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November 7, 2016

RNAi-Chemo Tag Team Slams Ovarian Cancer

  • Chemotherapy, always looking to join potent anticancer partnerships, is often disappointed. It has, for example, tried battling beside agents that would target the epidermal growth factor receptor (EGFR), a potent ally of cancers that form epithelial tumors. But these agents, which include tyrosine kinase inhibitors and small interfering RNAs (siRNAs), are like wrestlers that fail to secure the right holds, or stumble whenever they try to enter the ring.

    A more sure-footed partner for chemotherapy has been developed by scientists based at the Georgia Institute of Technology. These scientists, led by John McDonald, Ph.D., have devised a functionalized nanohydrogel siRNA delivery system. This system, in a mouse model of ovarian cancer, succeeded in honing in on ovarian tumors and sensitizing them to the chemotherapeutic agent called cisplatin. Together, the siRNA and the cisplatin dramatically shrank or even eliminated the tumors.

    These findings were detailed in a paper that appeared November 7 in the journal Scientific Reports, in an article entitled, “Targeted In Vivo Delivery of EGFR siRNA Inhibits Ovarian Cancer Growth and Enhances Drug Sensitivity.” The paper asserts that the mouse model results confirm predictions from previous cell line studies that “knockdown of EGFR may be of clinical significance in the treatment of epithelial tumors, especially with respect to the enhancement of platinum based therapies.”

    The new treatment has not been tested on humans, and research would be required by science and by law to demonstrate consistent results before preliminary human trials could become possible. Nonetheless, the Georgia Tech researchers are hopeful that if their continuing studies do prove to be consistent, the combination of the nanohydrogel with other therapeutic RNAs could represent a significant adjunct to chemotherapy in the treatment of a wide spectrum of cancers.

    "In many cancers, EGFR is overexpressed," Dr. McDonald said. "The problem is that because of this overexpression, many cellular functions, including cell replication and resistance to certain chemotherapy drugs, are dramatically cranked up."

    Dr. McDonald added that an overabundance of EGFRs found in a biopsy is usually a sign the cancer is aggressive and that patient prognosis is poor. "In 70% of ovarian cancer patients, EGFR is overexpressed at very high levels," he noted.

    The platinum-based chemotherapies used to treat ovarian cancers cause DNA damage, which switches on apoptosis, or cell suicide. When cells can't repair DNA damage, they're programmed to kill themselves to keep the damaged cells from spreading.

    The primary chemotherapy used to treat ovarian cancer works by coaxing cancer cells to trigger the suicide program, but having too many epidermal growth factor receptors gets in the way. "EGFR overexpression hinders apoptosis,” explains Dr. McDonald. “The cancer cells won't die. By knocking down EGRF, we make the cells hypersensitive to the drug. Apoptosis is reactivated."

    Existing EGFR-targeted drugs called tyrosine kinase inhibitors disrupt an EGFR function, but their success in treating ovarian cancer has been limited. "Clinicians have tried EGFR inhibitors to treat ovarian cancers for some years, and they only get about 20% of patients responding to it," Dr. McDonald pointed out. "Apparently, the particular EGFR function inhibited by these drugs is not critical to ovarian cancer."

    The siRNA designed by the Georgia Tech researchers attacks the cancer much closer to its root, which can overcome certain disadvantages seen with small-molecule drugs.

    “While the protein products of some of these genes are effectively inactivated by small inhibiting molecules, the majority (70–80%) of human genes are considered ‘non-druggable’ on the protein level,” wrote the authors of the Scientific Reports paper. “Additionally, since individual protein inhibitors are predicted to interact, on average, with >300 “off target” proteins, the negative side effects associated with protein level drug therapy can be significant.”

    Rather than attack EFGR at the protein level, the Georgia Tech approach knocks down EGFR at the RNA level. "Since EGFR is multifunctional, it's not exactly clear which malfunctions contribute to ovarian cancer growth. By completely knocking out its production in ovarian cancer cells, all EGFR functions are blocked."

    The nanohydrogel that delivers the siRNA to the cancer cells is a colloid ball of a common, compact organic molecule and about 98% water. Another molecule is added to the surface of the nanohydrogel as a guide. It makes the pellets adhere to the cancer cells like sticky cluster bombs. In the in vivo trials, the nanohydrogel’s siRNA carried a fluorescent tag, which allowed researchers to observe nanoparticles successfully honing in on the cancer cells.

    "We originally selected to target the EGFR gene because its activity is easily measured, and we wanted to use it simply as an indicator that our nanoparticle siRNA delivery system was working," Dr. McDonald related. "The fact that the EGFR knockdown so dramatically sensitized the cells to standard chemotherapy came as a bit of a surprise."

    At first, his team observed how the tumors responded to chemotherapy alone. Then they combined it with the nanoparticle treatment. "When we gave the chemotherapy alone, the response was moderate,” Dr. McDonald reported. “But with the addition of the nanoparticles, the tumor was either significantly reduced or completely gone."

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