A recent study published by David Pepin, PhD, et al shows a promising gene therapy treatment that can inhibit tumor growth in preclinical models of serous ovarian cancer.
David Pepin, PhD
David Pepin, PhD
Nonefficient screening, late presentation, and lack of effective therapeutic strategies collectively contribute to the highest death-to-incidence ratios observed in patients with ovarian cancer.1Recurrence is frequent, fatal, and often resistant to further chemotherapeutic intervention.
A study published recently by David Pepin, PhD, et al from Massachusetts General Hospital (MGH) inProceedings of National Academy of Sciencesshows a promising gene therapy treatment that can inhibit tumor growth in preclinical models of serous ovarian cancer.2The team looked at Müllerian-inhibiting substance (MIS) as a therapeutic gene for Müllerian-derived ovarian cancers. MIS is reported to inhibit growth of the stem cell-like/progenitor population of ovarian cancer cells, in addition to its known role in sex differentiation by inhibition of Müllerian duct development in the male embryos.3The engineered MIS gene was delivered utilizing Adeno-associated virus (AAV).
MIS, a member of the transforming growth factor-beta (TGF beta) multigene family, is produced as dimeric precursor that requires cleavage and dissociation to release bioactive C-terminal fragments. Recombinant human MIS (rhMIS), however, has limited potency due to low cleavage. The team engineered the cDNA to alter the cleavage site and the leader peptide sequence, resulting in production of MIS protein with higher potency due to increased primary cleavage and reduced secondary cleavage (LRMIS). An AAV9 construct with a ubiquitous CMV enhancer fused with chicken β-actin promoter, a synthetic intron, the LRMIS gene, and a rabbit β-globin poly-A signal was designed to deliver LRMIS for gene therapy.
A single inteperitoneal injection of AAV9-GFP control virus in Nu/Nu mice resulted in GFP expression (60 days later) with no overt toxicities or adverse responses in the mice, and serum levels of common blood toxicity markers were found to be within the normal range. Blood levels of MIS were found to be extremely stable during the 60-day extent of the experiment, and injections of 3E11 particles in C57BL6 mice resulted in continued expression for over 1 year.
In the study, 39% of patient ascites samples generated primary cancer cell lines, and 50% of these cell lines formed tumors after engraftment in NOD/SCID/IL2Rg (NSG) mice. The study showed that AAV9-LRMIS pretreatment, 3 weeks before exposure to patient cancer cell line in these mice, significantly inhibited the growth of xenografts. AAV9-LRMIS treatment after induction of palpable patient-derived xenografts also resulted in significant inhibition of growth in three of the five cell lines tested, with two exhibiting complete tumor regression within 14 days of treatment.
“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 David Pepin, PhD, lead author and instructor in the Department of Surgery, Harvard Medical School. He further added, “While we have not yet identified biomarkers of treatment responsesomething 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 studies confirm the susceptibility of chemoresistant tumors to this MIS gene therapy, the ability to inhibit tumor recurrence could significantly extend patient survival.”
Lead investigator Patricia K. Donahoe, MD, director of pediatric surgical research laboratories, chief emerita of pediatric surgical services at Massachusetts General Hospital and Marshall K. Bartlett Professor of Surgery at Harvard Medical School, said, “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. The ability to administer this MIS/AAV9 constructprepared by Guangping Gao, PhD, director of the Gene Therapy Program at the University of Massachusetts and a long-term leader in the field of gene therapy—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.”
References:
1. Ovarian Cancer: The Recognition and Initial Management of Ovarian Cancer.http://www.ncbi.nlm.nih.gov/books/NBK83860/. Accessed Augst 27, 2015.
2. Pépina D, Sosulski A, ZhangaL et al. AAV9 delivering a modified human Mullerian inhibiting substance as a gene therapy in patient-derived xenografts of ovarian cancer.Proc Natl Acad Sci U S A. 2015;112(32):E4418-27
3. Haqq CM, King CY, Ukiyama E et al. Molecular basis of mammalian sexual determination: activation of Müllerian inhibiting substance gene expression by SRY.Science. 1994;2:266(5190):1494-500. Review.
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