cancers Review Desmoplastic Small Round Cell Tumor: A Review of Main Molecular Abnormalities and Emerging Therapy Celso Abdon Mello 1,*, Fernando Augusto Batista Campos 1 , Tiago Goss Santos 2,3 , Maria Leticia Gobo Silva 4 , Giovana Tardin Torrezan 3,5 , Felipe D’Almeida Costa 6, Maria Nirvana Formiga 1, Ulisses Nicolau 1, Antonio Geraldo Nascimento 6, Cassia Silva 1, Maria Paula Curado 7 , Suely Akiko Nakagawa 8 , Ademar Lopes 8 and Samuel Aguiar Jr. 8 1 Department of Medical Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; [email protected] (F.A.B.C.); [email protected] (M.N.F.); [email protected] (U.N.); [email protected] (C.S.) 2 Laboratory of Tumor Biology and Biomarkers, International Center of Research CIPE, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; [email protected] 3 National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo 05403-010, Brazil; [email protected] 4 Department of Radiation Oncology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; [email protected] 5 Genomics and Molecular Biology Group, International Center of Research CIPE, A.C.Camargo Cancer Center, Sao Paulo 01508-010, Brazil 6 Department of Pathology, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; [email protected] (F.D.C.); [email protected] (A.G.N.) 7 Department of Epidemiology, A.C.Camargo Cancer Center, Sao Paulo 01508-010, Brazil; [email protected] 8 Department of Surgery, A.C.Camargo Cancer Center, Sao Paulo 01509-010, Brazil; [email protected] (S.A.N.); [email protected] (A.L.); Citation: Mello, C.A.; Campos, [email protected] (S.A.J.) F.A.B.; Santos, T.G.; Silva, M.L.G.; * Correspondence: [email protected]; Tel.: +55-11-2189-2779 Torrezan, G.T.; Costa, F.DA.; Formiga, M.N.; Nicolau, U.; Nascimento, A.G.; Simple Summary: Desmoplastic small round cell tumor is a rare neoplasm with extremely aggressive Silva, C.; et al. Desmoplastic Small behavior. Despite the multimodal treatment for newly diagnosed patients with chemotherapy, Round Cell Tumor: A Review of Main cytoreductive surgery and radiation, the cure rate is still low. For relapsed or progressive disease, Molecular Abnormalities and there is limited data regarding second and third-line therapies. Novel agents have shown only modest Emerging Therapy. Cancers 2021, 13, activity. Recent molecular changes have been identified in this disease and this opens opportunities 498. https://doi.org/10.3390/ to be explored in future clinical trials. cancers13030498 Abstract: Desmoplastic small round cell tumor (DSRCT) is an extremely rare, aggressive sarcoma Received: 10 December 2020 Accepted: 20 January 2021 affecting adolescents and young adults with male predominance. Generally, it originates from Published: 28 January 2021 the serosal surface of the abdominal cavity. The hallmark characteristic of DSRCT is the EWSR1– WT1 gene fusion. This translocation up-regulates the expression of PDGFRα, VEGF and other Publisher’s Note: MDPI stays neutral proteins related to tumor and vascular cell proliferation. Current management of DSRCT includes a with regard to jurisdictional claims in combination of chemotherapy, radiation and aggressive cytoreductive surgery plus intra-peritoneal published maps and institutional affil- hyperthermic chemotherapy (HIPEC). Despite advances in multimodal therapy, outcomes remain iations. poor since the majority of patients present disease recurrence and die within three years. The dismal survival makes DSRCT an orphan disease with an urgent need for new drugs. The treatment of advanced and recurrent disease with tyrosine kinase inhibitors, such as pazopanib, sunitinib, and mTOR inhibitors was evaluated by small trials. Recent studies using comprehensive molecular Copyright: © 2021 by the authors. profiling of DSRCT identified potential therapeutic targets. In this review, we aim to describe the Licensee MDPI, Basel, Switzerland. current studies conducted to better understand DSRCT biology and to explore the new therapeutic This article is an open access article strategies under investigation in preclinical models and in early phase clinical trials. distributed under the terms and conditions of the Creative Commons Keywords: desmoplastic small round cell tumor; treatment; prognosis; surgery; radiotherapy; Attribution (CC BY) license (https:// chemotherapy; tyrosine kinase receptor; target therapy; rare disease creativecommons.org/licenses/by/ 4.0/). Cancers 2021, 13, 498. https://doi.org/10.3390/cancers13030498 https://www.mdpi.com/journal/cancers Cancers 2021, 13, x 2 of 24 Cancers 2021, 13, 498 2 of 22 1.1. IntroductionIntroduction DesmoplasticDesmoplastic smallsmall roundround cellcell tumortumor (DSRCT)(DSRCT) isis anan extremelyextremely rare,rare, aggressiveaggressive sar-sar- coma.coma. It affectsaffects mainlymainly adolescentsadolescents andand youngyoung adultsadults andand originatesoriginates inin andand primarilyprimarily involvesinvolves thethe serosalserosal surfacessurfaces ofof thethe abdominalabdominal cavity.cavity. ItIt waswas firstfirst describeddescribed by by GeraldGerald and and RosaiRosai inin 1989 1989 as as a a newly newly characterized characterized clinicopathologic clinicopathologic entity entity [1]. [1]. Current Current management management of theof the disease disease includes includes a combination a combination of chemotherapy,of chemotherapy, radiation, radiation, and and aggressive aggressive surgical surgi- resectioncal resection [2,3 ][2,3] as summarized as summarized in Figure in Figure1. Despite 1. Despite advances advances in multimodal in multimodal therapy, therapy, the outcomethe outcome remains remains poor poor since since the majority the majority of patients of patients develop develop high rates high of rates disease of disease recur- rencerecurrence or die or within die within three three years years [4,5]. [4,5]. Due toDu thee to dismal the dismal survival, survival, DSRCT DSRCT has anhas urgent an ur- unmetgent unmet need forneed more for more effective effective and innovative and innovative therapeutic therapeutic options. options. FigureFigure 1.1. TherapeuticTherapeutic optionsoptions forfor desmoplasticdesmoplastic smallsmall roundround cellcell tumortumor (DSRCT).(DSRCT). BasedBased on on multiplemultiple retrospectivesretrospectives andand few prospective studies, studies, the the benefit benefit was was observed observed for for therapies therapies in ingreen, green, low low evidenceevidence ofof the the benefit benefit for for therapies therapies in in blue. blue. For For relapsed relapsed or or progressive progressive disease, disease, strategies strategies in in yellow yel- hadlow beenhad been used used and inand white in white are perspectives. are perspectiv HIPECes. HIPEC (hyperthermic (hyperthermic intraperitoneal intraperitoneal chemotherapy), chemo- RTKitherapy), (Receptor RTKi Tyrosine(Receptor Kinase Tyrosine inhibition), Kinase inhibiti ARi (Androgenon), ARi (Androgen Receptor inhibition),Receptor inhibition), VEGFi (Vascular VEGFi (Vascular Endothelial Growth Factor inhibition), IO (immune check point inhibition), IGFi (Insulin Endothelial Growth Factor inhibition), IO (immune check point inhibition), IGFi (Insulin Growth Growth Factor inhibiotion), mTORi (mammalian Target of Rapamycin inhibition), ABMT (autol- Factor inhibiotion), mTORi (mammalian Target of Rapamycin inhibition), ABMT (autologous bone ogous bone marrow transplant). marrow transplant). 1.1.1.1. DemographicsDemographics ofof DSRCTDSRCT DesmoplasticDesmoplastic smallsmall roundround cellcell tumortumor isis aa veryvery rareraresubtype subtypeof ofsarcoma. sarcoma. ForFor researchresearch purposes,purposes, DSRCTDSRCT casescases cancan bebe searchedsearched usingusing thethe histologyhistology andand behaviorbehavior (malignant)(malignant) classificationclassification codecode 8806/3.8806/3. Ther Theree is no uniformuniform definitiondefinition ofof rarerare sarcoma,sarcoma, however,however, thethe burdenburden of of rare rare cancer cancer in in our our current current days days is great.is great. The The US OrphanUS Orphan Drug Drug Act ofAct 1983 of 1983 defined de- rarefined diseases rare diseases as those as affectingthose affecting less than less 200,000 than 200,000 people people in the Unitedin the United States States [6]. In [6]. 2010, In Greenlee2010, Greenlee et al. [7 et] describedal. [7] describe the USd the burden US burden of rare cancersof rare cancers according according to the National to the National Cancer InstituteCancer Institute definition definition as those as cancers those withcancers fewer with than fewer 15 cases than per15 cases 100,000 per people 100,000 per people year. Moreper year. recently, More a recently, consortium a consortium from the European from the Union,European Surveillance Union, Surveillance of Rare Cancer of Rare in EuropeCancer (RARECARE)in Europe (RARECARE) [8], described [8], a newdescribed definition a new of raredefinition cancer of in rare Europe cancer as those in Europe with feweras those than with 6 cases fewer per than 100,000 6 cases people per 100,000 per year. people per year. InIn aa studystudy publishedpublished inin 20142014 [[9],9], aa totaltotal ofof 192192 casescases ofof DSRCTDSRCT werewere identifiedidentified inin thethe SEERSEER databasedatabase between between 1973 1973 to 2007.to 2007. The age-adjustedThe