone in liver cancer patients but failed to offer therapeutic benefit when combined with the approved liver and kidney cancer treatment Nexavar (sorafenib).

As in the NSCLC experiments, synergy was observed with Taceva and miR-34a at "high levels of cancer cell inhibition and, hence, occurs within the desirable range of activity," according to the PLoS One report.

Overall, the data suggest that patients with NSCLC and other cancers previously not suitable for Tarceva may be sensitive to treatment with the addition of Mirna's MRX34 — something that Bader believes could be fairly quickly moved into human testing.

"Both drugs are used in the clinic [already], so the clinical implementation of the combination could be very easily implemented," he said. "It's just a matter of funding."

In an email, Lammers indicated that such work could begin in the next few years.

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