Current Oncology Reports

, 16:401 | Cite as

Prospects and Pitfalls of Personalizing Therapies for Sarcomas: From Children, Adolescents, and Young Adults to the Elderly

Sarcomas (SR Patel, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Sarcomas


Sarcomas are a heterogeneous class of tumors that affect all ages, from children, adolescents, and young adults to the elderly. Within this panoply of tumor subtypes lies the opportunity to bring to bear a vision of personalized medicine in which the fast-paced evolution from the “one gene, one test, one drug” approach to a comprehensive “panomic,” multiplex, multianalyte method coupled with advances in bioinformatics platforms can unravel the biology of this disease. The increasingly enlarging repertoire of novel agents provides innumerable prospects in precision medicine. Personalized therapy covers the entire spectrum of cancer care, from risk factor assessment through prevention, risk reduction, therapy, follow-up after therapy, and survivorship care. Challenges remain in implementing the science of precision medicine in the clinic, including providing comprehensive multidisciplinary care and overcoming regulatory and economic hurdles, which must be facilitated within the collaborative framework of academia, industry, federal regulators, and third-party payers.


Sarcoma Personalized therapy Immunotherapy Targeted therapy Precision medicine Next-generation sequencing 



The author acknowledges research funding by the Shannon Wilkes Foundation osteosarcoma research funds and Bobe Howe research funds. The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support Grant CA016672.

Compliance with Ethics Guidelines

Conflict of Interest

Vivek Subbiah has received grants from the Shannon Wilkes Foundation, research support from Bayer, Genentech/Roche, GlaxoSmithKline, Nanocarrier, and Northwest Biotherapeutics, and grants from MD Anderson Hi CRSP funds.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.•
    Dienstmann R, Rodon J, Barretina J, Tabernero J. Genomic medicine frontier in human solid tumors: prospects and challenges. J Clin Oncol. 2013;31(15):1874–84. doi: 10.1200/JCO.2012.45.2268. This provides a very detailed overview of the challenges in genomics. PubMedCrossRefGoogle Scholar
  2. 2.•
    Meric-Bernstam F, Mills GB. Overcoming implementation challenges of personalized cancer therapy. Nat Rev Clin Oncol. 2012;9(9):542–8. doi: 10.1038/nrclinonc.2012.127. This is a good review of implementing personalized oncology. PubMedCrossRefGoogle Scholar
  3. 3.
    Linch M, Miah AB, Thway K, Judson IR, Benson C. Systemic treatment of soft-tissue sarcoma—gold standard and novel therapies. Nat Rev Clin Oncol. 2014;11(4):187–202. doi: 10.1038/nrclinonc.2014.26.PubMedCrossRefGoogle Scholar
  4. 4.•
    Meric-Bernstam F, Farhangfar C, Mendelsohn J, Mills GB. Building a personalized medicine infrastructure at a major cancer center. J Clin Oncol. 2013;31(15):1849–57. doi: 10.1200/JCO.2012.45.3043. This is a detailed review of capacity building effort for a personalized medicine program. PubMedCrossRefGoogle Scholar
  5. 5.
    Garraway LA, Verweij J, Ballman KV. Precision oncology: an overview. J Clin Oncol. 2013;31(15):1803–5. doi: 10.1200/JCO.2013.49.4799.PubMedCrossRefGoogle Scholar
  6. 6.
    Mendelsohn J. Personalizing oncology: perspectives and prospects. J Clin Oncol. 2013;31(15):1904–11. doi: 10.1200/JCO.2012.45.3605.PubMedCrossRefGoogle Scholar
  7. 7.
    Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501(7467):346–54. doi: 10.1038/nature12626.PubMedCrossRefGoogle Scholar
  8. 8.•
    Stebbing J, Paz K, Schwartz GK, Wexler LH, Maki R, Pollock RE, et al. Patient-derived xenografts for individualized care in advanced sarcoma. Cancer. 2014. doi: 10.1002/cncr.28696. This is the first report of patient-derived xenografts or the mouse avatar (“xenopatient”) approach in advanced sarcoma.Google Scholar
  9. 9.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.PubMedCrossRefGoogle Scholar
  10. 10.••
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi: 10.1016/j.cell.2011.02.013. This is one of the most important publications in cancer biology. PubMedCrossRefGoogle Scholar
  11. 11.
    Jardim DL, Conley A, Subbiah V. Comprehensive characterization of malignant phyllodes tumor by whole genomic and proteomic analysis: biological implications for targeted therapy opportunities. Orphanet J Rare Dis. 2013;8(1):112. doi: 10.1186/1750-1172-8-112.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.•
    Patel S. Exploring novel therapeutic targets in GIST: focus on the PI3K/Akt/mTOR pathway. Curr Oncol Rep. 2013;15(4):386–95. doi: 10.1007/s11912-013-0316-6. This is a nice review of therapeutic targets in GIST. PubMedCrossRefGoogle Scholar
  13. 13.
    Patel S. Long-term efficacy of imatinib for treatment of metastatic GIST. Cancer Chemother Pharmacol. 2013;72(2):277–86. doi: 10.1007/s00280-013-2135-8.PubMedCrossRefGoogle Scholar
  14. 14.••
    Patel S. Navigating risk stratification systems for the management of patients with GIST. Ann Surg Oncol. 2011;18(6):1698–704. doi: 10.1245/s10434-010-1496-z. This is a nice review of stratification in GIST. PubMedCrossRefGoogle Scholar
  15. 15.
    Blay JY, Le Cesne A, Cassier PA, Ray-Coquard IL. Gastrointestinal stromal tumors (GIST): a rare entity, a tumor model for personalized therapy, and yet ten different molecular subtypes. Discov Med. 2012;13(72):357–67.PubMedGoogle Scholar
  16. 16.
    Berry D. Multiplicities in cancer research: ubiquitous and necessary evils. J Natl Cancer Inst. 2012;104(15):1124–32. doi: 10.1093/jnci/djs301.PubMedCrossRefGoogle Scholar
  17. 17.
    Berry SM, Broglio KR, Groshen S, Berry DA. Bayesian hierarchical modeling of patient subpopulations: efficient designs of phase II oncology clinical trials. Clin Trials. 2013;10(5):720–34. doi: 10.1177/1740774513497539.PubMedCrossRefGoogle Scholar
  18. 18.••
    Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302. doi: 10.1016/S0140-6736(12)61857-1. This is a recent major trial in GIST that led to FDA approval of regorafenib in GIST. PubMedCrossRefGoogle Scholar
  19. 19.
    Luke JJ, D’Adamo DR, Dickson MA, Keohan ML, Carvajal RD, Maki RG, et al. The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin Cancer Res. 2012;18(9):2638–47. doi: 10.1158/1078-0432.CCR-11-3203.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–8. doi: 10.1200/JCO.2012.46.5476.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Le Cesne A, Cresta S, Maki RG, Blay JY, Verweij J, Poveda A, et al. A retrospective analysis of antitumour activity with trabectedin in translocation-related sarcomas. Eur J Cancer. 2012;48(16):3036–44. doi: 10.1016/j.ejca.2012.05.012.PubMedCrossRefGoogle Scholar
  22. 22.
    Butrynski JE, D’Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, Jhanwar SC, et al. Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N Engl J Med. 2010;363(18):1727–33. doi: 10.1056/NEJMoa1007056.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Falchook GS, Trent JC, Heinrich MC, Beadling C, Patterson J, Bastida CC, et al. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget. 2013;4(2):310–5.PubMedCentralPubMedGoogle Scholar
  24. 24.•
    Subbiah V, Murthy R, Anderson PM. [90Y]Yttrium microspheres radioembolotherapy in desmoplastic small round cell tumor hepatic metastases. J Clin Oncol. 2011;29(11):e292–4. doi: 10.1200/JCO.2010.32.4673. This is a report of radioembolization therapy in desmoplastic small round cell tumors with liver metastases. PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    McArthur GA, Chapman PB, Robert C, Larkin J, Haanen JB, Dummer R, et al. Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol. 2014;15(3):323–32. doi: 10.1016/S1470-2045(14)70012-9.PubMedCrossRefGoogle Scholar
  26. 26.
    Stites EC. The response of cancers to BRAF inhibition underscores the importance of cancer systems biology. Sci Signal. 2012;5(246):e46. doi: 10.1126/scisignal.2003354.CrossRefGoogle Scholar
  27. 27.
    Garbe C, Abusaif S, Eigentler TK. Vemurafenib. Recent Results Cancer Res. 2014;201:215–25. doi: 10.1007/978-3-642-54490-3_13.PubMedCrossRefGoogle Scholar
  28. 28.
    Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2013;381(9861):125–32. doi: 10.1016/S0140-6736(12)61134-9.PubMedCrossRefGoogle Scholar
  29. 29.••
    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature. 2012;483(7391):570–5. doi: 10.1038/nature11005. This is a work of major importance leading to a compendium of drug sensitivity in cancer cells. PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Brenner JC, Feng FY, Han S, Patel S, Goyal SV, Bou-Maroun LM, et al. PARP-1 inhibition as a targeted strategy to treat Ewing’s sarcoma. Cancer Res. 2012;72(7):1608–13. doi: 10.1158/0008-5472.CAN-11-3648.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338(6104):221. doi: 10.1126/science.1226344.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Subbiah V, Naing A, Brown RE, Chen H, Doyle L, LoRusso P, et al. Targeted morphoproteomic profiling of Ewing’s sarcoma treated with insulin-like growth factor 1 receptor (IGF1R) inhibitors: response/resistance signatures. PLoS One. 2011;6(4):e18424. doi: 10.1371/journal.pone.0018424.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.•
    Subbiah V, Brown RE, Jiang Y, Buryanek J, Hayes-Jordan A, Kurzrock R, et al. Morphoproteomic profiling of the mammalian target of rapamycin (mTOR) signaling pathway in desmoplastic small round cell tumor (EWS/WT1), Ewing’s sarcoma (EWS/FLI1) and Wilms’ tumor(WT1). PLoS One. 2013;8(7):e68985. doi: 10.1371/journal.pone.0068985. This presents analyses of response and resistance mechanisms of Ewing’s sarcoma to IGF1R therapy.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Subbiah V, Kurzrock R. Ewing’s sarcoma: overcoming the therapeutic plateau. Discov Med. 2012;13(73):405–15.PubMedCentralPubMedGoogle Scholar
  35. 35.
    Subbiah V, Anderson P. Targeted therapy of Ewing’s sarcoma. Sarcoma. 2011;2011:686985. doi: 10.1155/2011/686985.PubMedCentralPubMedGoogle Scholar
  36. 36.
    Subbiah V, Brown RE, McGuire MF, Buryanek J, Janku F, Younes A, et al. A novel immunomodulatory molecularly targeted strategy for refractory Hodgkin’s lymphoma. Oncotarget. 2014;5(1):95–102.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Subbiah V, Kurzrock R. Phase 1 clinical trials for sarcomas: the cutting edge. Curr Opin Oncol. 2011;23(4):352–60. doi: 10.1097/CCO.0b013e3283477a94.PubMedCrossRefGoogle Scholar
  38. 38.•
    Subbiah V, Brown RE, Buryanek J, Trent J, Ashkenazi A, Herbst R, et al. Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L/TRAIL (dulanermin), a dual proapoptotic receptor (DR4/DR5) agonist. Mol Cancer Ther. 2012;11(11):2541–6. doi: 10.1158/1535-7163.MCT-12-0358. This presents an analysis of response and resistance mechanisms of chondrosarcoma to anti-death receptor antibody therapy. PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Subbiah V, Westin SN, Wang K, Araujo D, Wang WL, Miller VA, et al. Targeted therapy by combined inhibition of the RAF and mTOR kinases in malignant spindle cell neoplasm harboring the KIAA1549-BRAF fusion protein. J Hematol Oncol. 2014;7(1):8. doi: 10.1186/1756-8722-7-8.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol. 2013;31(15):1834–41. doi: 10.1200/JCO.2012.45.3639.PubMedCrossRefGoogle Scholar
  41. 41.
    Bedard PL, Hansen AR, Ratain MJ, Siu LL. Tumour heterogeneity in the clinic. Nature. 2013;501(7467):355–64. doi: 10.1038/nature12627.PubMedCrossRefGoogle Scholar
  42. 42.
    Manara MC, Garofalo C, Ferrari S, Belfiore A, Scotlandi K. Designing novel therapies against sarcomas in the era of personalized medicine and economic crisis. Curr Pharm Des. 2013;19(30):5344–61.PubMedCrossRefGoogle Scholar
  43. 43.
    Subbiah V, Angelo LS, Kurzrock R. Insulin-like growth factor 1 receptor (IGF-1R) inhibitor: another arrow in the quiver - will it hit the moving target? Expert Opin Investig Drugs. 2011;20(11):1471–7. doi: 10.1517/13543784.2011.619978.PubMedCrossRefGoogle Scholar
  44. 44.••
    Pappo AS, Patel SR, Crowley J, Reinke DK, Kuenkele KP, Chawla SP, et al. R1507, a monoclonal antibody to the insulin-like growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of tumors: results of a phase II Sarcoma Alliance for Research Through Collaboration study. J Clin Oncol. 2011;29(34):4541–7. doi: 10.1200/JCO.2010.34.0000. This presents the results of an IGF1R inhibitor efficacy trial in Ewing’s sarcoma. PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Kurzrock R, Patnaik A, Aisner J, Warren T, Leong S, Benjamin R, et al. A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin Cancer Res. 2010;16(8):2458–65. doi: 10.1158/1078-0432.CCR-09-3220.PubMedCrossRefGoogle Scholar
  46. 46.
    Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS, et al. Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res. 2012;18(9):2625–31. doi: 10.1158/1078-0432.CCR-12-0061.PubMedCrossRefGoogle Scholar
  47. 47.
    Basu B, Olmos D, de Bono JS. Targeting IGF-1R: throwing out the baby with the bathwater? Br J Cancer. 2011;104(1):1–3. doi: 10.1038/sj.bjc.6606023.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA. If mammalian target of metformin indirectly is mammalian target of rapamycin, then the insulin-like growth factor-1 receptor axis will audit the efficacy of metformin in cancer clinical trials. J Clin Oncol. 2009;27(33):e207–9. doi: 10.1200/JCO.2009.24.5456. author reply e210. PubMedCrossRefGoogle Scholar
  49. 49.
    Kleinberg DL, Ameri P, Singh B. Pasireotide, an IGF-I action inhibitor, prevents growth hormone and estradiol-induced mammary hyperplasia. Pituitary. 2011;14(1):44–52. doi: 10.1007/s11102-010-0257-0.PubMedCrossRefGoogle Scholar
  50. 50.••
    Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29(7):917–24. doi: 10.1200/JCO.2010.32.2537. This reports a clinical trial showing immunotherapy responses in synovial sarcoma. PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Pollack SM, Jungbluth AA, Hoch BL, Farrar EA, Bleakley M, Schneider DJ, et al. NY-ESO-1 is a ubiquitous immunotherapeutic target antigen for patients with myxoid/round cell liposarcoma. Cancer. 2012;118(18):4564–70. doi: 10.1002/cncr.27446.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.•
    Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Medi. 2011;17(9):1094–100. doi: 10.1038/nm.2438. This is preclinical work demonstrating combination of targeted and immune therapy. CrossRefGoogle Scholar
  53. 53.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366(10):883–92. doi: 10.1056/NEJMoa1113205.PubMedCrossRefGoogle Scholar
  54. 54.
    DeRose YS, Wang G, Lin YC, Bernard PS, Buys SS, Ebbert MT, et al. Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011;17(11):1514–20. doi: 10.1038/nm.2454.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, et al. A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011;1(6):508–23. doi: 10.1158/2159-8290.CD-11-0109.PubMedCrossRefGoogle Scholar
  56. 56.
    Hidalgo M, Bruckheimer E, Rajeshkumar NV, Garrido-Laguna I, De Oliveira E, Rubio-Viqueira B, et al. A pilot clinical study of treatment guided by personalized tumorgrafts in patients with advanced cancer. Mol Cancer Ther. 2011;10(8):1311–6. doi: 10.1158/1535-7163.MCT-11-0233.PubMedCrossRefGoogle Scholar
  57. 57.
    Lee DP, Skolnik JM, Adamson PC. Pediatric phase I trials in oncology: an analysis of study conduct efficiency. J Clin Oncol. 2005;23(33):8431–41. doi: 10.1200/JCO.2005.02.1568.PubMedCrossRefGoogle Scholar
  58. 58.
    Coccia PF, Pappo AS, Altman J, Bhatia S, Borinstein SC, Flynn J, et al. Adolescent and young adult oncology, version 22014. J Natl Compr Cancer Netw. 2014;12(1):21–32. quiz 32. Google Scholar
  59. 59.
    Coccia PF, Altman J, Bhatia S, Borinstein SC, Flynn J, George S, et al. Adolescent and young adult oncology. Clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2012;10(9):1112–50.Google Scholar
  60. 60.
    Bleyer A. Young adult oncology: the patients and their survival challenges. CA Cancer J Clin. 2007;57(4):242–55.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine and Division of PediatricsThe University of Texas MD Anderson Cancer CenterHoustonUSA

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