Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour

S Stacchiotti, M Saponara, R Frapolli, M Tortoreto, D Cominetti, S Provenzano, T Negri, G P Dagrada, A Gronchi, C Colombo, B Vincenzi, G Badalamenti, V Zuco, S L Renne, P Collini, C Morosi, A P Dei Tos, E Bello, S Pilotti, P G CasaliM D'Incalci, N Zaffaroni

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Abstract

BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.

MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.

RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.

CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

Original languageEnglish
Pages (from-to)84-92
Number of pages9
JournalEuropean Journal of Cancer
Volume76
DOIs
Publication statusPublished - May 2017

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trabectedin
eribulin
Solitary Fibrous Tumors
Dacarbazine
Heterografts
Doxorubicin
Neoplasms
Ifosfamide
Disease-Free Survival

Keywords

  • Adult
  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Blotting, Western
  • Cerebellar Neoplasms
  • Dacarbazine
  • Dioxoles
  • Disease-Free Survival
  • Doxorubicin
  • Female
  • Furans
  • Humans
  • Ifosfamide
  • Ketones
  • Kidney Neoplasms
  • Male
  • Meningeal Neoplasms
  • Mice, SCID
  • Middle Aged
  • Pleural Neoplasms
  • Response Evaluation Criteria in Solid Tumors
  • Retroperitoneal Neoplasms
  • Retrospective Studies
  • Soft Tissue Neoplasms
  • Solitary Fibrous Tumors
  • Survival Rate
  • Tetrahydroisoquinolines
  • Xenograft Model Antitumor Assays
  • Journal Article

Cite this

@article{bd80e6c3188a4e859ae67af916626db9,
title = "Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour",
abstract = "BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80{\%} in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.",
keywords = "Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols, Blotting, Western, Cerebellar Neoplasms, Dacarbazine, Dioxoles, Disease-Free Survival, Doxorubicin, Female, Furans, Humans, Ifosfamide, Ketones, Kidney Neoplasms, Male, Meningeal Neoplasms, Mice, SCID, Middle Aged, Pleural Neoplasms, Response Evaluation Criteria in Solid Tumors, Retroperitoneal Neoplasms, Retrospective Studies, Soft Tissue Neoplasms, Solitary Fibrous Tumors, Survival Rate, Tetrahydroisoquinolines, Xenograft Model Antitumor Assays, Journal Article",
author = "S Stacchiotti and M Saponara and R Frapolli and M Tortoreto and D Cominetti and S Provenzano and T Negri and Dagrada, {G P} and A Gronchi and C Colombo and B Vincenzi and G Badalamenti and V Zuco and Renne, {S L} and P Collini and C Morosi and {Dei Tos}, {A P} and E Bello and S Pilotti and Casali, {P G} and M D'Incalci and N Zaffaroni",
note = "Copyright {\circledC} 2017 Elsevier Ltd. All rights reserved.",
year = "2017",
month = "5",
doi = "10.1016/j.ejca.2017.02.002",
language = "English",
volume = "76",
pages = "84--92",
journal = "European Journal of Cancer",
issn = "0959-8049",
publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - Patient-derived solitary fibrous tumour xenografts predict high sensitivity to doxorubicin/dacarbazine combination confirmed in the clinic and highlight the potential effectiveness of trabectedin or eribulin against this tumour

AU - Stacchiotti, S

AU - Saponara, M

AU - Frapolli, R

AU - Tortoreto, M

AU - Cominetti, D

AU - Provenzano, S

AU - Negri, T

AU - Dagrada, G P

AU - Gronchi, A

AU - Colombo, C

AU - Vincenzi, B

AU - Badalamenti, G

AU - Zuco, V

AU - Renne, S L

AU - Collini, P

AU - Morosi, C

AU - Dei Tos, A P

AU - Bello, E

AU - Pilotti, S

AU - Casali, P G

AU - D'Incalci, M

AU - Zaffaroni, N

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/5

Y1 - 2017/5

N2 - BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

AB - BACKGROUND: Preclinical models that mimic pathological and molecular features of solitary fibrous tumour (SFT) represent an important tool to select effective regimes and novel compounds to be tested in the clinic. This study was aimed at developing two preclinical models of SFT, assessing their predictive value in the clinic and selecting potential novel effective treatments.MATERIAL AND METHODS: Two dedifferentiated-SFT (D-SFT) models obtained from patients' biopsies were grown in immunodeficient mice. The antitumour activity on these models of doxorubicin, dacarbazine (DTIC), ifosfamide (monotherapy or combination), trabectedin and eribulin was tested. Twelve SFT patients were treated with doxorubicin and DTIC. Response by RECIST, progression-free survival and overall survival were retrospectively evaluated, distinguishing malignant-SFT (M-SFT) and D-SFT.RESULTS: Two D-SFT patient-derived xenografts (PDXs) that represent the first available preclinical in vivo models of SFT were developed and characterised. Doxorubicin/DTIC, DTIC/ifosfamide, doxorubicin/ifosfamide combinations consistently induced better antitumour activity than the single-agents. Particularly, doxorubicin/DTIC combination caused a max tumour volume inhibition >80% in both models. Doxorubicin/DTIC combo showed activity also in the case-series. Best RECIST responses were: 6 responses (M-SFT = 2 of 7, D-SFT = 4 of 5), 1 stable disease, 5 progressions, with a 6-month median progression-free survival (M-SFT = 6, D-SFT = 10 months). The PDXs were very sensitive to trabectedin and eribulin.CONCLUSION: Doxorubicin plus DTIC combination was effective in our two D-SFT mice models and appeared to be active also in the clinic, especially in high-grade D-SFT patients. Among additional drugs tested in the PDXs, trabectedin and eribulin were highly effective, providing a rational to test these drugs in D-SFT patients.

KW - Adult

KW - Aged

KW - Animals

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Blotting, Western

KW - Cerebellar Neoplasms

KW - Dacarbazine

KW - Dioxoles

KW - Disease-Free Survival

KW - Doxorubicin

KW - Female

KW - Furans

KW - Humans

KW - Ifosfamide

KW - Ketones

KW - Kidney Neoplasms

KW - Male

KW - Meningeal Neoplasms

KW - Mice, SCID

KW - Middle Aged

KW - Pleural Neoplasms

KW - Response Evaluation Criteria in Solid Tumors

KW - Retroperitoneal Neoplasms

KW - Retrospective Studies

KW - Soft Tissue Neoplasms

KW - Solitary Fibrous Tumors

KW - Survival Rate

KW - Tetrahydroisoquinolines

KW - Xenograft Model Antitumor Assays

KW - Journal Article

U2 - 10.1016/j.ejca.2017.02.002

DO - 10.1016/j.ejca.2017.02.002

M3 - Article

C2 - 28284173

VL - 76

SP - 84

EP - 92

JO - European Journal of Cancer

JF - European Journal of Cancer

SN - 0959-8049

ER -