Modified Mullerian-Inhibiting Substance Suppresses Growth of Some Recurrent Ovarian Tumors in Mouse Model
Use of gene therapy to deliver a protein that suppresses the development of female reproductive organs may improve the survival of patients with ovarian cancer that has recurred after chemotherapy. In a study published by Pepin et al in PNAS Early Edition, a Massachusetts General Hospital (MGH) research team described how a single injection of a modified version of Mullerian-inhibiting substance (MIS), a protein critical to sexual development, carried on a commonly used viral vector suppressed the growth of chemotherapy-resistant ovarian tumors in a mouse model. Although not all the tested tumors—grown from cells grafted from patient tumors—were sensitive to this treatment, the investigators also outlined a noninvasive way of screening cancer cells in vitro for treatment responsiveness.
“Our findings are important because there are currently no therapeutic options for recurrent, chemoresistant ovarian cancer,” said David Pepin, PhD, of the MGH Pediatric Surgical Research Laboratories.
MIS Suppression
During embryonic development, MIS is secreted by tissues in male embryos to prevent maturation of the Mullerian duct, which otherwise would give rise to female reproductive organs. The potential of MIS to treat ovarian cancer and other reproductive tumors has been studied for many years by Patricia Donahoe, MD, Director of the MGH Pediatric Surgical Research Laboratories.
Previous investigations by Dr. Donahoe's team have showed that MIS suppresses ovarian cancer growth, both in animals and in human cell lines, by targeting the cancer stem cells that survive chemotherapy. However, previous methods of producing MIS were unable to generate sufficient quantities of high-quality protein for preclinical testing.
The current study employed a modified form of the MIS gene to generate protein of greater purity and effectiveness, combined with the accepted viral vector AAV9 for delivery into the peritoneal cavity, a common site for the recurrence of ovarian cancer. The modified MIS/AAV9 construct was tested against tumor cells taken from ascites fluid that had accumulated within the abdomens of several patients with recurrent ovarian cancer. Initial experiments confirmed that these cells expressed the MIS receptor protein, carried markers indicating their identity as cancer stem cells, and that their growth was inhibited in vitro by MIS.
Study Results
The effectiveness of the MIS/AAV9 construct was tested in mice into which ovarian cancer cells were implanted. Treatment with MIS/AAV9 3 weeks prior to tumor implantation significantly inhibited tumor growth.
In a more clinically relevant experiment, applying the therapy to mice in which tumors already had been induced by implantation of cancer cells from five different patients resulted in significant inhibition of further growth of tumors generated from the cells of three of the five patients. Analysis of tumor samples from more than 200 patients revealed that 88% expressed some level of the MIS receptor, with 65% expressing moderate or high protein expression.
“Since the response to MIS gene therapy is not the same for all patients, it will be important to first screen each patient's tumors to ensure they will respond,” said Dr. Pepin. “While we have not yet identified biomarkers of treatment response—something we are currently searching for—we have described a way to rapidly grow tumor cells from ascites to be evaluated for drug sensitivity. If further study confirms the susceptibility of chemoresistant tumors to this MIS gene therapy, the ability to inhibit tumor recurrence could significantly extend patient survival.”
“All of the implanted tumor cells were from patients who failed all previous therapies, so a 60% response rate is quite significant for a single agent,” said Dr. Donahoe. “The ability to administer this MIS/AAV9 construct as a single, long-acting injection makes the use of this effective but complex protein both clinically feasible and patient-friendly. Our results provide proof of concept and predict a translation into patient care that was not previously possible.”
Dr. Donahoe is the corresponding author of the PNAS article.
This study was supported by the Ovarian Cancer Research Fund, the Sudna Gar Foundation, the Department of Defense Award, and the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
