Development of Effective Leiomyoma in vitro Model Systems

Historical Background:  Despite the high prevalence and morbidity, study of leiomyomas was difficult due to the lack of in vitro model systems.  In order to characterize the mechanism of leiomyoma genesis and continued growth, in vitro models were needed to perform functional studies.

Central Findings:  Development of immortalized human leiomyoma and patient-matched myometrial cell lines.

Influence of the Findings:  Internationally used in vitro model systems used to advance understanding of human disease.

Specific Role:  Primary Investigator

References

1. Malik M, Catherino WH. Novel method to characterize primary cultures of leiomyoma and myometrium using confirmatory biomarker gene arrays.  Fertil Steril 2007;87:1166-72.
2. Malik M, Catherino WH. Development and validation of a three-dimensional in vitro model  for uterine leiomyoma and patient-matched myometrium.  Fertil Steril 2012;97:1287-93.
3. Levy G, Malik M, Britten J, Gilden M, Segars J, Catherino WH. Liarozole inhibits transforming growth factor-b3-mediated extracellular matrix formation in human three-dimensional leiomyoma cultures.  Fertil Steril 2014;102:272-81.
4. Malik M, Britten J, Segars J, Catherino WH. Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to Fasudil, a Rho-kinase inhibitor, as compared to 2-dimensional cultures.  Reprod Sci 2014;21:1126-38.

Characterization of Molecular Regulation Resulting in the Leiomyoma Phenotype

Historical Background:  The defining phenotypic characteristic of leiomyomas is the excessive and aberrant fibrosis, although the mechanism of this fibrosis was unclear.  The excessive fibrosis results in increasing bulk of the tumors, and this bulk is responsible for the symptoms associated with leiomyomas.

Central Findings:  Transforming growth factor beta stimulated fibrosis, while retinoic acid inhibited fibrosis.

Influence of the Findings:  Dramatic insight into the mechanism of leiomyoma fibrosis, providing direction for novel therapeutic intervention.

Specific Role:  Primary Investigator

References

1. Catherino WH, Leppert PC, Stenmark MH, Payson M, Nieman LK, Segars JH. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.  Genes Chrom Cancer 2004;40:204-17.
2. Malik M, Webb J, Catherino WH. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells.  Clin Endocrinol 2008;69:462-70.
3. Norian JM, Malik M, Parker CY, Joseph D, Leppert PC, Segars JH, Catherino WH. Transforming growth factor-β3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas.  Reprod Sci 2009;16:1153-64.
4. Joseph DS, Malik M, Nurudeen S, Catherino WH. Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta 3.  Fertil Steril 2010;93:1500-8.

Rapid Assessment of Novel Therapeutics for Human Leiomyomas

Historical Background:  There is currently no long-term FDA-approved medical therapy for leiomyomas.  The only FDA-approved therapies have substantial side-effects, and as such are used for short-term regulation of symptoms prior to surgical intervention.

Central Findings:  We have confirmed impact of medical therapies with known clinical efficacy, as well as novel therapies not yet tested in clinical trials.

Influence of the Findings:  We have confirmed that clinically efficacious therapies act, at least in part, by decreasing fibrosis.  Further, we have a rapid method of testing novel therapeutics.

Specific Role:  Primary Investigator

References

1. Catherino WH, Malik M, Driggers P, Chappel S, Segars J, Davis J. Novel, orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation without adversely affecting endometrium or myometrium.  J Steroid Biochem Mol Biol 2010;122:279-86.
2. Gilden M, Malik M, Britten J, Delgado T, Levy G, Catherino WH. Leiomyoma fibrosis inhibited by liarozole, a retinoic acid metabolic blocking agent.  Fertil Steril 2012;98:1557-62.
3. Wright D, Britten J. Malik M, Catherino WH. Relugolix and elagolix directly inhibit leiomyoma extracellular matrix production in 2-dimensional and 3-D cell cultures.  F S Sci 2022;3:299-308.
4. Malik M, Britten JL, DeAngelis A, Sitler C, Moran S, Roura-Monillor JA, Driggers P, Catherino WH. Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of extracellular matrix.  F S Sci 2023;4:74-89.

Complete list of 114 publications in My Bibliography:

URL:  http://www.ncbi.nlm.nih.gov/pubmed/?term=catherino+w+%5Bau%5D

Dr. Catherino completed medical and graduate school training at the University of Wisconsin-Madison, residency training at Duke University Medical Center, and fellowship training at the NIH.  He became Board Certified in OB/GYN in 2005, REI in 2007, and has been a Boards Examiner, served on the REI Qualifying and Certifying Division Committee, and ultimately joined the Board of Directors for the Division of REI for ABOG.  He became Research Director in 2004, and has been promoted to Full Professor with Tenure in the Department of Obstetrics and Gynecology at USUHS in 2013.  He is currently the Vice Chair of Research in the Department, where he studies the molecular mechanisms of fibroid development.  He has authored over 130 peer-reviewed manuscripts, and has been continuously funded. Dr. Catherino is the inaugural Editor-in-Chief of Fertility and Sterility – Science.  He serves at the American Board of Obstetrics and Gynecology as a Division Member for Reproductive Endocrinology and Infertility.  He cares for a wide array of patients at Walter Reed National Military Medical Center and the National Institutes of Health.