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III IIHIIII USOO5550316A United States Patent (19) 11 Patent Number: 5,550,316 Mintz 45) Date of Patent: Aug

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III IIHIIII USOO5550316A United States Patent (19) 11 Patent Number: 5,550,316 Mintz 45) Date of Patent: Aug III IIHIIII USOO5550316A United States Patent (19) 11 Patent Number: 5,550,316 Mintz 45) Date of Patent: Aug. 27, 1996 54) TRANSGENIC ANIMAL MODEL SYSTEM M Bradlet al. (1991) Proc Natl AcadSci, USA 88:164-168. FOR HUMAN CUTANEOUS MELANOMA K N Broadley et al (1989) Laboratory Investigation 61:571-575. 75) Inventor: Beatrice Mintz, Elkins Park, Pa. Hesketh (1995) The Oncogene Facts Book, pp. 32-42. (73) Assignee: Fox Chase Cancer Center, Strojek et al (1988) Genetic Engineering: Principles and Philadelphia, Pa. methods, 10:238. Loudon et al (1993) Clin Exp Pharmacol Physiol 20: 21 Appl. No.: 11,060 283-288. 22 Filed: Jan. 29, 1993 Primary Examiner-Jacqueline M. Stone Related U.S. Application Data Assistant Examiner-Bruce R. Campell Attorney, Agent, or Firm-Pennie & Edmonds 63 Continuation-in-part of Ser. No. 636,798, Jan. 2, 1991, abandoned. 57) ABSTRACT (51 Int. CI.' ................ C12N 15/00; A01K 67/00 52) U.S. Cl. ..................... 800/2; 800/DIG. 1; 435/172.3; The present invention relates to transgenic animal model 536/23.1; 536/23.72; 536/24.1; 424/9.2 systems for human cutaneous melanoma. It is based, at least Field of Search ................................... 800/2, DIG. 1; in part, on the discovery that, in susceptible transgenic mice, (58) accelerated formation of melanoma tumors occurred near 435/172.3; 536/23.1, 23.72, 24.1; 424/9 the wound borders of skin grafts carrying the Tyr-SV40E References Cited transgene, indicating that factors present during wound (56) healing facilitate the formation of cutaneous melanoma in PUBLICATIONS susceptible tissue. B Mintz et al (1993) Proc Natl. Acad. Sci USA 90:8817-882. R Halaban (1991) Cancer Metastasis Rev 10(2):129-140. 2 Claims, 13 Drawing Sheets 110 340 32O es s 1OO 3OO 28O 9 O 260 24O 78OO 22O 2OO 6 O 8 O O O 2O 3O 40 50 6 O TOTAL IRRADANCE (m)/cm2) O 2O 3O 4. O H-------- UVB IRRADANCE (m)/cm2) U.S. Patent Aug. 27, 1996 Sheet 1 of 13 5,550,316 IHUD8I108IIIpUIHIIIpulH | '0|- 917–! IIIpulH IIIpulH U.S. Patent Aug. 27, 1996 Sheet 2 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 3 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 4 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 5 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 6 of 13 5,550,316 & U.S. Patent Aug. 27, 1996 Sheet 7 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 8 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 9 of 13 5,550,316 0 O 2O 30 40 5O 60 TOTAL IRRADIANCE (m)/cm2) O 2O 30 40 -------- UVB IRRADIANCE (m)/cm2) F. G. 4 U.S. Patent Aug. 27, 1996 Sheet 10 of 13 5,550,316 110 340 : 32O S OO es 3 300 as th S. e 2. 90 280 ? - - LL l C9 260 Us S2 2 m : 80 240 g C He 220 2 70 g 2OO 2t C C - - U 60 180 a O O 2O 30 40 50 60 TOTAL IRRADANCE (m)/cm2) O 2O 3O 40 H------- UVB IRRADIANCE (mu/cm2) F G. 5 U.S. Patent Aug. 27, 1996 Sheet 11 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 12 of 13 5,550,316 U.S. Patent Aug. 27, 1996 Sheet 13 of 13 5,550,316 5,550,316 1. 2 TRANSGENIC ANIMAL MODEL SYSTEM 51:4815-4820; Rodeck and Herlyn, 1991, Cancer Metasta FOR HUMAN CUTANEOUS MELANOMA sis Rev. 10:89-101; Dotto et al., 1989, J. Cell Biol. 109:3115-3128; contradicted by Yamanishi et al., 1992, This is a continuation-in-part of U.S. Ser. No. 07/636, Cancer Res. 52:5024-5029); transforming growth factors 798, filed Jan. 2, 1991, (abandoned). alpha and beta (Albino et al., 1991, Cancer Res. 51:4815-4820; Rodeck and Herlyn, 1991, Cancer Metasta 1. INTRODUCTION sis Rev. 10:89-101); hepatocyte growth factor/scatter factor (Halaban et al., 1992, Oncogene 7:2195-2206); tumor The present invention relates to transgenic animal model necrosis factor alpha and/or beta (Kirnbauer et al., 1992, J. systems for human cutaneous melanoma. It is based, at least 10 Invest. Dermatol. 98:320-326; Krutmann et al., 1992, J. in part, on the discovery that, in susceptible transgenic mice, Invest. Dermatol.98:923-928); platelet derived growth fac accelerated formation of melanoma tumors occurred near tor (Rodeck and Herlyn, 1991, Cancer Metastasis Rev. the wound borders of skin grafts carrying the Tyr-SV40E 10:89-101); and various interleukins (Kirnbauer et al., 1992, transgene, indicating that factors present during wound J. Invest. Dermatol. 98:320-326; partly contradicted by Lu healing facilitate the formation of cutaneous melanoma in 15 et al., 1992, Proc. Natl. Acad. Sci. 89:9215-9219). Beckeret susceptible tissue. al. (1992, Oncogene 7:2303-2313) implicates the fibroblast growth factor receptor in melanomagenesis. Other studies 2. BACKGROUND OF THE INVENTION suggest that molecules that influence intracellular adhesion (Kirnbauer et al., J. Invest. Dermatol. 98:320–326; Krut 2.1. MELANOMA 20 mann et al., J. Invest. Dermatol. 98:923–928) or tissue Primary malignant melanoma of the skin is the leading protease activity (Mueller et al., 1992, Proc. Natl. Acad. Sci. cause of death from any skin disease (see Fitzpatrick et al., U.S.A. 89:11832-11836) may be involved in the progres 1983, in “Harrison's Principles of Internal Medicine,” Edi sion of human melanoma disease. tion, Petersdorf et al. eds., McGraw Hill, New York, pp. Thus, the literature is diverse and occasionally contradic 836-838). Melanoma has been estimated to account for 1 25 tory regarding the genesis and progression of melanoma. percent of all skin cancers, with an incidence of approxi Furthermore, it is unclear what factors are involved in the mately 4.5 in 100,000 person-years in Caucasians and 0.6 in initiation of events which lead to melanoma, as opposed to 100,000 person years in Blacks in the U.S. (Ibid., p. 368). those operative in the progression of disease. A better The incidence of melanoma is higher in light-skinned per understanding of the disease process could be obtained using sons and increases with geographical proximity to the equa 30 a suitable animal model of human melanoma. The model tor (Id.). could then also serve to test agents which might exacerbate Because chemotherapy is frequently ineffective in treat the disease, and to test preventative or curative treatment ing melanoma, and because melanomas have a propensity strategies. for metastasis (Foos et al., 1983, in "Intraocular Tumors', eds. Lommatzsch et al., Springer-Verlag, Berlin pp. 51–57), 35 early detection followed by surgical excision is a key 2.2. TRANSGENIC ANIMAL MODELS OF element in successful treatment of the disease. The five-year MELANOMA survival decreases in proportion to the depth of tumor Transgenic mice having an integrated recombinant gene invasion (Id.). With less than 0.85 mm of invasion, the five 40 comprised of the tyrosinase promoter and the simian virus year survival is about 99 percent; this drops to less than 10 40 (SV40) early region containing transforming sequences percent in metastatic melanoma. (the "Tyr-SV40E" transgene, FIG. 1) which results in selec The incidence of melanoma has increased sharply over tive expression of SV40 large T ("T") and small t (“t”) the last few decades. In the Connecticut Registry, between antigen genes in melanocytes and other pigmented cells, 1935 and 1939, the incidence of melanoma was 1.2/10 45 have been produced (Bradl et al., 1991, Proc. Natl. Acad. persons/year; this increased to 4.8/10 persons/year in Sci. U.S.A.88:164-168; Klein-Szanto et al., 1991, Proc. 1965-1969, to 7.2/10 persons/year in 1976–1977, and to Natl. Acad. Sci. U.S.A. 88:169–173; Bradlet al., 1991, Proc. 9/10 persons/year in 1979–1980. By the year 2000, one in Natl. Acad. Sci. U.S.A. 88:6447-6451; Larue et al., 1992, 90 Caucasians in the United States is expected to develop the Proc. Natl. Acad. Sci. U.S.A. 89:9534-9538). Different lines disease (Rigel et al., 1987, J. Am. Acad. Dermatol. 50 of these mice were produced from the same inbred strain 17:1050-1053). (C57BL/6) and are genetically identical except for the Melanomas are highly variable with respect to aberrant number of copies and chromosome site of integration char gene expression and chromosomal lesions but share a com acteristic of each line. Both ocular and cutaneous melano mon characteristic of an acquired independence from envi mas, and melanomas of various tissues, were found to ronmental growth factors that are needed for proliferation of 55 develop in lines of these transgenic mice. The tumors were normal melanocytes (Halaban, 1991, Cancer Metastasis hypomelanotic and histopathologically similar to human Rev. 10:129-140). In normal melanocyte proliferation as melanomas (Id.). In general, mice of lines with larger well as uncontrolled melanoma growth, receptors with numbers of transgene copies are highly susceptible and tyrosine kinase activity, such as certain growth factor recep developed eye melanomas sooner than mice with smaller tors, appear to play an important role (Id.; Becker et al., 60 numbers of transgene copies and low susceptibility. Eye 1992, Oncogene 7:2303-2313). Various studies have sug melanomas usually originated at a very young age, chiefly gested that a number of growth factors may be involved in from the retinal pigment epithelium (see also Mintz and melanomagenesis (Kock et al., 1991, Cancer Treat.
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