Topic review

CDKs in Sarcoma

Subjects: Pathology & Pathobiology View times: 122
Submitted by: Jordan Kohlmeyer

Definition

Sarcomas represent one of the most challenging tumor types to treat due to their diverse nature and our incomplete understanding of their underlying biology. Recent work suggests cyclin-dependent kinase (CDK) pathway activation is a powerful driver of sarcomagenesis. CDK proteins participate in numerous cellular processes required for normal cell function, but their dysregulation is a hallmark of many pathologies including cancer. The contributions and significance of aberrant CDK activity to sarcoma development, however, is only partly understood. Here, we describe what is known about CDK-related alterations in the most common subtypes of sarcoma and highlight areas that warrant further investigation. As disruptions in CDK pathways appear in most, if not all, subtypes of sarcoma, we discuss the history and value of pharmacologically targeting CDKs to combat these tumors. The goals of this review are to (1) assess the prevalence and importance of CDK pathway alterations in sarcomas, (2) highlight the gap in knowledge for certain CDKs in these tumors, and (3) provide insight into studies focused on CDK inhibition for sarcoma treatment. Overall, growing evidence demonstrates a crucial role for activated CDKs in sarcoma development and as important targets for sarcoma therapy.

1. Introduction

Sarcomas are rare, highly diverse malignancies. They account for just 1% of all adult human cancers, although their frequency is significantly greater (roughly 20%) among pediatric tumors. These lesions arise from mesenchymal tissue, where approximately 80% occur in soft tissue and 20% in bone [1]. Currently, there are over 70 subtypes that classify lesions based on tissue resemblance and molecular characteristics [2]. Two broad groups of sarcomas exist—those with simple karyotypes, often characterized by a specific, disease-driving alterations and those with complex karyotypes, where there are multiple genomic losses, gains, and amplifications [1]. Standard treatment for localized disease remains surgical resection with adjuvant radiation and/or chemotherapy used in certain types of sarcoma. Regrettably, many patients experience recurrence and metastasis, requiring systemic therapies that are unfortunately not very effective. Additionally, since these lesions are heterogeneous, responses to generalized treatments are variable and typically do not translate between different subtypes [3]. To combat sarcomas more effectively, the key pathways promoting their development and progression need to be elucidated. Recent advances suggest that activating alterations in cyclin-dependent kinase (CDK) pathways are major drivers of sarcomagenesis.

CDKs are serine/threonine kinases involved in key cellular processes, primarily cell cycle progression and transcription. As monomeric proteins, CDKs lack Enzymatic Activity due to a structural conformation that buries the catalytic and substrate binding domains [4]. To become active, CDKs require association with a regulatory subunit known as a cyclin, hence their designation as cyclin-dependent kinases. Humans have 20 CDKs that are classically divided into two main groups— cell cycle (CDKs 1, 2, 3, 4, 6, and 7) and transcriptional (tCDKs 7, 8, 9, 12, 13, and 19), with CDK7 contributing to both processes. Many CDKs that control cell cycle progression can bind multiple cyclins, allowing for dynamic regulation throughout the cell cycle as well as increased substrate possibilities. CDKs associated with transcription bind a single, specific cyclin, whose expression is not regulated in a cell cycle-dependent manner [5]. “Other” CDKs (5, 10, 11, 14–18, and 20) do not fit into the two canonical roles and, instead, exhibit diverse functions that are often tissue specific. For example, CDK11 variants have multiple functions in mediating transcription, mitosis, hormone receptor signaling, autophagy, and apoptosis [5][6]. Likewise, in the nervous system CDK5 promotes neurite outgrowth and synaptogenesis while in pancreatic β cells it reduces insulin secretion [7][8][9]. As CDKs control crucial processes required for cell survival and propagation, their hyperactivation (typically through mutation, gene amplification, or altered expression of their regulators) is commonly observed in cancer.

The rarity and diversity of sarcomas has slowed efforts to identify key mutations driving these cancers. In addition, sarcomas are sometimes simplistically viewed as a single entity or described in broad, unspecified terms. As our knowledge of sarcoma biology has increased, there is a growing appreciation for CDK pathway dysregulation in promoting disease progression. This review discusses the current knowledge about CDK and CDK-related aberrations in the most common subtypes of sarcoma in both adult and pediatric patients. Additional consideration is given to CDK-targeted therapy in the pre-clinical setting as well as recent clinical trials.

Table 1 provides a consolidated listing of the genetic alterations in CDKs and CDK pathways within each human sarcoma, strongly predicting the hyperactivation of tumor promoting CDKs in these cancers. Notable overlap exists in the genetic alterations found within multiple sarcomas although there are unique genomic events that also distinguish each sarcoma type. A recent analysis of genomic profiles and clinical outcomes in two independent datasets of diverse soft tissue sarcomas identified the most frequently altered genes shared by most sarcomas, namely TP53, CDKN2A, RB1, NF1, and ATRX [10]. Strikingly, CDKN2A was the only gene whose inactivation was associated with worse overall survival across all types of localized soft tissue sarcomas. CDKN2A is a fascinating gene in cancer biology as it encodes not just one, but two powerful tumor suppressors [11][12]. Through shared DNA sequences that are translated in different reading frames, CDKN2A yields the p16INK4a inhibitor of CDK4 and CDK6 as well as the ‘Alternative Reading Frame’ protein, ARF [13]. While p16INK4a functions by activating the retinoblastoma (RB1) tumor suppressor, ARF inhibits cancer through multiple mechanisms including activation of p53. Thus, the observation that CDKN2A loss correlates with worse patient survival across many sarcoma types suggests a central role for the p16INK4a-CDK4/6-RB1 and/or ARF signaling pathways in sarcoma pathogenesis.

 Table 1. Genetic alterations of CDK pathway genes in sarcoma

Gene

Protein

Alteration

Sarcoma Subtype

RB1

Retinoblastoma

Deletion, Mutation

UPS [10][14][15], MFS [10][16], PLPS [17][18],
LMS [10][17][19], CS [20], OS [21][22],
EwS [23], MPNST [24]

CDKN2A

p16INK4a and ARF

Deletion, Mutation

UPS [10][25], MFS [10][16], LMS [26],
MPNST [10][27][28][29][30][24][31][32][33][34][35][36], CS [20],
 ARMS [37], OS [21][22], EwS [23]

CDKN2B

p15INK4b

Deletion

MFS [10][16], MPNST [10][32][36]

CCND
1-3

Cyclin D1-3

Amplification

MFS [16], LMS [26], CS [20], OS [21][22]

CDK4

CDK4

Amplification

UPS [24], WD/DDLPS [10][18], SS [38], CS [20], ARMS [39][40], OS [21][22]

CDK6

CDK6

Amplification

MFS [13][41]

MDM2

Mdm2

Amplification

UPS [25], MFS [16], WD/DDLPS [13][17][18], CS [20], ARMS [37][40], OS [21][22]

TP53

p53

Deletion, Mutation

UPS [13][41], MFS [13][16], PLPS [18], CS [20], ARMS [37], OS [21][22], EwS [23], MPNST [13][24], LMS [13][17][42]

KRAS

Ras

Amplification

Mutation

UPS [47], ARMS [40]

NF1

Neurofibromin

Mutation

UPS [13], MFS [13][51], MPNST [13][27][28][29][30][24], ARMS [37][40]

ATRX

ATRX chromatin remodeler

Mutation

UPS [13], MFS [13], LPS [13]

TLS

Translocated in liposarcoma

translocation, (12;16)

M/RCLPS [18]

CHOP

C/EBP homologous protein

MYC

MYC

Amplification

LMS [42], ARMS [39], OS [21][22],
MPNST [32]

PTEN

Phosphatase and tensin homolog

Deletion

LMS [19], OS [21][22], MPNST [30][43]

SUZ12

Suppressor of zeste 12 protein homolog

Mutation

MPNST [28][29][30][24][31]

EED

Embryonic ectoderm development

Mutation

MPNST [28][29][30][24][31]

SSX

Synovial sarcoma, X

translocation, (X;18)

SS [44]

SS18

Synovial sarcoma translocation, chr18

IDH

Isocitrate dehydrogenase

Mutation

CS [45]

CDKN1C

p57KIP2

Deletion

ERMS [46]

PAX1

Paired box 1

translocation, (2;13)

ARMS [40]

FOXO1

Forkhead box O1

BRAF

B-Raf

Mutation

ARMS [40]

PIK3CA

p110a

Mutation

ARMS [40]

TWIST1

Twist family bHLH transcription factor 1

Amplification

OS [21][22]

CCNE1

Cyclin E1

Amplification

OS [21][22], MPNST [47]

EWSR1

Ewing sarcoma breakpoint region 1

translocation, (11;22)

EwS [48]

FLI1

Friend leukemia integration 1

Abbreviations: UPS, undifferentiated pleiomorphic sarcoma; MFS, myxofibrosarcoma; WD/DDLPS, well- and de-differentiated liposarcoma; M/RCLPS, myxoid/round cell liposarcoma; LMS, leiomyosarcoma; MPNST, malignant peripheral nerve sheath tumor; SS, synovial sarcoma; CS, chondrosarcoma; ERMS, embryonal rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; OS, osteosarcoma; EwS, Ewing sarcoma

2. Summary

Despite the diverse nature of sarcomas, activation of CDK pathways is a common alteration contributing to their development and progression. One of the more frequent changes is inactivation of the CDKN2A locus, resulting in loss of ARF-p53 and p16INK4a-RB1 tumor suppressive signaling and consequent hyperactivation of cell cycle CDKs. Loss of other CDK inhibitors, such as p27, and upregulation of cyclin partners, such as cyclins D and E, are also predominant events leading to aberrant CDK activation in sarcomas. While more remains to be learned about the roles and significance of CDKs in the many different types of sarcomas, especially for CDKs with transcriptional or other activities besides cell cycle regulation, it is clear these kinases are key players in sarcoma biology. Continued studies of CDK dysfunction in sarcomagenesis are expected to solidify their importance in this disease and further justify CDK-based therapies for patients. Currently, there is high enthusiasm in the clinic for newer generation CDK inhibitors that target CDK4 and CDK6, such as palbociclib, as these drugs are more specific and less toxic than earlier, more broadly acting compounds.

Based on impressive anti-tumor activities in pre-clinical studies, CDK4/6 inhibitors have become a central component of current phase 1 and 2 clinical trials for various types of sarcoma. These drugs offer promising treatment options for sarcoma patients who are in dire need of effective therapies to treat their cancers. Most of the ongoing clinical trials for sarcoma have just started accruing patients and many involve combination therapy to prevent acquired resistance to CDK-targeted monotherapy. Early phase studies in select soft tissue sarcoma subtypes are showing promising results, particularly for liposarcoma where there is frequent CDK4 amplification. In a phase 2 study of patients with advanced or metastatic well-differentiated / dedifferentiated liposarcoma (NCT01209598), palbociclib therapy resulted in occasional tumor response along with a favorable progression-free survival rate of 57% at 12 weeks [42]. Currently, there is a multi-center phase 2 trial of palbociclib monotherapy in Spain for patients who have advanced sarcomas with elevated expression of CDK4 (NCT03242382). Moreover, CDK4/6 inhibitors are recognized as high priority agents by the Children’s Oncology Group for testing in metastatic, relapsed Ewing sarcoma [43]. As our understanding of the CDKs expands and we learn more about their individual roles in sarcoma pathogenesis, it is fair to say these kinases represent increasingly valuable targets in the treatment of sarcomas.

The entry is from 10.3390/ijms21083018

References

  1. Bleloch, J.S.; Ballim, R.D.; Kimani, S.; Parkes, J.; Panieri, E.; Willmer, T.; Prince, S. Managing sarcoma: where have we come from and where are we going? Ther. Adv. Med. Oncol. 2017, 9, 637–659.
  2. Jared W. Potter; Kevin B. Jones; Jared J. Barrott; Sarcoma-The standard-bearer in cancer discovery.. Critical Reviews in Oncology/Hematology 2018, 126, 1-5, 10.1016/j.critrevonc.2018.03.007.
  3. Amanda R. Dancsok; Karama Asleh; Torsten O. Nielsen; Advances in sarcoma diagnostics and treatment. Oncotarget 2016, 8, 7068-7093, 10.18632/oncotarget.12548.
  4. S. Lim; Philipp Kaldis; Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development 2013, 140, 3079-3093, 10.1242/dev.091744.
  5. Marcos Malumbres; Cyclins and Cyclin-dependent Kinases. Encyclopedia of Systems Biology 2013, , 509-512, 10.1007/978-1-4419-9863-7_10.
  6. Yubing Zhou; Jacson K. Shen; Francis J. Hornicek; QuanCheng Kan; Zhenfeng Duan; The emerging roles and therapeutic potential of cyclin-dependent kinase 11 (CDK11) in human cancer. Oncotarget 2016, 7, 40846-40859, 10.18632/oncotarget.8519.
  7. Per Hydbring; Marcos Malumbres; Piotr Sicinski; Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nature Reviews Molecular Cell Biology 2016, 17, 280-292, 10.1038/nrm.2016.27.
  8. Daniel Wood; Jane A. Endicott; Structural insights into the functional diversity of the CDK–cyclin family. Open Biology 2018, 8, 180112, 10.1098/rsob.180112.
  9. Alison Shupp; Mathew C. Casimiro; Richard G. Pestell; Biological functions of CDK5 and potential CDK5 targeted clinical treatments. Oncotarget 2017, 8, 17373-17382, 10.18632/oncotarget.14538.
  10. Nam Q. Bui; Joanna Przybyl; Sally E. Trabucco; Garrett Frampton; Trevor Hastie; Matt Van De Rijn; Kristen N. Ganjoo; A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis.. Clinical Sarcoma Research 2019, 9, 12-11, 10.1186/s13569-019-0122-5.
  11. Charles J. Sherr; Ink4-Arf locus in cancer and aging. WIREs Developmental Biology 2012, 1, 731-741, 10.1002/wdev.40.
  12. Quelle, Dawn; Nteeba, Jackson, Darbro, Benjamin; The INK4a/ARF Locus. Encyclopedia of Cell Biology 2016, 1, 447-457, 10.1016/B978-0-12-394447-4.30060-8.
  13. D E Quelle; F Zindy; R A Ashmun; C J Sherr; Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.. Cell 1995, 83, , .
  14. Louis Guillou; Alain Aurias; Soft tissue sarcomas with complex genomic profiles. Virchows Archiv 2009, 456, 201-217, 10.1007/s00428-009-0853-4.
  15. F Chibon; A Mairal; P Fréneaux; P Terrier; J M Coindre; X Sastre; A Aurias; The RB1 gene is the target of chromosome 13 deletions in malignant fibrous histiocytoma.. Cancer Research 2000, 60, , .
  16. Koichi Ogura; Fumie Hosoda; Yasuhito Arai; Hiromi Nakamura; Natsuko Hama; Yasushi Totoki; Akihiko Yoshida; Momoko Nagai; Mamoru Kato; Erika Arakawa; et al. Integrated genetic and epigenetic analysis of myxofibrosarcoma.. Nature Communications 2018, 9, 2765, 10.1038/s41467-018-03891-9.
  17. Sofia Daniela Carvalho; Daniel Pissaloux; Amandine Crombe; Jean-Michel Coindre; François Le Loarer; Pleomorphic Sarcomas. Surgical Pathology Clinics 2019, 12, 63-105, 10.1016/j.path.2018.10.004.
  18. Aimee Crago; Samuel Singer; Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma.. Current Opinion in Oncology 2011, 23, 373-8, 10.1097/CCO.0b013e32834796e6.
  19. Narasimhan P. Agaram; Lei Zhang; Francois LeLoarer; Tarik Silk; Yun-Shao Sung; Sasinya N. Scott; Deborah Kuk; Li-Xuan Qin; Michael F. Berger; Cristina R. Antonescu; et al. Targeted exome sequencing profiles genetic alterations in leiomyosarcoma.. Genes, Chromosomes and Cancer 2015, 55, 124-30, 10.1002/gcc.22318.
  20. Speetjens, F.M.; de Jong, Y.; Gelderblom, H.; Bovee, J.V.M.G. Molecular oncogenesis of chondrosarcoma: impact for targeted treatment. Curr. Opin. Oncol. 2016, 28, 314–322.
  21. Maya Kansara; Michele W.L. Teng; Mark J. Smyth; David M. Thomas; Translational biology of osteosarcoma. Nature Reviews Cancer 2014, 14, 722-735, 10.1038/nrc3838.
  22. Yubing Zhou; Jacson K. Shen; Zujiang Yu; Francis J. Hornicek; QuanCheng Kan; Zhenfeng Duan; Expression and therapeutic implications of cyclin-dependent kinase 4 (CDK4) in osteosarcoma. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2018, 1864, 1573-1582, 10.1016/j.bbadis.2018.02.004.
  23. Elizabeth C. Toomey; Joshua D. Schiffman; S L Lessnick; Recent advances in the molecular pathogenesis of Ewing's sarcoma. Oncogene 2010, 29, 4504-16, 10.1038/onc.2010.205.
  24. Andrew S. Brohl; Elliot Kahen; Sean J. Yoder; Jamie K. Teer; Damon R. Reed; The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation.. Scientific Reports 2017, 7, 14992, 10.1038/s41598-017-15183-1.
  25. Ann H. Reid; Mark M. Tsai; David J. Venzon; Cynthia F. Wright; E. E. Lack; Timothy J. O’Leary; MDM2 Amplification, P53 Mutation, and Accumulation of the P53 Gene Product in Malignant Fibrous Histiocytoma. Diagnostic Molecular Pathology 1996, 5, 65-73, 10.1097/00019606-199603000-00010.
  26. A. P. Dei Tos; R. Maestro; C. Doglioni; S. Piccinin; D. D. Libera; M. Boiocchi; C. D. Fletcher; Tumor suppressor genes and related molecules in leiomyosarcoma.. The American Journal of Pathology 1996, 148, 1037-1045, .
  27. Justin Korfhage; David B. Lombard; Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside.. Molecular Cancer Research 2019, 17, 1417-1428, 10.1158/1541-7786.MCR-19-0147.
  28. Markku Miettinen; Cristina R. Antonescu; Christopher D. M. Fletcher; AeRang Kim; Alexander J. Lazar; Martha M. Quezado; Karlyne M. Reilly; Anat Stemmer-Rachamimov; Uglas R. Stewart; David Viskochil; et al. Histopathologic evaluation of atypical neurofibromatous tumors and their transformation into malignant peripheral nerve sheath tumor in patients with neurofibromatosis 1—a consensus overview. Human Pathology 2017, 67, 1-10, 10.1016/j.humpath.2017.05.010.
  29. Verena Staedtke; Ren-Yuan Bai; Jaishri Blakeley; Cancer of the Peripheral Nerve in Neurofibromatosis Type 1. Neurotherapeutics 2017, 14, 298-306, 10.1007/s13311-017-0518-y.
  30. AeRang Kim; Uglas R. Stewart; Karlyne M. Reilly; David Viskochil; Markku M. Miettinen; Brigitte C. Widemann; Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies. Sarcoma 2017, 2017, 1-10, 10.1155/2017/7429697.
  31. William Lee; Sewit Teckie; Thomas Wiesner; Leili Ran; Carlos N. Prieto Granada; Mingyan Lin; Sinan Zhu; Zhen Cao; Yupu Liang; Andrea Sboner; et al. PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nature Genetics 2014, 46, 1227-1232, 10.1038/ng.3095.
  32. Jilong Yang; Antti Ylipää; Yan Sun; Hong Zheng; Kexin Chen; Matti Nykter; Jonathan C Trent; Nancy Ratner; Dina C. Lev; W Zhang; et al. Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment.. Clinical Cancer Research 2011, 17, 7563-73, 10.1158/1078-0432.CCR-11-1707.
  33. Trude Holmeide Agesen; Vivi Ann Flørenes; Willemina M. Molenaar; Guro E. Lind; Jeanne-Marie Berner; Boudewijn E. C. Plaat Md; Rudy Komdeur; Ola Myklebost; Eva Van Den Berg; Ragnhild A. Lothe; et al. Expression patterns of cell cycle components in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors.. Journal of Neuropathology & Experimental Neurology 2005, 64, 74-81, 10.1093/jnen/64.1.74.
  34. Federica Perrone; Silvia Tabano; Federica Colombo; Gianpaolo Dagrada; Sarah Birindelli; Alessandro Gronchi; Maurizio Colecchia; Marco A Pierotti; Silvana Pilotti; p15INK4b, p14ARF, and p16INK4a inactivation in sporadic and neurofibromatosis type 1-related malignant peripheral nerve sheath tumors.. Clinical Cancer Research 2003, 9, , .
  35. G. Petur Nielsen; Anat O. Stemmer-Rachamimov; Yasushi Ino; Michael Boe Møller; Andrew E. Rosenberg; David N. Louis; Malignant Transformation of Neurofibromas in Neurofibromatosis 1 Is Associated with CDKN2A/p16 Inactivation. The American Journal of Pathology 1999, 155, 1879-1884, 10.1016/s0002-9440(10)65507-1.
  36. Eline Beert; Hilde Brems; Bruno Daniëls; Ivo De Wever; Frank Van Calenbergh; Joseph Schoenaers; Maria Debiec-Rychter; Olivier Gevaert; Thomas De Raedt; Annick Van Den Bruel; et al. Atypical neurofibromas in neurofibromatosis type 1 are premalignant tumors. Genes, Chromosomes and Cancer 2011, 50, 1021-1032, 10.1002/gcc.20921.
  37. Jack F. Shern; L. Chen; Juliann Chmielecki; Jun S. Wei; Rajesh Patidar; Mara Rosenberg; Lauren Ambrogio; Daniel Auclair; Jianjun Wang; Young K. Song; et al. Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.. Cancer Discovery 2014, 4, 216-31, 10.1158/2159-8290.CD-13-0639.
  38. Xiaoyang Li; Cassandra Garbutt; Francis John Hornicek; Zhenfeng Duan; Abstract 2315: Inhibition of cyclin-dependent kinase 4 as a potential therapeutic strategy for treatment of synovial sarcoma. Molecular and Cellular Biology 2018, 78, 2315-2315, 10.1158/1538-7445.am2018-2315.
  39. Lei Zhang; Chiayeng Wang; Cecilia Riquelme; Yoshiaki Pérez-Kato; M. Verónica Ponce-Castañeda; José Esparza-López; Gerardo González-Núñez; Valentín Mendoza; Victor Troncoso; Fernando López-Casillas; et al. PAX3-FKHR Transformation Increases 26 S Proteasome-dependent Degradation of p27Kip1, a Potential Role for Elevated Skp2 Expression. Journal of Biological Chemistry 2002, 278, 27-36, 10.1074/jbc.m205424200.
  40. Jack F. Shern; Marielle E. Yohe; Javed Khan; Pediatric Rhabdomyosarcoma.. Critical Reviews™ in Oncogenesis 2015, 20, 227-43, .
  41. Jen-Wei Tsai; Chien-Feng Li; Yu-Chien Kao; Jun-Wen Wang; Fu-Min Fang; Yu-Hui Wang; Wen-Ren Wu; Li-Ching Wu; Chung-Hsi Hsing; Shau-Hsuan Li; et al. Recurrent Amplification at 7q21.2 Targets CDK6 Gene in Primary Myxofibrosarcomas and Identifies CDK6 Overexpression as an Independent Adverse Prognosticator. Annals of Surgical Oncology 2012, 19, 2716-2725, 10.1245/s10434-012-2317-3.
  42. Julian Musa; Florencia Cidre-Aranaz; Marie-Ming Aynaud; Martin F. Orth; Maximilian M. L. Knott; Olivier Mirabeau; Gal Mazor; Mor Varon; Tilman L. B. Hölting; Sandrine Grossetête; et al. Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes. Nature Communications 2019, 10, 4128-10, 10.1038/s41467-019-12071-2.
  43. M. A. Dickson; Gary K. Schwartz; Mary Louise Keohan; Sandra P. D’Angelo; Inal M. Gounder; Ping Chi; Cristina R. Antonescu; Jonathan Landa; Li-Xuan Qin; Aimee M. Crago; et al. Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.. JAMA Oncology 2016, 2, 937-40, 10.1001/jamaoncol.2016.0264.
  44. Matthew J. McBride; John Pulice; Robert T. Nakayama; Nazar Mashtalir; Davis R. Ingram; Jacob D. Jaffe; Jack F. Shern; Javed Khan; Jason L. Hornick; Alexander J. Lazar; et al. Abstract PR11: SSX-mediated chromatin engagement and targeting of BAF complexes activates oncogenic transcription in synovial sarcoma. Abstracts: Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA 2018, 24, PR11-PR11, 10.1158/1557-3265.sarcomas17-pr11.
  45. Gabriel Tinoco; Breelyn Wilky; Ana Paz-Mejia; Andrew Rosenberg; Jonathan C Trent; The Biology and Management of Cartilaginous Tumors: A Role For Targeting Isocitrate Dehydrogenase. American Society of Clinical Oncology Educational Book 2015, 35, e648-e655, 10.14694/edbook_am.2015.35.e648.
  46. Shujuan J. Xia; Joseph Pressey; Frederic G. Barr; Molecular pathogenesis of rhabdomyosarcoma.. Cancer Biology & Therapy 2002, 1, 97-104, 10.4161/cbt.51.
  47. Helen P. Kourea; Carlos Cordon-Cardo; Maria Dudas; Denis Leung; James M. Woodruff; Expression of p27kip and Other Cell Cycle Regulators in Malignant Peripheral Nerve Sheath Tumors and Neurofibromas. The American Journal of Pathology 1999, 155, 1885-1891, 10.1016/s0002-9440(10)65508-3.
  48. Max Ml Knott; Marlene Dallmayer; Thomas G. P. Grünewald; Next steps in preventing Ewing sarcoma progression. Future Oncology 2016, 12, 1-4, 10.2217/fon.15.298.
  49. Julian Musa; Florencia Cidre-Aranaz; Marie-Ming Aynaud; Martin F. Orth; Maximilian M. L. Knott; Olivier Mirabeau; Gal Mazor; Mor Varon; Tilman L. B. Hölting; Sandrine Grossetête; et al. Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes. Nature Communications 2019, 10, 4128-10, 10.1038/s41467-019-12071-2.
  50. M. A. Dickson; Gary K. Schwartz; Mary Louise Keohan; Sandra P. D’Angelo; Inal M. Gounder; Ping Chi; Cristina R. Antonescu; Jonathan Landa; Li-Xuan Qin; Aimee M. Crago; et al. Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial.. JAMA Oncology 2016, 2, 937-40, 10.1001/jamaoncol.2016.0264.
  51. Jordi Barretina; Barry S. Taylor; Shantanu Banerji; Alexis H. Ramos; Mariana Lagos-Quintana; Penelope L. Decarolis; Kinjal Shah; Nicholas D. Socci; Barbara A. Weir; Alan Ho; et al. Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nature Genetics 2010, 42, 715-721, 10.1038/ng.619.

Related entries