Combining Chemo With mTOR Inhibitors Shows Promise in pNETS

Combining the chemotherapy streptozotocin with drugs that target the mTOR pathway may be an effective way to treat pancreatic neuroendocrine tumors (pNETs), according to findings presented at the 2015 North American Neuroendocrine Tumor Society symposium. Using the two types of drugs together was found to effectively target tumors in both in vivo and in vitro preclinical studies.

Most pNETs are generally resistant to chemotherapy because they have a low proliferation rate and defects in their apoptotic pathway. Therapies that target the mTOR pathway have shown some benefit against pNETs, but their effect is limited.

Based on the literature, researchers have hypothesized that overactivation of the mTOR pathway could lead to resistance to streptozotocin, according to lead author Cécile Vercherat, PhD, a researcher at the Centre de Recherche en Cancérologie de Lyon (CRCL) in Lyon, France. Thus, she and her team decided to combine streptozotocin with a drug that inhibits mTOR.

In the current study, the investigators evaluated streptozotocin in combination with four different mTOR inhibitors: everolimus (Afinitor) and three experimental agents—MK2206, BKM120, and BEZ235.

Streptozotocin, a natural product that was originally developed as an antibiotic, has been used to treat pancreatic islet cell tumors since the 1980s. It is the standard first-line chemotherapy for pNETs that cannot be treated with surgery.

The FDA approved everolimus in 2011 to treat pNETs, but its effect is limited because the majority of patients develop resistance to the drug.

In the first part of the research, the investigators used the insulinoma cell lines INS-1E and MIN6 to evaluate cell viability, proliferation, and apoptosis when streptozotocin was combined with mTOR inhibitors. They found that all four combinations had a synergistic effect, leading to heterogeneous mTOR pathway inhibition and increased apoptosis.

Somewhat surprisingly, Vercherat said, they found that when insulinoma cell lines were treated with streptozotocin, there was a “transient but important activation of the mTOR pathway.”

The four combinations were also evaluated in animal models that were created by injecting tumor cells into the spleens of mice. This experimental model results in primary tumors that form on the spleen and tumor nodules that form in the liver.

The animals were divided into groups for treatment with a control and groups for the four different mTOR inhibitors, each combined with streptozotocin. All four experimental groups showed decreased tumor dissemination, which was measured by a reduction in the tumor surface, and a decrease in the mean tumor size in the liver nodules, although there were differences seen in the effectiveness of the different mTOR inhibitors.

Side effects, including hyperglycemia, were seen in the mice treated with BKM120, but the researchers were able to avoid this effect by decreasing the dose.

The results of the experiments both in vivo and in vitro suggested a synergistic effect between the two types of treatment. According to the researchers, the findings of their study suggest that the combination of mTOR inhibitors and streptozotocin should be evaluated in clinical trials.

Vercherat C, Bourguillault F, Hervieu V, et al. mTOR pathway inhibition sensitizes insulinoma cells to streptozotocin induced apoptosis. Presented at: 2015 NANETS Symposium; October 15-17; Austin, TX. Abstract B14.

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