Mullerian Inhibiting Substance (MIS) causes regression of female reproductive tract structures in the male fetus. To investigate whether MIS can be a therapeutic for ovarian cancer, which originates from the Mullerian duct derived coelomic epithelium, binding of MIS to both ovarian cancer cell lines and primary ascites cells from patients with stage III or IV cystadenocarcinoma was demonstrated. These cells express the MIS type II receptor mRNA and respond to MIS in growth inhibition assays. These experiments paralleled efforts to produce MIS that would be suitable for clinical trial in humans because of concern over mouse immunogens in the immunoaffinity purification of MIS and the preponderance of high molecular weight aggregates and multiple products of the primary and secondary cleavage sites of holo MIS. In order to address those concerns, preliminary studies were done that indicate conditioned serum free media from MIS transfected mammalian cells could be used to advantage to produce a homogeneous preparation of MIS by size exclusion chromatography with an FPLC system. Peptides with high affinity can also be used in purification, and tobacco sources for rhMIS will be compared to mammalian sources. Thus, the first Specific Aim is to purify homogenous MIS using these approaches and to scale up production for use in clinical trials. The second Specific Aim is to crystallize MIS or its derivative in order to begin the process of characterizing the secondary structure of MIS and understand the molecular interactions both between the amino and carboxy terminal MIS domains and between the C terminal domain and its receptor. The third Specific Aim is to determine if the MIS type II receptor is mutated in patients with ovarian cancer by sequence analysis and correlate absence of functional receptor with the occurance of ovarian cancer. The fourth Specific Aim is to study the tissue specific and developmental expression of the MIS type II receptor using antibodies developed during the past grant and others to be developed during the course of the proposed grant. A homogeneous MIS product whose structure is defined by crystallography, which can be scaled up for human use in clinical trials against human ovarian cancer, can then be used in parallel with MIS type II receptor molecular probes and antibodies to select tumors appropriate for such therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA017393-29
Application #
6632991
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Hecht, Toby T
Project Start
1978-06-01
Project End
2005-04-30
Budget Start
2003-05-01
Budget End
2005-04-30
Support Year
29
Fiscal Year
2003
Total Cost
$459,325
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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