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Research at Mass General
My group molecularly interrogates gynecologic tumors to identify genes or proteins and their corresponding signaling pathways that contribute to malignant transformation, the pathology of the disease, recurrence and/or resistance to therapy. Once key factors or pathways are identified, we actively test novel anticancer drugs to determine their efficacy in tumor explant models. To accomplish this we maintain a Gyn focused Tissue Repository. The repository infrastructure is extensive and is designed to collect malignant and benign tissues along with clinically annotated information. To complement the banking efforts my group has developed a Bio-Banking infrastructure. To this end we utilize a well-established in vivo experimental system in which primary tumors collected from ovarian and endometrial cancer patients at the time of initial surgery are grown in NOD/SCID mice. These explanted tumors and the primary tumors are genotyped and undergo cryopreservation using state of the art techniques. Once thawed, the tumors can be propagated in vivo through serial transplantation over several passages while retaining their original genotype and histophenotype. This allows for the generation of large cohorts of matched xenograft tumors ready for use in multi-armed therapeutic experiments. Our work to date provides evidence to suggest the clinical course of the primary tumor mimics the behavior and responses we have seen in our explants further supporting the potential clinical utility of our xenograft model. In addition, we can use our models to assess the efficacy of dual or sequential therapy. Specifically, we assess whether novel anti-cancer agents work better as a single agent or in conjunction with the standard of care or another anti-cancer agent.
As a result of our multiple interactions with pharmaceutical companies we have become more proactive in formulating stronger collaborations with the intent to develop novel inhibitors of oncogenic pathways, identify susceptible immune checkpoints, test new immune treatment strategies, and generate specific antibody drug conjugates for the treatment of women diagnosed with endometrial or ovarian cancer.
My group has extensively studied and continues to conduct research focused on the functional contribution of sub populations of gynecologic cancer cells that have stem like characteristics a contributing to the pathology and high recurrence rate. Our research provided valuable rationale for identifying targetable cells and testing combination therapies that can be tested in clinical trials for women with recurrent and refractory gynecologic cancer.
Tumor-associated carbohydrate antigens (TACAs) are promising therapeutic targets. Increased presence of Sialyl-Thomsen-nouveau antigen (STn), a TACA, correlates with worsened outcome and chemoresistance in ovarian cancer (OvCa). However, our recent studies suggest that many of the previous published reports that supported this conclusion utilized STn antibodies that may not be as specific as originally proposed. We are working with a panel of murine and humanized antibodies that bind with high specificity to all glycoforms of STn. Our preliminary data utilizing these novel highly specific STn antibodies suggests that STn is present in a significant subset of OvCa cells and tumors. From a therapeutic standpoint, we are testing STn-antibody drug conjugates (ADC) in in vitro and in vivo models.
In addition to in depth studies on gynecologic malignances we also focus on benign diseases that impact reproductive aged women. Specifically, we have and continue to be focused on endometriosis and leiomyoma. These non-malignant diseases can have a devastating negative impact on women's health and quality of life. Despite the prevalence of the disease, very little progress have been made in long-term solutions with the exception of surgical removal of the of uterus. We have used mouse models as well as primary human tissues to assess the mechanisms by which specific cell signaling factors positively or negatively impact the development, progression and/or pathological properties associated with these diseases.
Bo Rueda, PhDDirector, Vincent Center for Reproductive Biology, Massachusetts General Hospital Director, Clinical Fellows Research Program, Department of Obstetrics and Gynecology, Massachusetts General HospitalAssociate Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School Affiliated Faculty, Harvard Stem Cell Institute Affiliated Faculty, Massachusetts General Hospital Cancer Center
Whitfield Growdon, MD
Linah Al-Alem, PhDAndrew Baker, PhDUnnati Pandya, PhD
Celeste DiGloria, Clinical Research Coordinator II Bianca Zarrella, Research Technician IIDominique Zarrella, Research Technician II
Complete list of published work in MyBibliography:
He C, Lv X, Huang C, Angeletti PC, Hua G, Dong J, Zhou J, Wang Z, Ma B, Chen X, Lambert PF, Rueda BR, Davis JS, Wang C. A Human Papillomavirus-Independent Cervical Cancer Animal Model Reveals Unconventional Mechanisms of Cervical Carcinogenesis. Cell Rep. 2019, 26(10):2636-2650.e5. doi: 10.1016/j.celrep.2019.02.004.
He C, Lv X, Huang C, Hua G, Ma B, Chen X, Angeletti PC, Dong J, Zhou J, Wang Z, Rueda BR, Davis JS, Wang C. YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis. EMBO Rep. 2019 Mar;20(3). pii: e44948. doi: 10.15252/embr.201744948.
Bellio C, DiGloria C, Foster R, James K, Konstantinopoulos PA, Growdon WB, Rueda BR. PARP inhibition induces enrichment of DNA repair proficient CD133 and CD117 positive ovarian cancer stem cells. Mol Cancer Res. 2018 Nov 6. pii: molcanres.0594.2018. doi: 10.1158/1541-7786.MCR-18-0594. [Epub ahead of print] PMID:30401718.
Chiu YH, Karmon AE, Gaskins AJ, Arvizu M, Williams PL, Souter I, Rueda BR, Hauser R, Chavarro JE; Serum omega-3 fatty acids and treatment outcomes among women undergoing assisted reproduction. EARTH Study Team.Hum Reprod. 2018 Jan 1;33(1):156-165. doi: 10.1093/humrep/dex335.PMID:29136189
Cardozo ER, Foster R, Karmon AE, Lee AE, Gatune LW, Rueda BR, Styer AK. MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma. Reprod Biol Endocrinol. 2018 May 11;16(1):46. doi: 10.1186/s12958-018-0364-8. PMID:29747655
Starbuck K, Al-Alem L, Eavarone DA, Hernandez SF, Bellio C, Prendergast JM, Stein J, Dransfield DT, Zarrella B, Growdon WB, Behrens J, Foster R, Rueda BR. Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-nouveau. Oncotarget. 2018 May 1;9(33):23289-23305. doi: 10.18632/oncotarget.25289. eCollection 2018 May 1.PMID:29796189
Eavarone DA, Al-Alem L, Lugovskoy A, Prendergast JM, Nazer RI, Stein JN, Dransfield DT, Behrens J, Rueda BR. Humanized anti-Sialyl-Tn antibodies for the treatment of ovarian carcinoma. PLoS One. 2018 Jul 27;13(7):e0201314. doi: 10.1371/journal.pone.0201314. eCollection 2018.PMID:30052649
Bregar A, Deshpande A, Grange C, Zi T, Stall J, Hirsch H, Reeves J, Sathyanarayanan S, Growdon WB, Rueda BR. Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors. Gynecologic oncology. 2017; 145(3):446-452. PubMed [journal] PMID:28347512
Prendergast JM, Galvao da Silva AP, Eavarone DA, Ghaderi D, Zhang M, Brady D, Wicks J, DeSander J, Behrens J, Rueda BR. Novel anti-Sialyl-Tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity. mAbs. 2017; 9(4):615-627. PubMed [journal] PMID: 28281872PMCID: PMC5419082
Bajwa P, Nielsen S, Lombard JM, Rassam L, Nahar P, Rueda BR, Wilkinson JE, Miller RA, Tanwar PS. Overactive mTOR signaling leads to endometrial hyperplasia in aged women and mice. Oncotarget. 2017; 8(5):7265-7275. PubMed [journal] PMID: 27980219 PMCID: PMC5352319
Garrett LA, Growdon WB, Rueda BR, Foster R. Influence of a novel histone deacetylase inhibitor panobinostat (LBH589) on the growth of ovarian cancer. Journal of ovarian research. 2016; 9(1):58. PubMed [journal] PMID: 27633667 PMCID: PMC5025559
Guan Y, Guo L, Zukerberg L, Rueda BR, Styer AK. MicroRNA-15b regulates reversion-inducing cysteine-rich protein with Kazal motifs (RECK) expression in human uterine leiomyoma. Reproductive biology and endocrinology : RB&E. 2016; 14(1):45. PubMed [journal] PMID: 27530410 PMCID: PMC4988044
Styer AK, Rueda BR. The Epidemiology and Genetics of Uterine Leiomyoma. Best practice & research. Clinical obstetrics & gynaecology. 2016; 34:3-12. PubMed [journal] PMID: 26725703
Hernandez SF, Chisholm S, Borger D, Foster R, Rueda BR, Growdon WB. Ridaforolimus improves the anti-tumor activity of dual HER2 blockade in uterine serous carcinoma in vivo models with HER2 gene amplification and PIK3CA mutation. Gynecol Oncol. 2016 Apr 1. pii: S0090-8258(16)30083- X. doi: 10.1016/j.ygyno.2016.03.027. 141(3):570-579. PubMed [journal] PMID: 27017985
Roussel-Gervais A, Couture C, Langlais D, Takayasu S, Balsalobre A, Rueda BR, Zukerberg LR, Figarella-Branger D, Brue T, Drouin J. The Cables1 Gene in Glucocorticoid Regulation of Pituitary Corticotrope Growth and Cushing Disease. The Journal of clinical endocrinology and metabolism. 2016; 101(2):513-22. PubMed [journal] PMID: 26695862
Clark NC, Friel AM, Pru CA, Zhang L, Shioda T, Rueda BR, Peluso JJ, Pru JK Progesterone receptor membrane component 1 promotes survival of human breast cancer cells and the growth of xenograft tumors. Cancer biology & therapy. 2016; 17(3):262-71. PubMed [journal] PMID: 26785864 PMCID: PMC4847980
Hernandez SF, Vahidi NA, Park S, Weitzel RP, Tisdale J, Rueda BR, Wolff EF. Characterization of extracellular DDX4- or Ddx4-positive ovarian cells. Nature medicine. 2015; 21(10):1114-6. PubMed [journal] PMID: 26444630
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