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Drug for Preventing, Treating Or Preventing Metastasis of Giant Cell Tumor That Occurs in Bone Or Soft Parts, Chondrosarcoma, Or

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Drug for Preventing, Treating Or Preventing Metastasis of Giant Cell Tumor That Occurs in Bone Or Soft Parts, Chondrosarcoma, Or (19) TZZ¥ZZ¥_T (11) EP 3 050 573 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 153(4) EPC (43) Date of publication: (51) Int Cl.: 03.08.2016 Bulletin 2016/31 A61K 45/00 (2006.01) A61K 31/167 (2006.01) A61K 31/196 (2006.01) A61K 31/38 (2006.01) (2006.01) (2006.01) (21) Application number: 14847606.2 A61K 31/405 A61K 31/427 A61K 31/663 (2006.01) A61K 39/395 (2006.01) (2006.01) (2006.01) (22) Date of filing: 25.09.2014 A61L 27/00 A61L 31/00 A61P 19/00 (2006.01) A61P 35/00 (2006.01) G01N 33/15 (2006.01) G01N 33/50 (2006.01) G01N 33/68 (2006.01) G01N 33/92 (2006.01) (86) International application number: PCT/JP2014/075542 (87) International publication number: WO 2015/046388 (02.04.2015 Gazette 2015/13) (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • TAKEUCHI, Akihiko GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Kanazawa-shi PL PT RO RS SE SI SK SM TR Ishikawa 920-1164 (JP) Designated Extension States: • TSUCHIYA, Hiroyuki BA ME Kanazawa-shi Ishikawa 920-1164 (JP) (30) Priority: 25.09.2013 JP 2013199076 (74) Representative: Beckmann, Claus (71) Applicant: Nippon Chemiphar Co., Ltd. Kraus & Weisert Tokyo 101-0032 (JP) Patentanwälte PartGmbB Thomas-Wimmer-Ring 15 80539 München (DE) (54) DRUG FOR PREVENTING, TREATING OR PREVENTING METASTASIS OF GIANT CELL TUMOR THAT OCCURS IN BONE OR SOFT PARTS, CHONDROSARCOMA, OR OSTEOSARCOMA, LOCAL INJECTION FOR ARTERIAL EMBOLIZATION, AND ARTIFICIAL BONE (57) The present invention provides an agent for pro- phylactic treatment, therapeutic treatment, or prevention of metastasis of giant cell tumor occurring in a bone and soft tissue, chondrosarcoma, or bone sarcoma, a local infusion for artery embolization, and an artificial bone, which comprises a substance having a PPAR γ-agonistic activity and/or a PPARγ expression-inducing activity as an active ingredient. The agent for prophylactic treat- ment, therapeutic treatment, or prevention of metastasis, the local infusion for artery embolization, and the artificial bone of the present invention are a radical therapeutic agent or radical therapeutic material that can cause ap- optosis in giant cell tumor occurring in a bone and soft tissue, chondrosarcoma, or bone sarcoma to make the tumor disappear, and can induce differentiation of the tumor into fat cells to make the tumor disappear. EP 3 050 573 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 3 050 573 A1 2 Description [0005] As for occurring positions of giant cell tumor of bone (GCTB), it frequently occurs in long tubular bones, Technical Field and it occurs in a distal end of the thighbone (namely, just above the knee) or a proximal end of the tibia (name- [0001] The present invention relates to an agent for 5 ly, just below the knee) in approximately half of the total prophylactic treatment, therapeutic treatment, or preven- cases. Next to these positions, giant cell tumor of bone tion of metastasis of giant cell tumor occurring in a bone (GCTB) frequently occurs at a distal end of the radius and soft tissue, chondrosarcoma, or bone sarcoma, and (namely, the jointing position of the thumb on the radius, the like, which uses a substance having a PPARγ-ago- which is the bone on the side of the thumb among the nistic activity and/or a PPAR γ expression-inducing activ- 10 twobones connecting theelbow and the wrist), a proximal ity. The present invention also relates to a local infusion end of the humerus (namely, just under the shoulder), for artery embolization or artificial bone, which comprises and the sacrum (namely, the inverse triangle bone near a substance having a PPARγ-agonistic activity and/or a the inferior extremity of the backbone, locating at the PPA-RY expression-inducing activity. The present inven- center of the pelvis), which are mentioned in the descend- tion further relates to a screening method for selecting a 15 ing order of occurring frequency. There are no symptoms substancethat inducesapoptosis orfat cell differentiation peculiar to giant cell tumor of bone (GCTB), and the sub- in giant cell tumor occurring in bone and soft tissue, chon- jective symptoms are such nonspecific symptoms as a drosarcoma, or bone sarcoma, as an agent for prophy- pain of affected part due to microfracture caused by re- lactic treatment, therapeutic treatment, or prevention of duction of bone strength, spontaneous pain, load-bear- metastasis of giant cell tumor occurring in bone and soft 20 ing pain, swelling, sense of heat, and difficulty in moving tissue, chondrosarcoma, or bone sarcoma. joint. [0006] Although giant cell tumor of bone (GCTB) is Background Art classified as benign tumor, it shows characteristics be- tween those of malignant and benign tumors, such as [0002] As giant cell tumors occurring in a bone and soft 25 high proliferation velocity and high recurrence rate of 10 tissue, there are known osteoclastoma occurring in a to 30%. In several percents of the cases of giant cell bone (giant cell tumor of bone, henceforth referred to as tumor of bone, it metastasizes to the lung within 1 to 10 "GCTB"), giant cell tumor of tendon sheath-localized type years, and 25% of such patients die from proliferation of occurring in a soft tissue (henceforth referred to as the tumor. Giant cell tumor of bone (GCTB) may rarely "GCTT"), pigmented villonodular synovitis (henceforth 30 convert into highly malignant sarcoma, and it is reported referred to as "PVNS"), and the like. In this specification, that, as for the prognosis of such cases, five-year survival GCTB, GCTT, and PVNS are collectively referred to as rate of such patients treated with chemotherapeutic treat- giant cell tumors. In general, among the giant cell tumors, ment and extensive resection was 50%. especially the giant cell tumor of tendon sheath (GCTT) [0007] Since giant cell tumor of bone occurring before and the pigmented villonodular synovitis (PVNS) may be 35 stop of increase of body height due to closing of the ep- generically named giant cell tumors of tendon sheath. In iphyseal plate, or giant cell tumor of bone found at an this specification, the term giant cell tumor of tendon early stage exists at the metaphysis (namely, an end part sheath refers to the giant cell tumor of tendon sheath- of diaphysis of a long tubular bone locating on the dia- localized type (GCTT) in a narrow sense, and for referring physis side with respect to the epiphysis constituting a to the giant cell tumors of tendon sheath in a broad sense, 40 part of joint), it is fundamentally considered to be a tumor the term tenosynovial giant cell tumors is used. that occurs in the metaphysis and quickly infiltrates in the [0003] As a tumor occurring in a bone and soft tissue, epiphysis. Hyperplasia of multinucleated giant cells and chondrosarcoma is also known. Similarly, as a malignant monocyte cells constitutes the major part of the patho- tumor primarily occurring in a bone tissue, bone sarcoma logical findings, and spindle cells are observed between is known. 45 them. The morphology and functions of the multinucle- [0004] Giant cell tumor of bone (GCTB) is a benign ated giant cells are similar to those of osteoclasts. It is tumor frequently occurring in circumferences of the knee thought that the body of the tumor of giant cell tumor of joints of young to middle- or advanced-aged persons, bone consists of spindle cells similar to fibroblasts and and accounts for 3 to 8% of the primitive bone tumors, osteoblastsexisting in the stroma, and the multinucleated and 15 to 20% of benign bone tumors. The morbidity of 50 giant cells and monocyte cells are cells gathering in re- the giant cell tumor of bone (GCTB) is slightly higher in sponse to a cytokine produced by the tumor cells. Al- women, and patients’ man-and-woman ratio is 1:1.3 to though it is considered that giant cell tumor of bone is 1.5. Giant cell tumor of bone (GCTB) frequently occurs probably a tumor originating in undifferentiated mesen- in 20 to 45 years old persons, and it is said that about chymal cells in the bone marrow, cell origin thereof is 150 persons newly develop this disease in every year in 55 unknown. Japan. Giant cell tumor of bone (GCTB) accounts for [0008] There is only ablative operation as the radical about 5% of all bone tumors, and about 20% of benign therapy of giant cell tumor of bone (GCTB). In usual ab- bone tumors. lative operations, phenol treatment, alcohol treatment, 2 3 EP 3 050 573 A1 4 zinc chloride treatment, freezing with liquid nitrogen, and toms of giant cell tumor of tendon sheath (GCTT), and it thermotherapeutic treatment using heat of polymeriza- occurs as hypodermic tumor in fingers with no substantial tion of methyl methacrylate bone cement are performed pain, shows slow proliferation, and generally passes sev- after curettage or excision of the lesion, for the purpose eral years until it is diagnosed by a medical examination of annihilating remaining tumor cells to prevent recur- 5 of a medical practitioner. rence, and the recurrence rate of 30 to 50% observed [0013] As the pathology of giant cell tumor of tendon without such treatments as mentioned above is thereby sheath (GCTT), orbicular-ovate to spindle-shaped histi- successfully lowered to 10 to 25%. ocyte-like monocytes showing diffusible proliferation and [0009] Although it is rare for giant cell tumor of bone osteoclast-like multinucleated giant cells are intermin- (GCTB) to follow a fatal process, it is a disease of which 10 gled in tumors showing clear borders.
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