{"paper_id":"617d5878-cbfa-4d19-9304-d68bbe21ea66","body_text":"targets & mechanis ms\nSciBX: Science–Business eXchange Copyright © 2012 Nature Publishing Group 1\nAdditional studies in endometrial and endometriotic tissue from the \nmouse models showed that Tnf-a upregulated matrix metalloproteinase \n9 ( Mmp9), which in turn cleaved full-length Src1 to produce the \nfragment ( see  Figure 1, “ SRC1 fragments on the endometriotic \npathway”). \nLastly, the team showed that mice deficient in Tnf-a, Mmp9 or Src1 \nhad endometriotic lesions that were up to five times smaller than lesions \nin wild-type control models.\nIn its report in Nature Medicine ,1 the team noted that the role of \nthe TNF-a-MMP9– SRC1 fragment pathway in endometriosis agreed \nwith a host of previous studies. These included papers that described an \nassociation between high peritoneal levels of TNF-a and endometriosis \nprogression in patients, 4 showed a treatment effect for anti- TNF-a \nantibodies in rat 5 and baboon 6 models of the disease, and found \nhigher levels of MMPs in invasive endometriotic cells than in normal \nendometrial cells from patients and chicken models.7,8\nTrial and trial again?\nOf the three proteins in the pathway, the SRC1 fragment is the logical \ntherapeutic target, team leader Bert O’Malley told SciBX.\n“Drugs that inhibit TNF- a are already available, but their \nimmunosuppressive activity has severe side effects, such as increased \nrisk of pneumonia, tuberculosis and—worst of all—cancer, while \ninhibiting MMP9 can also have musculoskeletal and many other side \neffects, ” he said.\nO’Malley is professor and chair of molecular and cellular biology at \nthe Baylor College of Medicine.\nOther endometriosis researchers agreed that the potential side effects \nof MMP9 inhibition ruled out the proteinase as an endometriosis target. \nOpinions were mixed on whether TNF-a or the SRC1 fragment will be \nthe better therapeutic target.\nThomas D’Hooghe, coordinator of the Leuven University Fertility \nCenter at University Hospitals Leuven and leader of the baboon model \nstudy, said the findings in the new paper actually bolster the case for \nTNF- a as a therapeutic target in \nendometriosis. “ TNF- a inhibitors \nshould be explored in a relevant \nclinical study, since all nonhuman \nprimate studies suggest a treatment \neffect for them, ” he said.\nD’Hooghe is also professor of \nmedicine at Catholic University \nLeuven  and adjunct professor of \nmedicine at Y ale University.\nThomas Collet, president and \nCEO of Meditrina Pharmaceuticals \nInc. , cautioned that anti- TNF- a \ntherapy already has failed in at least one clinical trial to treat the disease.\nIn 2008, researchers from University Hospitals Leuven, the \nUniversity of Oxford  and Johnson & Johnson ’s Centocor Inc. unit \nreported that Remicade infliximab , the pharma’s chimeric mAb \nagainst TNF-a, failed to reduce pain and lesion growth in a Phase II \nFragmentary  \nprogress in  \nendometriosis\nBy Michael J. Haas, Senior Writer\nA team from the Baylor College of Medicine  has treated endometrio-\nsis in mice by blocking a pathway that produces a fragment of nuclear \nreceptor coactivator 1 in endometrial tissue. 1 Now, small molecule \ninhibitors are needed to elucidate the fragment’s precise role in endome-\ntriosis and determine whether other pathway components are potential \ndisease targets as well.\nEndometriosis affects about 10% of women of reproductive age \nand involves the ectopic growth of tissue from the uterine lining \n(endometrium) in the peritoneal cavity, resulting in pelvic pain, \ninfertility and other symptoms. The underlying pathogenesis of the \ndisease is not well understood. What is known is that endometriotic \nlesions produce high levels of estrogen that enable growth of the lesion.\nAs a result most therapies reduce levels of estradiol  and other \nestrogens. Treatments include GnRH/LHRH receptor –targeting \ncompounds, aromatase  inhibitors or contraceptives that can only \nhalt—not reverse—lesion growth and may not completely control pain. \nAdditionally, these therapies can have side effects such as cognitive \ndeficits, hirsutism (excessive hairiness), the inability to conceive and an \nincreased risk of osteoporosis.\nPrevious studies have shown that levels of nuclear receptor \ncoactivator 1 ( NCOA1; SRC1) were lower in patients’ endometriotic \ntissue than in their normal endometrial tissue. However, the studies \ndid not investigate whether the protein actually played a role in the \ndisease.2,3\nThus, the Baylor College of Medicine team decided to take a closer look \nat whether SRC1 might be a therapeutic target to treat endometriosis.\nThe group began by confirming that endometriotic tissues from \npatients and mouse models of the indication had lower levels of intact \n(160 kDa) SRC1 than normal endometrial tissues. In doing so, the team \nfound endometriotic tissue from patients and models had higher levels \nof a 70 kDa, C-terminal fragment of SRC1.\nIn human endometrial cell lines, overexpression of the SRC1 \nfragment induced greater invasiveness than overexpression of full-\nlength SRC1 by promoting epithelial-mesenchymal transition (EMT). \nThe fragment also enabled the cell lines to evade normal caspase-\nmediated apoptosis that is triggered by the proinflammatory cytokine \ntumor necrosis factor-a (TNF-a) and occurs in endometrial cells during \nmenstruation.\n“TNF-a inhibitors \nshould be explored in a \nrelevant clinical study, \nsince all nonhuman \nprimate studies suggest \na treatment effect for \nthem.” \n—Thomas D’Hooghe,  \nUniversity Hospitals Leuven\n\nSciBX: Science–Business eXchange Copyright © 2012 Nature Publishing Group 2\nanalysis targets & mechanis ms\ntrial to treat endometriosis. 9\nD’Hooghe countered that patients in the infliximab trial “were \nthose awaiting surgery for fibrotic, deeply invasive endometriotic \nnodules. We know that drug therapy has only limited success in such \npatients and that surgery is the best option for them. ” Thus, it was not \nsurprising that infliximab failed to have an effect in this population,  \nhe said.\nInstead, he wanted to see anti- TNF-a antibodies tested “in women \nwith peritoneal endometriosis, who may have some small growths on \ntheir ovaries and a significant inflammatory phenotype” but less severe \noverall disease than the infliximab trial participants.\nEija Lundström, medical director at Debiopharm Group , agreed \nwith O’Malley that TNF-a inhibitors were probably not ideal therapies \nfor endometriosis.\nPamorelin LA triptorelin , a GnRH/LHRH receptor agonist from \nDebiopharm and Galenica Ltd.’s Vifor Pharma Ltd. unit, is approved \nto treat endometriosis, female infertility and advanced hormone-\ndependent prostate cancer.\n“ Anything that could target the lesions locally without suppressing \nestradiol production would be advantageous” over current estrogen-\nsuppressing therapies, said James Symons, VP of clinical development \nat Meditrina.\nMeditrina’s MPI-676, an anastrozole-based aromatase inhibitor, is in \nPhase II testing to treat endometriosis.\nJ&J, Merck & Co. Inc. and Mitsubishi Tanabe Pharma Corp. market \nRemicade to treat rheumatoid arthritis (RA) and other autoimmune \ndiseases. J&J also markets the antibody to treat Beh çet’s disease and \nspinal cord injury (SCI).\nIf the SRC1 fragment is deemed a better target than TNF-a, “it will \nbe important to identify the intercellular partners of the SRC1 fragment” \nin addition to procaspase-8 , said Michael Teifel, VP of preclinical \ndevelopment at Aeterna Zentaris Inc.’s Aeterna Zentaris GmbH unit. \nThe reason, he said, is selective inhibition of the SRC1 fragment could \nblock its antiapoptotic effects on endometrial cells but would not \nnecessarily prevent it from promoting EMT.\nFurthermore, the Src1 knockout models used by the team cannot \ndistinguish between the fragment’s role in disease onset and disease \nprogression, said Joachim Fensterle, director of translational medicine \nat Aeterna Zentaris GmbH. “Validation of the pathway as a target for \nestablished disease would require additional in vivo experiments, such \nas a model in which Src1 could be conditionally knocked out or knocked \ndown at different stages of disease, ” he said.\nD’Hooghe added that he wants to see SRC1 fragment inhibitors \ntested in mouse and baboon models of endometriosis.\nAEZS-115, a GnRH/LHRH receptor antagonist peptidomimetic from \nAeterna Zentaris, is in preclinical development to treat endometriosis.\nMore broadly, Collet said any potential therapy to treat endometriosis \nhas to account for the heterogeneity of the clinical presentation of the \ndisease. \n“For instance, while high estrogen levels are linked to disease \nprogression, postmenopausal women can present with endometriosis” \ndespite having lower estrogen levels than premenopausal women, \nwhich suggests several etiologies may contribute to disease onset or \nprogression, he said.\nOvary\nOvary\nLesionEndometrium\nTNF- α\nInvasive, apoptosis-resistant \n(endometriotic) cells\nTNF\nreceptor\nEndometrial cell\nApoptosis\nSRC1\n90 70\nEMT\nCASP8\nUterus\nProcaspase 8\n70\nMMP9\nSRC1\na g\nb f\nc e(1)\ne(2)\nd\nFour TNF- α inhibitors are marketed to treat rheumatoid arthritis (RA), \nCrohn’s disease, inflammatory bowel disease (IBD), psoriasis, ankylosing \nspondylitis and/or other autoimmune diseases: Humira adulimumab, a \nhuman mAb against TNF- α from Abbott Laboratories (NYSE:ABT) and \nEisai Co. Ltd.  (T okyo:4523; Osaka:4523); Enbrel etanercept, a \nrecombinant p75 TNF receptor linked to the Fc portion of human IgG1 \n(TNFr:Fc) from Amgen Inc. (NASDAQ:AMGN), Pfizer Inc. (NYSE:PFE) \nand T akeda Pharmaceutical Co. Ltd.  (T okyo:4502); Remicade infliximab, \na chimeric mAb against TNF- α from Johnson & Johnson  (NYSE:JNJ),  \nMerck & Co. Inc.  (NYSE:MRK) and Mitisubishi T anabe Pharma Corp.  \n(T okyo:4508; Osaka:4508); and Cimzia certolizumab pegol, a pegylated \nhumanized antibody fragment against TNF- α from UCB Group \n(Euronext:UBC) and Astellas Pharma Inc. (T okyo:4503).\nAdditionally, Johnson & Johnson markets Remicade to treat Behçet’s \ndisease and spinal cord injury (SCI); and Marnac Inc. ,  Ildong \nPharmaceutical Co. Ltd. , InterMune Inc. (NASDAQ:ITMN) and Shionogi \n& Co. Ltd.  (T okyo:4507; Osaka:4507) market Esbriet pirfenidone, a small \nmolecule inhibitor of proinflammatory cytokines such as TNF- α and \nprofibrotic cytokines, to treat pulmonary fibrosis.\nFigure 1. SRC1 fragments on the endometriotic pathway. according to a study in Nature Medicine, inhibition of a pathway that produces \na fragment of nuclear receptor coactivator 1 (nc Oa1; src 1) in endometrial (uterine lining) cells could help treat endometriosis.\nDuring menstruation, cells shed from the endometrium [a] can respond to local increases in tumor necrosis factor-a (tn F-a) [b] by \nupregulating matrix metalloproteinase 9 (mmP9) [c], which cleaves a 70 kDa, c -terminal fragment from full-length (160 kDa) src 1 [d]. in \nturn, the fragment prevents tn F-a-induced activation of procaspase-8 to caspase-8 (cas P8; Flice ) [e(1)] and consequent apoptotic sig-\nnaling, and it promotes the epithelial-mesenchymal transition (emt ) [e(2)] by an unknown mechanism, thereby inducing antiapoptotic and \ninvasive phenotypes, respectively. t hese characteristics are the hallmarks of endometriotic cells [f] and enable them to form endometriotic \nlesions [g] on the ovaries and/or elsewhere in the peritoneum.\n\nSciBX: Science–Business eXchange Copyright © 2012 Nature Publishing Group 3\nanalysis targets & mechanisms\n“ Also, pain symptoms don’t necessarily correlate with the size or the \nsite of the lesion” but instead result from variability between individual \npatients and their pain experiences, Symons said.\n“The key question is whether the findings reported in Nature \nMedicine could apply to all patients, ” Collet said.\nO’Malley said his team has already conducted screens and identified \ninhibitors of the SRC1 fragment. The researchers plan to test the \nmolecules in mice and potentially in monkey models.\nHis team also is considering testing the inhibitors in combination \nwith existing therapies to look for potential additive or synergistic \neffects.\n“It is possible that inhibitors of the pathway identified by the \nNature Medicine  team could have an additive or synergistic effect \nin combination with other therapies” to treat endometriosis, noted \nLundström.\nLonger term, the team wants to run prospective studies in \npatients to determine how broad a role the SRC1 fragment plays in \nendometriosis and to begin looking for specific links between that \ndisease and cancer.\nO’Malley said endometriotic cells undergo EMT and exhibit \ninvasiveness similar to that seen in early stage cancers, and statistical \nstudies have shown that endometriosis predisposes women to ovarian, \nuterine, colon, breast and other cancers.\nThe relationship between endometriosis and cancer is still poorly \nunderstood, he said.\nIf future studies uncover mechanistic links between the two \ndiseases, “I think physicians will have to treat women who have \nendometriosis with more than just long-term therapies that address \nsymptoms of pain, ” he said.\nBaylor College of Medicine has applied for a patent covering the \nSRC1 fragment inhibitors, and the findings are available for partnering \nor licensing, he said.\nHaas, M.J. SciBX 5(26); doi:10.1038/scibx.2012.670 \nPublished online June 28, 2012\nreFerences\n1.  han, s.J. et al. Nat. Med.; published online June 3, 2012; \ndoi:10.1038/nm.2826 \nContact: Bert W. O’malley, Baylor college of medicine,  \nhouston, t exas \ne-mail: berto@bcm.tmc.edu\n2. suzuki, a. et al. Virchows Arch. 456, 433–441 (2010)\n3.  Kumagami, a. et al. J. Obstet. Gynaecol. Res. 37, 1269–1276 (2011)\n4. Bedaiwy, m.a. et al. Hum. Reprod. 17, 426–431 (2002)\n5.  islimye, m. et al. Eur. J. Obstet. Gynecol. Reprod. Biol. 159, \n184–189 (2011)\n6. Falconer, h. et al. Hum. Reprod. 21, 1856–1862 (2006)\n7. Osteen, K.g. et al. Semin. Reprod. Med. 21, 155–164 (2003)\n8. nap, a.W. et al. Hum. Reprod. 19, 2180–2187 (2004)\n9. Koninckx, P .r. et al. Hum. Reprod. 23, 2017–2023 (2008)\ncOmPanies anD institUtiOns mentiOneD\n  Aeterna Zentaris Inc. (tsX:aeZ; nasDaQ:aeZs), Quebec city, \nQuebec, canada\n Baylor College of Medicine, houston, t exas\n Catholic University Leuven, leuven, Belgium\n Debiopharm Group, lausanne, switzerland\n Galenica Ltd. (siX:galn), Bern, switzerland\n Johnson & Johnson (nyse:JnJ), new Brunswick, n.J.\n Meditrina Pharmaceuticals Inc., ann arbor, mich.\n Merck & Co. Inc. (nyse:mrK), Whitehouse station, n.J.\n  Mitsubishi Tanabe Pharma Corp. (tokyo:4508; Osaka:4508), \nOsaka, Japan\n University Hospitals Leuven, leuven, Belgium\n University of Oxford, Oxford, U.K.\n Yale University, new haven, conn.","source_license":"CC0","license_restricted":false}