Novel Proteasome Inhibitors

Chapter

Abstract

Proteasome inhibition is a rational approach to the therapy of multiple myeloma both alone and in combination with other agents, where proteasome inhibitors help induce chemosensitization and overcome drug resistance. These concepts were initially validated with laboratory-grade proteasome inhibitors and then with the clinically relevant peptide boronic acid bortezomib. A second generation of proteasome inhibitors is now being evaluated both preclinically and clinically, including carfilzomib, CEP-18770, marizomib, and MLN9708, among others. Though all of these agents target predominantly the chymotrypsin-like activity of the proteasome expressed by the β5 subunit, they also have novel and unique properties, including different chemistries, pharmacokinetics, proteasome binding characteristics, and other proteasome subunit specificities. Characterization of these agents has provided a strong rationale for their translation into the clinic, and initial studies suggest that at least several of them could become part of our future chemotherapeutic armamentarium against myeloma. In this chapter, these various properties of the so-called second-generation proteasome inhibitors will be examined, and the biological and clinical basis of their potential will be reviewed.

Keywords

Boron Anemia Neuropathy Diarrhea Doxorubicin 

Abbreviations

Bax

Bcl-2-associated X protein

Bcl-2

B cell CLL/lymphoma-2

BH3

Bcl-2 homology 3

Bid

BH3-interacting domain death agonist

BIM

Bcl-2-interacting mediator of cell death

Bor

Bortezomib

CDK

Cyclin-dependent kinase

ChT-L

Chymotrypsin-like

C-L

Caspase-like

CR

Complete remission

DLT

Dose-limiting toxicity

DOR

Duration of response

IκB

Inhibitor of nuclear factor kappa B

IPSI

Immunoproteasome-specific inhibitor

ISS

International Staging System

JNK

c-Jun-N-terminal kinase

Len

Lenalidomide

LMP

Low molecular mass polypeptide

Mcl-1

Myeloid cell leukemia sequence 1

MECL

Multicatalytic endopeptidase complex-like

MR

Minor response

MTD

Maximum tolerated dose

NF-κB

Nuclear factor kappa B

ORR

Overall response rate

PBMCs

Peripheral blood mononuclear cells

PGPH

Post-glutamyl peptide hydrolyzing also referred to as the caspase-like (C-L) activity

PR

Partial remission

RANKL

Tumor necrosis factor-mediated receptor activator of NF-κB ligand

sCR

Stringent CR

Smac

Second mitochondria-derived activator of caspases

T-L

Trypsin-like

Thal

Thalidomide

TTP

Time to progression

UPR

Unfolded protein response

VGPR

Very good PR

Notes

Acknowledgements

The author would like to acknowledge research support from the National Cancer Institute (P50-CA-142509, P01-CA-124787, R01-CA-102278, R01-CA-134786), as well as the Multiple Myeloma Research Foundation and The Leukemia & Lymphoma Society.

References

  1. 1.
    Orlowski RZ, Stinchcombe TE, Mitchell BS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20(22):4420–7PubMedCrossRefGoogle Scholar
  2. 2.
    Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–17PubMedCrossRefGoogle Scholar
  3. 3.
    Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–98PubMedCrossRefGoogle Scholar
  4. 4.
    Orlowski RZ, Nagler A, Sonneveld P et al (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25(25):3892–901PubMedCrossRefGoogle Scholar
  5. 5.
    San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–17PubMedCrossRefGoogle Scholar
  6. 6.
    Rock KL, Gramm C, Rothstein L et al (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78:761–71PubMedCrossRefGoogle Scholar
  7. 7.
    Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14(6):1649–57PubMedCrossRefGoogle Scholar
  8. 8.
    Shah JJ, Orlowski RZ (2009) Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 23(11):1964–79PubMedCrossRefGoogle Scholar
  9. 9.
    Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 15(5–6):243–9PubMedCrossRefGoogle Scholar
  10. 10.
    Adams J, Behnke M, Chen S et al (1998) Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 8(4):333–8PubMedCrossRefGoogle Scholar
  11. 11.
    Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–22PubMedGoogle Scholar
  12. 12.
    Hanada M, Sugawara K, Kaneta K et al (1992) Epoxomicin, a new antitumor agent of microbial origin. J Antibiot 45(11):1746–52PubMedCrossRefGoogle Scholar
  13. 13.
    Sin N, Kim KB, Elofsson M et al (1999) Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorg Med Chem Lett 9:2283–8PubMedCrossRefGoogle Scholar
  14. 14.
    Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM (1999) Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA 96(18):10403–8PubMedCrossRefGoogle Scholar
  15. 15.
    Kim KB, Myung J, Sin N, Crews CM (1999) Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency. Bioorg Med Chem Lett 9(23):3335–40PubMedCrossRefGoogle Scholar
  16. 16.
    Kuhn DJ, Chen Q, Voorhees PM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110(9):3281–90PubMedCrossRefGoogle Scholar
  17. 17.
    Demo SD, Kirk CJ, Aujay MA et al (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67(13):6383–91PubMedCrossRefGoogle Scholar
  18. 18.
    Parlati F, Lee SJ, Aujay M et al (2009) Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114(16):3439–47PubMedCrossRefGoogle Scholar
  19. 19.
    Paoluzzi L, Gonen M, Bhagat G et al (2008) The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 112(7): 2906–16PubMedCrossRefGoogle Scholar
  20. 20.
    Paoluzzi L, Gonen M, Gardner JR et al (2008) Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 111(11):5350–8PubMedCrossRefGoogle Scholar
  21. 21.
    Dasmahapatra G, Lembersky D, Kramer L et al (2010) The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 115(22):4478–87PubMedCrossRefGoogle Scholar
  22. 22.
    DiLiberto M, Huang X, Zewdu R et al (2009) Selective inhibition of CDK4/CDK6 sensitizes bone marrow myeloma cells for killing by proteasome inhibitors carfilzomib and PR-047 through cell cycle-dependent expression of pro-apoptotic Noxa and Bim. Blood (ASH Annual Meeting Abstract) 114:2854Google Scholar
  23. 23.
    Huang X, Di Liberto M, Ely S et al (2009) Induction of sequential G1 arrest and synchronous S phase entry by reversible CDK4/CDK6 inhibition sensitizes myeloma cells for cytotoxic killing through loss of IRF-4. Blood (ASH Annual Meeting Abstract) 114:299Google Scholar
  24. 24.
    O’Connor OA, Stewart AK, Vallone M et al (2009) A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res 15(22):7085–91PubMedCrossRefGoogle Scholar
  25. 25.
    Arastu-Kapur S, Shenk K, Parlati F, Bennett MK (2008) Non-proteasomal targets of proteasome inhibitors bortezomib and carfilzomib. Blood (ASH Annual Meeting Abstract) 112:2657Google Scholar
  26. 26.
    Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L, Goy A (2007) Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies. Blood (ASH Annual Meeting Abstract ) 110:411Google Scholar
  27. 27.
    Jagannath S, Vij R, Stewart K et al (2009) Final results of PX-171–003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). J Clin Oncol 27(15s), ASCO Annual Meeting Abstract 8504Google Scholar
  28. 28.
  29. 29.
    Siegel D, Wang L, Orlowski RZ et al (2009) PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM); updated results from the bortezomib-treated cohort. Blood (ASH Annual Meeting Abstract) 114:303Google Scholar
  30. 30.
    Wang L, Siegel D, Kaufman JL et al (2009) Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM). Blood (ASH Annual Meeting Abstract) 114:302Google Scholar
  31. 31.
    Richardson PG, Weller E, Jagannath S et al (2009) Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 27(34):5713–9PubMedCrossRefGoogle Scholar
  32. 32.
    Richardson PG, Weller E, Lonial S et al (2010) Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116(5):679–86PubMedCrossRefGoogle Scholar
  33. 33.
    Bensinger W, Wang M, Orlowski RZ et al (2010) Dose-escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) plus low-dose dexamethasone (Dex) (CRd) in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol 28(15s), ASCO Annual Meeting Abstract 8029Google Scholar
  34. 34.
    Muchamuel T, Aujay M, Bennett MK et al (2008) Preclinical pharmacology and in vitro characterization of PR-047, an oral inhibitor of the 20S proteasome. Blood (ASH Annual Meeting Abstract) 112:3671Google Scholar
  35. 35.
    Zhou HJ, Aujay MA, Bennett MK et al (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52(9):3028–38PubMedCrossRefGoogle Scholar
  36. 36.
    Muchamuel T, Kapur S, Kirk CJ et al (2009) Dose intensive administration of PR-047, a novel orally bioavailable inhibitor of the 20S proteasome, is well tolerated in experimental animals. Blood (ASH Annual Meeting Abstract) 114:4910Google Scholar
  37. 37.
    Roccaro AM, Sacco A, Aujay M et al (2010) Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood 115(20):4051–60PubMedCrossRefGoogle Scholar
  38. 38.
    Huang X, Bailey K, Di Liberto M et al (2008) Induction of sustained early G1 arrest by selective inhibition of CDK4 and CDK6 primes myeloma cells for synergistic killing by proteasome inhibitors carfilzomib and PR-047. Blood (ASH Annual Meeting Abstract) 112:3670Google Scholar
  39. 39.
    Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42(3):355–7PubMedCrossRefGoogle Scholar
  40. 40.
    Fenteany G, Schreiber SL (1998) Lactacystin, proteasome function, and cell fate. J Biol Chem 273(15):8545–8PubMedCrossRefGoogle Scholar
  41. 41.
    Ling T, Potts BC, Macherla VR (2010) Concise formal synthesis of (−)-salinosporamide A (marizomib) using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy. J Org Chem 75(11):3882–5PubMedCrossRefGoogle Scholar
  42. 42.
    Chauhan D, Catley L, Li G et al (2005) A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8(5):407–19PubMedCrossRefGoogle Scholar
  43. 43.
    Singh AV, Palladino MA, Lloyd GK, Potts BC, Chauhan D, Anderson KC (2010) Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol 149(4):550–9PubMedCrossRefGoogle Scholar
  44. 44.
    Ahn KS, Sethi G, Chao TH et al (2007) Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. Blood 110(7):2286–95PubMedCrossRefGoogle Scholar
  45. 45.
    Chauhan D, Singh A, Brahmandam M et al (2008) Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111(3):1654–64PubMedCrossRefGoogle Scholar
  46. 46.
    Roccaro AM, Leleu X, Sacco A et al (2008) Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia. Blood 111(9):4752–63PubMedCrossRefGoogle Scholar
  47. 47.
    Chauhan D, Singh AV, Ciccarelli B, Richardson PG, Palladino MA, Anderson KC (2010) Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115(4):834–45PubMedCrossRefGoogle Scholar
  48. 48.
    Huang X, Louie T, Di Liberto M et al (2007) Targeting cdk4/6 in combination therapy overcomes proteasome inhibitor resistance in multiple myeloma through synergistic mitochondria depolarization. Blood (ASH Annual Meeting Abstracts) 110:667Google Scholar
  49. 49.
    Kurzrock R, Hamlin P, Younes A et al (2007) Phase 1 clinical trial of a novel proteasome inhibitor (NPI-0052) in patients with lymphomas and solid tumors. Blood (ASH Annual Meeting Abstract) 110:4504Google Scholar
  50. 50.
    Hamlin PA, Aghajanian C, Hong D et al (2008) First-in-human phase 1 dose escalation study of NPI-0052, a novel proteasome inhibitor, in patients with lymphoma and solid tumor. Blood (ASH Annual Meeting Abstracts) 112:4939Google Scholar
  51. 51.
    Hamlin PA, Aghajanian C, Younes A et al (2009) First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052. J Clin Oncol 27(15s):3516, ASCO Annual Meeting AbstractGoogle Scholar
  52. 52.
    Price T, Padrik P, Townsend A et al (2008) Clinical trial of NPI-0052 (2nd generation proteasome inhibitor) in patients having advanced malignancies with expanded RP2D cohorts in lymphoma and CLL. Blood 112:4934, ASH Annual Meeting AbstractGoogle Scholar
  53. 53.
    Townsend AR, Millward M, Price T et al (2009) Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm). J Clin Oncol 27(15s):3582, ASCO Annual Meeting AbstractGoogle Scholar
  54. 54.
    Spencer A, Millward M, Mainwaring P et al (2009) Phase 1 clinical trial of the novel structure proteasome inhibitor NPI-0052. Blood 114:2693, ASH Annual Meeting AbstractGoogle Scholar
  55. 55.
    Richardson P, Hofmeister C, Jakubowiak A et al (2009) Phase 1 clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstract) 114:431Google Scholar
  56. 56.
    Dorsey BD, Iqbal M, Chatterjee S et al (2008) Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem 51(4):1068–72PubMedCrossRefGoogle Scholar
  57. 57.
    Piva R, Ruggeri B, Williams M et al (2008) CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111(5):2765–75PubMedCrossRefGoogle Scholar
  58. 58.
    Trippier PC, McGuigan C, Balzarini J (2010) Phenylboronic-acid-based carbohydrate binders as antiviral therapeutics: monophenylboronic acids. Antivir Chem Chemother 20(6):249–57PubMedGoogle Scholar
  59. 59.
    Sanchez E, Li M, Steinberg JA et al (2010) The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol 148(4):569–81PubMedCrossRefGoogle Scholar
  60. 60.
    Marangon E, Sala F, Sessa C, et al. Pharmacokinetics and pharmacodynamics of the new proteasome inhibitor CEP-18770 Preliminary results from a phase I study. J Am Soc Mass Spectrom 2009;20(5, Supplement 1):Annual ASMS Meeting Abstract 452Google Scholar
  61. 61.
    Kupperman E, Lee EC, Cao Y et al (2010) Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 70(5):1970–80PubMedCrossRefGoogle Scholar
  62. 62.
    Donelan J, Bannerman B, Bano K et al (2009) Antitumor activity of MLN9708, a second-generation proteasome inhibitor, in preclinical models of lymphoma. Blood 114:3724, ASH Annual Meeting AbstractCrossRefGoogle Scholar
  63. 63.
    Lee E, Bannerman B, Fitzgerald M et al (2009) MLN9708 elicits pharmacodynamic response in the bone marrow compartment and has strong antitumor activity in a preclinical intraosseous model of plasma cell malignancy. Blood 114:1834, ASH Annual Meeting AbstractGoogle Scholar
  64. 64.
    Fitzgerald M, Cao Y, Bannerman B et al (2009) Evaluating the antitumor activity of MLN9708 in a disseminated mouse model of double transgenic iMyc Ca/Bcl-XL plasma cell malignancy. Blood 114:3835, ASH Annual Meeting AbstractGoogle Scholar
  65. 65.
    Janz S, Van Ness BG, Neppalli V et al (2009) The novel proteasome inhibitor MLN9708 demonstrates efficacy in a genetically-engineered mouse model of denovo plasma cell malignancy. Blood 114:3849, ASH Annual Meeting AbstractGoogle Scholar
  66. 66.
    Rodler ET, Infante JR, Siu LL et al (2010) First-in-human, phase I dose-escalation study of investigational drug MLN9708, a second-generation proteasome inhibitor, in advanced nonhematologic malignancies. J Clin Oncol 28:3071, ASCO Annual Meeting AbstractGoogle Scholar
  67. 67.
    Kloetzel PM, Ossendorp F (2004) Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 16(1):76–81PubMedCrossRefGoogle Scholar
  68. 68.
    Kuhn DJ, Hunsucker SA, Chen Q, Voorhees PM, Orlowski M, Orlowski RZ (2009) Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113(19):4667–76PubMedCrossRefGoogle Scholar
  69. 69.
    Muchamuel T, Basler M, Aujay MA et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15(7):781–7PubMedCrossRefGoogle Scholar
  70. 70.
    Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–65PubMedGoogle Scholar
  71. 71.
    Yasui H, Hideshima T, Richardson PG, Anderson KC (2006) Novel therapeutic strategies ­targeting growth factor signalling cascades in multiple myeloma. Br J Haematol 132(4): 385–97PubMedGoogle Scholar
  72. 72.
    Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for Translational Therapeutics. Cancer 110(9):1911–28PubMedCrossRefGoogle Scholar
  73. 73.
    Voorhees PM, Chen Q, Kuhn DJ et al (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 13(21):6469–78PubMedCrossRefGoogle Scholar
  74. 74.
    Voorhees PM, Chen Q, Small GW et al (2009) Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 145(4):481–90PubMedCrossRefGoogle Scholar
  75. 75.
    Singh AV, Bandi M, Aujay M et al (2009) PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7 blocks multiple myeloma cell growth both in vitro and In vivo. Blood 114:612, ASH Annual Meeting AbstractCrossRefGoogle Scholar
  76. 76.
    Jagannath S, Barlogie B, Berenson JR et al (2005) Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer 103(6):1195–200PubMedCrossRefGoogle Scholar
  77. 77.
    Chanan-Khan AA, Kaufman JL, Mehta J et al (2007) Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109(6):2604–6PubMedCrossRefGoogle Scholar
  78. 78.
    Blade J, Sonneveld P, SanMiguel F et al (2008) Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: efficacy and safety in patients with renal function impairment. Clin Lymphoma Myeloma 8(6):352–5PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.The Department of Lymphoma & MyelomaThe University of Texas M. D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Experimental TherapeuticsThe University of Texas M. D. Anderson Cancer CenterHoustonUSA

Personalised recommendations