Mullerian Inhibiting Substance (MIS) is a biological modifier developed in our laboratory for use in the treatment of tumors of Mullerian duct origin, namely ovarian, endometrial, and cervical carcinomas, all of which express MIS type II receptors (MISRII) and respond to MIS in growth inhibitory assays. MIS was recently found to be equally effective against breast and prostate cancers. However, the focus in this grant is on ovarian cancer because of its lethality and the lack of a therapeutic regimen capable of providing long term benefit to a high percentage of patients. MIS and its receptors have been cloned and multiple sources have been explored for the production of recombinant human (rh)MIS, including E.coli, yeast, baculovirus, mammalian cells, plants, and milk. The rhMIS with the best yield, reproducible biologic activity and efficacy against tumors, and the least contamination, thus far, is produced in mammalian cells and isolated from serum free media. A specific MIS ELISA has been developed to follow its production and pharmacokinetics, and antibodies developed to MIS receptors make it possible to preselect patients who may respond to MIS. 1) MIS will be produced in transfected mammalian cells and purified from serum free media using methods which adhere to FDA standards for human use. 2) The formulation produced will be tested against ovarian carcinoma cell lines in vivo and in vitro, alone, and in combination first with doxorubicin, which shows synergy with MIS and later, with other cytotoxic drugs. RhMIS pharmacokinetics will be studied in mice in order to design future treatment schedules. 3) MIS-C alone and in combination with its receptors will be cocrystallized for structure function studies to guide future rational drug design. The inhibitory effect of rhMIS in vivo against ovarian carcinomas is compelling. These experiments will pave the way for use of MIS in the clinic and will define a source for scale up to meet FDA standards. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA017393-32
Application #
7247904
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Muszynski, Karen
Project Start
1978-06-01
Project End
2010-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
32
Fiscal Year
2007
Total Cost
$324,140
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Chung, Youn Jee; Kim, Hyun Jung; Park, Sang Ho et al. (2015) Transcriptome analysis reveals that Müllerian inhibiting substance regulates signaling pathways that contribute to endometrial carcinogenesis. Int J Oncol 46:2039-46
Pépin, David; Sosulski, Amanda; Zhang, Lihua et al. (2015) 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 112:E4418-27
Park, Joo Hyun; Tanaka, Yoshihiro; Arango, Nelson A et al. (2014) Induction of WNT inhibitory factor 1 expression by Müllerian inhibiting substance/antiMullerian hormone in the Müllerian duct mesenchyme is linked to Müllerian duct regression. Dev Biol 386:227-36
Arango, Nelson Alexander; Li, Li; Dabir, Deepa et al. (2013) Meiosis I arrest abnormalities lead to severe oligozoospermia in meiosis 1 arresting protein (M1ap)-deficient mice. Biol Reprod 88:76
Pépin, D; Hoang, M; Nicolaou, F et al. (2013) An albumin leader sequence coupled with a cleavage site modification enhances the yield of recombinant C-terminal Mullerian Inhibiting Substance. Technology 1:63-71
Song, Jae Yen; Jo, Hyun Hee; Kim, Mee Ran et al. (2012) Expression of Müllerian inhibiting substance type II receptor and antiproliferative effects of MIS on human cervical cancer. Int J Oncol 40:2013-21
Namkung, Jeong; Song, Jae Yen; Jo, Hyun Hee et al. (2012) Mullerian inhibiting substance induces apoptosis of human endometrial stromal cells in endometriosis. J Clin Endocrinol Metab 97:3224-30
Meirelles, Katia; Benedict, Leo Andrew; Dombkowski, David et al. (2012) Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proc Natl Acad Sci U S A 109:2358-63
Hwang, Seong Jin; Suh, Min Jung; Yoon, Joo Hee et al. (2011) Identification of characteristic molecular signature of Müllerian inhibiting substance in human HPV-related cervical cancer cells. Int J Oncol 39:811-20
Clarkson, Andrew N; Talbot, Caroline L; Wang, Pei-Yu et al. (2011) Müllerian inhibiting substance is anterogradely transported and does not attenuate avulsion-induced death of hypoglossal motor neurons. Exp Neurol 231:304-8

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