Use of VNN1 as a biomarker and a therapeutic target in sarcomas

Patent metadata

Field	Value
Publication number	US-11579147-B2
Application number	US-201816649860-A
Country	US
Kind code	B2
Filing date	Sep 25, 2018
Priority date	Sep 25, 2017
Publication date	Feb 14, 2023
Grant date	Feb 14, 2023

Abstract

Sarcomas are rare malignant tumors arising from the mesenchymal tissues at all body sites. The inventors show that in a mouse model of p16/p19 deficiency prone to tumor development, the absence of the mouse pantetheinase Vnn1 enhances the frequency of aggressive fibrosarcomas. They also show that reintroduction of a catalytically active form of the Vnn1 pantetheinase limits tumor growth in vivo. Interestingly, VNN1 expression in human sarcomas is associated with reduced aggressiveness and lower risk of metastatic relapse in patients. In conclusion, Vnn1 represents a novel marker of sarcoma and may modulate tumor aggressiveness by sustaining myofibroblast cell differentiation, thereby limiting evolution towards undifferentiated tumors. The present invention relates to the use of Vnn1 as a biomarker and a therapeutic target in sarcomas.

First claim

The invention claimed is:

1. A method of predicting the survival time of a patient suffering from a sarcoma comprising,
i) determining the activity or expression level of vanin-1 (Vnn1) in a tumor tissue sample obtained from the patient,
ii) comparing the level determined at step i) with a predetermined reference value and
iii) concluding that the patient will have a long survival time when the level determined at step i) is higher than the predetermined reference value or concluding that the patient will have a short survival time when the level determined at step i) is lower than the predetermined reference value.

2. The method of claim 1 wherein the subject suffers from a sarcoma selected from the group consisting of chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, and telangiectaltic sarcoma.

3. The method of claim 1 wherein the patient suffers from soft tissue sarcoma.

4. The method of claim 1 wherein the patient suffers from a fibrosarcoma.

5. A method of treating a sarcoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one agent selected from the group consisting of i) a polypeptide (P) having an amino acid sequence having at least 80% of identity with SEQ ID NO:1, ii) a nucleic acid molecule encoding for the polypeptide (P), iii) pantothenate, iv) pantethine and iii) a combination of pantothenate and cysteamine (CEA).

6. The method of claim 5 wherein the patient was previously determined as having a poor prognosis by
i) determining the activity or expression level of vanin-1 (Vnn1) in a tumor tissue sample obtained from the patient,
ii) comparing the activity or expression level determined at step i) with a predetermined reference value and
iii) treating the sarcoma in the patient when the activity or expression level determined at step i) is lower than the predetermined reference value.

7. A method of treating a sarcoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one agent selected from the group consisting of a polypeptide having the amino acid sequence of SEQ ID NO:1, a nucleic acid molecule encoding the polypeptide, pantethine, pantothenate and a combination of pantothenate and cysteamine (CEA).

8. The method of claim 7 wherein the patient was previously determined as having a poor prognosis by
i) determining the activity or expression level of vanin-1 (Vnn1) in a tumor tissue sample obtained from the patient,
ii) comparing the activity or expression level determined at step i) with a predetermined reference value and
iii) treating the sarcoma in the patient when the activity or expression level determined at step i) is lower than the predetermined reference value.

Assignees

• Inst Nat Sante Rech Med
• Univ Aix Marseille
• Centre Nat Rech Scient
• Univ Claude Bernard—Lyon 1
• Centre Leon Berard
• Univ Claude Bernard Lyon
• Centre Leon Bernard

Inventors

• Naquet Philippe
• Galland Franck
• Millet Virginie
• Blay Jean-Yves
• Giessner Caroline

Classifications

• G01N33/57585

  involving compounds identifiable in body fluids · CPC title

• G01N33/57557 Primary

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C12Y305/01092

  Pantetheine hydrolase (3.5.1.92) · CPC title

• A61K31/145

  having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) (isothiourea A61K31/155) · CPC title