CAMBRIDGE, Mass.—Attempting both to curb the threat ofovarian cancer and to provide perhaps the first effective therapy for advancedovarian cancer, researchers with the Massachusetts Institute of Technology(MIT) and the Lankenau Institute for Medical Research (LIMR) in Wynnewood, Pa.,have reported that a nanoparticle delivery system carrying a "killer gene" haseffectively suppressed ovarian tumor growth in mice.
In the United States alone, ovarian cancer causes more than15,000 deaths annually and ranks as the fifth-leading cause of cancer-relateddeath in women as well as the leading cause of death from gynecologic cancers.Much of this because the disease is generally diagnosed at a relatively latestage, and effective therapies are available neither for late-stage diseasevictims nor for those with cancer recurrence, note MIT and Lankenauresearchers.
The research findings were published in the Aug. 1 issue ofthe journal Cancer Research, and addresshow the nanotech method delivers a gene that produces the diphtheria toxin,which kills cells by disrupting their ability to manufacture proteins. Aftersome additional preclinical studies have been undertaken, human trials areexpected within a year or two, says Daniel Anderson, research associate in theDavid H. Koch Institute for Integrative Cancer Research at MIT and a seniorauthor of the paper.
"Unlike chemotherapy, which can destroy both cancer andhealthy cells and lead to many adverse effects, this new therapy specificallytargets cancer cells and leaves the healthy cells alone," affirms Dr. JanetSawicki, a professor at LIMR who lead the LIMR researchers in this work. "Ourhope is to begin doing clinical trials in patients in the next 18 to 24 monthsand then potentially tailor this therapy to treat different solid tumor typesincluding pancreatic, prostate and cervical cancers."
Anderson and others from MIT, including professor RobertLanger, along with the LIMR team, found that the gene-therapy treatment wasequally as effective, and in some cases more effective, than the traditionalchemotherapy combination of cisplatin and paclitaxel. Furthermore, it did nothave the toxic side effects of chemotherapy because the gene is engineered tobe overexpressed in ovarian cells but is inactive in other cell types.
The researchers went an extra step to keep the therapytumor-focused by administering the nanoparticles via injection into theperitoneal cavity of the mice. This cavity encases abdominal organs such as thestomach, liver, spleen, ovaries and uterus, and ovarian cancer is known toinitially spread throughout the peritoneal cavity. The new nanoparticles weremade with positively charged, biodegradable polymers that, when mixed together,can spontaneously assemble with DNA to form nanoparticles. The polymer-DNAnanoparticle can deliver functional DNA when injected into or near the targetedtissue. Reportedly, there is no clinical precedent for the use of this C32-117poly(beta-amino ester) polymer as a delivery vehicle.
The researchers also note in their paper that, given therapid shutdown of protein synthesis following uptake and expression ofdiphtheria toxin-encoding (DT-A) DNA, it is likely that cells will show noresistance to the nanotherapy, meaning that it may be possible to administerDT-A nanotherapy over an extended period of time to suppress tumor growth, andperhaps even reduce tumor burden.
"Currently, ovarian cancer patients are treated withchemotherapeutics following surgical debulking. Further studies…will be aimedat assessing the therapeutic efficacy of DT-A nanotherapy as an adjuvanttherapy to surgical debulking," the researchers wrote.
The MIT-Lankenau team has been working on this method forseveral years now because they wanted an alternative to viral delivery methods,which they felt were associated with too many safety risks. In addition toovarian and other types of cancer, these nanoparticles have demonstratedpotential for treating viral infections as well, the researchers note.
Future studies already in the planning stages by theMIT-Lankenau team are expected to examine the effectiveness ofnanoparticle-delivered diphtheria toxin genes in other types of cancer,including brain, lung and liver cancers.
