US2016363596A1PendingUtilityA1
Signatures and determinants associated with prostate cancer progression and methods of use thereof

Assignee: DEPINHO RONALD APriority: Jun 27, 2011Filed: Aug 26, 2016Published: Dec 15, 2016
Est. expiryJun 27, 2031(~4.9 yrs left)· nominal 20-yr term from priority
Inventors:Ronald A. Depinho Zhihu Ding Chang-Jiun Wu Lynda Chin
G01N 33/5758G01N 33/57555G01N 33/5011C12Q 2600/118A01K 2267/0331G01N 33/57484G01N 33/57434A01K 2227/105C12Q 2600/136C12Q 2600/158C12Q 1/6886A01K 67/0276C12Q 2600/156C12Q 2600/106G01N 2800/52G01N 2800/56A61N 5/10
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Claims
Abstract

The present invention provides a set of DETERMINANTS (e.g., genes and gene products) that can accurately inform about the risk of cancer progression and recurrence, as well as methods of their use.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A method for predicting prognosis of a cancer patient, comprising:
 obtaining a tissue sample from the patient, and   measuring the levels of two or more DETERMINANTS selected from   (a) Cyclin D1, SPP1, Smad4 and PTEN; or from   (b) ATP5A1, ATP6V1C1, CUL2, CYC1, DCC, ERCC3, MBD2, MTERF, PARD3, PTK2, RBL2, SMAD2, SMAD4, and SMAD7;   in the sample, wherein the measured levels are indicative of the prognosis of the cancer patient.   
     
     
         2 . The method of  claim 1 , further comprising measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         3 . A method for predicting prognosis of a cancer patient, comprising:
 obtaining a tissue sample from the patient, and   measuring the levels of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-741 of Table 2 in the sample,   wherein the measured levels are indicative of the prognosis of the cancer patient.   
     
     
         4 . The method of any one of  claims 1 - 3 , wherein the prognosis is that the patient is at a low risk of having metastatic cancer or recurrence of cancer. 
     
     
         5 . The method of any one of  claims 1 - 3 , wherein the prognosis is that the patient is at a high risk of having metastatic cancer or recurrence of cancer. 
     
     
         6 . A method for identifying a cancer patient in need of adjuvant therapy, comprising:
 obtaining a tissue sample from the patient, and   measuring the levels of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-741 of Table 2 in the sample,   wherein the measured levels indicate that the patient is in need of adjuvant therapy.   
     
     
         7 . The method of  claim 6 , wherein the adjuvant therapy is selected from the group consisting of radiation therapy, chemotherapy, immunotherapy, hormone therapy, and targeted therapy. 
     
     
         8 . The method of  claim 6 , wherein the patient has been subjected to a standard of care therapy. 
     
     
         9 . The method of  claim 8 , wherein the standard of care therapy is surgery, radiation, chemotherapy, or androgen ablation. 
     
     
         10 . The method of  claim 7 , wherein the targeted therapy targets another component of a signaling pathway in which one or more of the selected DETERMINANTS is a component. 
     
     
         11 . The method of  claim 7 , wherein the targeted therapy targets one or more of the selected DETERMINANTS. 
     
     
         12 . A method for treating a cancer patient, comprising:
 measuring the levels of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-741 of Table 2 in a tissue sample from the patient,   treating the patient with adjuvant therapy if the measured levels indicate that the patient is at a high risk of having metastatic cancer or recurrence of cancer.   
     
     
         13 . The method of  claim 12 , wherein the adjuvant therapy is an experimental therapy. 
     
     
         14 . The method of any one of the above claims, wherein the patient has prostate cancer. 
     
     
         15 . A method for monitoring the progression of a tumor in a patient comprising:
 obtaining a tumor tissue sample from the patient, and   measuring the levels of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-741 of Table 2 in the sample,   wherein the measured levels are indicative of the progression of the tumor in the patient.   
     
     
         16 . The method of  claim 15 , wherein a clinically significant alteration in the measured levels between the tumor tissue sample taken form the patient at two different time points is indicative of the progression of the tumor in the patient. 
     
     
         17 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from Table 3. 
     
     
         18 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from Table 5. 
     
     
         19 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS comprise one or more of MAP3K8, RAD21, and TUSC3. 
     
     
         20 . The method of any one of  claims 3 - 19 , further comprising measuring the levels of one or more of PTEN, cyclin D1, SMAD4, and SPP1. 
     
     
         21 . The method of any one of  claims 3 - 19 , further comprising measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         22 . The method of any one of  claims 3 - 16 , wherein the selected DETERMINANTS comprise one or more of ATP5A1, ATP6V1C1, CUL2, CYC1, DCC, ERCC3, MBD2, MTERF, PARD3, PTK2, RBL2, SMAD2, SMAD4, SMAD7, DNAJC15, KIF5B, LECT1, DSG2, ACAA2, ASAP1, LMO7, SVIL, DSC2, PCDH9, WDR7, LAMA3, PCDH8, MKX, MSR1, and POLR2K. 
     
     
         23 . The method of  claim 22 , further comprising measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         24 . The method of  claim 22 , wherein the selected DETERMINANTS comprise one or more of ATP5A1, ATP6V1C1, CUL2, CYC1, DCC, ERCC3, MBD2, MTERF, PARD3, PTK2, RBL2, SMAD2, SMAD4, and SMAD7. 
     
     
         25 . The method of  claim 24 , further comprising measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         26 . The method of  claim 22 , wherein the selected DETERMINANTS comprise one or more of DNAJC15, KIF5B, LECT1, DSG2, ACAA2, ASAP1, LMO7, SVIL, DSC2, PCDH9, SMAD7, WDR7,  LAMA 3, PCDH8, MKX, MSR1, and POLR2K. 
     
     
         27 . The method of  claim 22 , wherein the selected DETERMINANTS comprise one or more of DNAJC15, KIF5B, LECT1, DSG2, ACAA2, ASAP1, and LMO7. 
     
     
         28 . The method of  claim 22 , wherein the selected DETERMINANTS comprise one or more of SVIL, DSC2, PCDH9, SMAD7, WDR7, LAMA3, PCDH8, MKX, MSR1, and POLR2K. 
     
     
         29 . The method of any one of  claims 26 - 28 , further comprising measuring the levels of one or more of PTEN, cyclin D1, SMAD4, and SPP1. 
     
     
         30 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 1-300 of Table 2 and wherein the measured levels of the selected DETERMINANTS have a clinically significant increase. 
     
     
         31 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 301-741 of Table 2 and wherein the measured levels of the selected DETERMINANTS have a clinically significant decrease. 
     
     
         32 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 8, 9, 12, 13, 18-20, 22, 23, 34, 41, 48-50, 56, 64, 65, 70, 72-79, 81, 84, 87, 88, 102, 104, 114, 124, 134, 139, 154, 169-172, 185, 186, 193, 196, 199, 203, 204, 207, 209, 212, 217, 218, 221, 245, 247, 248, 254, 257, 260, 263, 264, 268, 269, 277, 279-281, 283, 284, 286, 287, 292, 294, and 296-298 of Table 3 and wherein the measured levels of the selected DETERMINANTS have a clinically significant increase. 
     
     
         33 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 303, 308, 310, 312, 313, 316, 319, 322, 324, 326, 328, 329, 343, 353, 360, 368, 371, 376, 378, 384, 386, 389, 391, 392, 398, 400, 403, 404, 405, 406, 407, 412, 416, 421, 422, 424, 430, 432, 435, 437, 440, 445, 446, 451, 459, 466, 468, 469, 470, 471, 473, 477, 481, 482, 484, 485, 486, 487, 490, 492, 493, 494, 496, 498, 502, 503, 505, 506, 509, 514, 515, 520, 521, 522, 525, 526, 527, 530, 533, 534, 536, 542, 547, 552, 553, 554, 555, 563, 570, 580, 582, 584, 585, 586, 587, 589, 592, 594, 595, 599, 600, 603, 604, 612, 614, 616, 617, 622, 625, 628, 629, 632, 637, 642, 648, 651, 652, 654, 655, 656, 658, 659, 660, 661, 662, 666, 669, 670, 671, 675, 676, 680, 681, 682, 685, 687, 689, 690, 691, 692, 695, 711, 718, 719, 722, 723, 724, 725, 730, 735, and 740 of Table 3 and wherein the measured levels of the selected DETERMINANTS have a clinically significant decrease. 
     
     
         34 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 9, 12, 18, 19, 22, 23, 41, 56, 70, 72, 75, 76, 77, 87, 102, 114, 134, 139, 171, 172, 185, 196, 199, 207, 209, 217, 221, 247, 248, 260, 263, 264, 268, 269, 279, 296, and 298 of Table 5 and wherein the measured levels of the selected DETERMINANTS have a clinically significant increase. 
     
     
         35 . The method of any one of  claims 3 - 16 , wherein said two or more DETERMINANTS are selected from the group consisting of DETERMINANTS 308, 312, 319, 322, 324, 326, 328, 329, 343, 371, 378, 386, 389, 391, 392, 400, 416, 422, 424, 440, 445, 466, 471, 481, 482, 484, 490, 492, 493, 494, 496, 498, 503, 505, 506, 514, 521, 522, 525, 526, 527, 533, 542, 554, 555, 570, 582, 584, 585, 586, 592, 594, 595, 612, 617, 628, 629, 637, 642, 648, 651, 658, 659, 660, 661, 675, 680, 681, 685, 687, 692, 718, 719, 723, 730, and 735 of Table 5 and wherein the measured levels of the selected DETERMINANTS have a clinically significant decrease. 
     
     
         36 . The method of any one of  claims 3 - 16 , wherein at least one of the two or more DETERMINANTS are selected from DETERMINANTS 1-300 of Table 2 and at least one of the two or more DETERMINANTS are selected from DETERMINANTS 301-741 of Table 2. 
     
     
         37 . The method of any one of  claims 3 - 16 , wherein at least one of the two or more DETERMINANTS are selected from DETERMINANTS 8, 9, 12, 13, 18-20, 22, 23, 34, 41, 48-50, 56, 64, 65, 70, 72-79, 81, 84, 87, 88, 102, 104, 114, 124, 134, 139, 154, 169-172, 185, 186, 193, 196, 199, 203, 204, 207, 209, 212, 217, 218, 221, 245, 247, 248, 254, 257, 260, 263, 264, 268, 269, 277, 279-281, 283, 284, 286, 287, 292, 294, and 296-298 of Table 3 and at least one of the two or more DETERMINANTS are selected from DETERMINANTS 303, 308, 310, 312, 313, 316, 319, 322, 324, 326, 328, 329, 343, 353, 360, 368, 371, 376, 378, 384, 386, 389, 391, 392, 398, 400, 403, 404, 405, 406, 407, 412, 416, 421, 422, 424, 430, 432, 435, 437, 440, 445, 446, 451, 459, 466, 468, 469, 470, 471, 473, 477, 481, 482, 484, 485, 486, 487, 490, 492, 493, 494, 496, 498, 502, 503, 505, 506, 509, 514, 515, 520, 521, 522, 525, 526, 527, 530, 533, 534, 536, 542, 547, 552, 553, 554, 555, 563, 570, 580, 582, 584, 585, 586, 587, 589, 592, 594, 595, 599, 600, 603, 604, 612, 614, 616, 617, 622, 625, 628, 629, 632, 637, 642, 648, 651, 652, 654, 655, 656, 658, 659, 660, 661, 662, 666, 669, 670, 671, 675, 676, 680, 681, 682, 685, 687, 689, 690, 691, 692, 695, 711, 718, 719, 722, 723, 724, 725, 730, 735, and 740 of Table 3. 
     
     
         38 . The method of any one of  claims 3 - 16 , wherein at least one of the two or more DETERMINANTS are selected from DETERMINANTS 9, 12, 18, 19, 22, 23, 41, 56, 70, 72, 75, 76, 77, 87, 102, 114, 134, 139, 171, 172, 185, 196, 199, 207, 209, 217, 221, 247, 248, 260, 263, 264, 268, 269, 279, 296, and 298 of Table 5 and at least one of the two or more DETERMINANTS are selected from DETERMINANTS 308, 312, 319, 322, 324, 326, 328, 329, 343, 371, 378, 386, 389, 391, 392, 400, 416, 422, 424, 440, 445, 466, 471, 481, 482, 484, 490, 492, 493, 494, 496, 498, 503, 505, 506, 514, 521, 522, 525, 526, 527, 533, 542, 554, 555, 570, 582, 584, 585, 586, 592, 594, 595, 612, 617, 628, 629, 637, 642, 648, 651, 658, 659, 660, 661, 675, 680, 681, 685, 687, 692, 718, 719, 723, 730, and 735 of Table 5. 
     
     
         39 . The method of any one of the above claims, wherein the levels of the two or more DETERMINANTS are detected electrophoretically, immunochemically or by non-invasive imaging. 
     
     
         40 . The method of  claim 39 , wherein the immunochemical detection is by radioimmunoassay, immunofluorescence assay or by an enzyme-linked immunosorbent assay. 
     
     
         41 . The method of any one of the above claims, wherein the subject has a primary tumor, a recurrent tumor, or metastatic cancer. 
     
     
         42 . The method of any one of the above claims, wherein the measuring step comprises detecting the DNA copy number alteration of the selected DETERMINANTS. 
     
     
         43 . The method of  claim 42 , wherein the DNA copy number alteration of the selected DETERMINANTS indicates DNA gain. 
     
     
         44 . The method of  claim 42 , wherein the DNA copy number alteration of the selected DETERMINANTS indicates DNA loss. 
     
     
         45 . The method of any one of the above claims, wherein the measuring step comprises measuring the RNA transcript levels of the selected DETERMINANTS. 
     
     
         46 . The method of  claim 45 , wherein the RNA transcript levels are determined by microarray, quantitative RT-PCR, sequencing, nCounter® multiparameter quantitative detection assay, branched DNA assay, or quantitative nuclease protection assay. 
     
     
         47 . The method of any one of the above claims, wherein the measuring step comprises measuring the protein levels of the selected DETERMINANTS. 
     
     
         48 . The method of  claim 47 , wherein the protein levels are measured by antibodies or fragments thereof. 
     
     
         49 . The method of  claim 48 , wherein the protein levels are measured by immunohistochemistry or immunofluorescence. 
     
     
         50 . The method of  claim 47 , wherein the measuring step comprises measuring the protein level of a selected DETERMINANT in subcellular compartments. 
     
     
         51 . The method of  claim 50 , wherein the measuring step comprises measuring the protein level of a selected DETERMINANT in the nucleus relative to the protein level of the DETERMINANT in the cytoplasm. 
     
     
         52 . The method of  claim 50 , wherein the measuring step comprises measuring the protein level of a selected DETERMINANT in the nucleus or in the cytoplasm. 
     
     
         53 . The method of any one of the above claims, wherein the noncancerous cells are excluded from the tissue sample. 
     
     
         54 . The method of any one of the above claims, wherein the measuring step comprises separately measuring the levels of the DETERMINANTS. 
     
     
         55 . The method of any one of the above claims, wherein the measuring step comprises measuring the levels of the DETERMINANTS in a multiplex reaction. 
     
     
         56 . The method of any one of the above claims, wherein the sample is a solid tissue sample, a bodily fluid sample, or circulating tumor cells. 
     
     
         57 . The method of  claim 56 , wherein the bodily fluid sample is blood, plasma, urine, saliva, lymph fluid, cerebrospinal fluid (CSF), synovial fluid, cystic fluid, ascites, pleural effusion, interstitial fluid, or ocular fluid. 
     
     
         58 . The method of  claim 56 , wherein the solid tissue sample is a formalin-fixed paraffin embedded tissue sample, a snap-frozen tissue sample, an ethanol-fixed tissue sample, a tissue sample fixed with an organic solvent, a tissue sample fixed with plastic or epoxy, a cross-linked tissue sample, a surgically removed tumor tissue, or a biopsy sample. 
     
     
         59 . The method of  claim 58 , wherein said biopsy sample is a core biopsy, an excisional tissue biopsy, or an incisional tissue biopsy. 
     
     
         60 . The method of any one of the above claims, wherein the tissue sample is a cancerous tissue sample. 
     
     
         61 . The method of  claim 60 , wherein the cancerous tissue is prostate cancer tissue. 
     
     
         62 . The method of any one of the above claims, further comprising measuring at least one standard parameter associated with said cancer. 
     
     
         63 . The method of  claim 60 , wherein the at least one standard parameter is selected from the group consisting of tumor stage, tumor grade, tumor size, tumor visual characteristics, tumor location, tumor growth, lymph node status, tumor thickness (Breslow score), ulceration, age of onset, PSA level, PSA kinetics, or Gleason score. 
     
     
         64 . A kit for measuring the levels of two or more DETERMINANTS selected from the group consisting of DETERMINANTS 1-741 of Table 2, comprising reagents for specifically measuring the levels of the selected DETERMINANTS. 
     
     
         65 . The kit of  claim 64 , wherein the two or more DETERMINANTS are selected from Table 3. 
     
     
         66 . The kit of  claim 64 , wherein the two or more DETERMINANTS are selected from Table 5. 
     
     
         67 . A kit for measuring the levels of two or more DETERMINANTS selected from the group consisting of MAP3K8, RAD21, TUSC3, PTEN, SMAD4, cyclin D1, and SPP1, comprising reagents for specifically measuring the levels of the selected DETERMINANTS. 
     
     
         68 . A kit for measuring the levels of two or more DETERMINANTS selected from the group consisting of ATP5A1, ATP6V1C1, CUL2, CYC1, DCC, ERCC3, MBD2, MTERF, PARD3, PTK2, RBL2, SMAD2, SMAD4, SMAD7, DNAJC15, KIF5B, LECT1, DSG2, ACAA2, ASAP1, LMO7, SVIL, DSC2, PCDH9, WDR7, LAMA3, PCDH8, MKX, MSR1, and POLR2K, comprising reagents for specifically measuring the levels of the selected DETERMINANTS. 
     
     
         69 . The kit of  claim 68 , further comprising reagents for specifically measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         70 . The kit of  claim 68 , wherein the selected DETERMINANTS comprise one or more of ATP5A1, ATP6V1C1, CUL2, CYC1, DCC, ERCC3, MBD2, MTERF, PARD3, PTK2, RBL2, SMAD2, SMAD4, and SMAD7. 
     
     
         71 . The kit of  claim 70 , further comprising reagents for specifically measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         72 . The kit of  claim 68 , wherein the selected DETERMINANTS comprise one or more of DNAJC15, KIF5B, LECT1, DSG2, ACAA2, ASAP1, LMO7, SVIL, DSC2, PCDH9, WDR7, LAMA3, PCDH8, MKX, MSR1, SMAD7, and POLR2K. 
     
     
         73 . The kit of  claim 72 , further comprising reagents for specifically measuring the levels of one or more of PTEN, cyclin D1, and SPP1. 
     
     
         74 . The kit of any one of  claims 64 - 73 , wherein the reagents comprise one or more antibodies or fragments thereof. 
     
     
         75 . The kit of any one of  claims 64 - 73 , wherein the reagents comprise one or more oligonucleotides. 
     
     
         76 . The kit of any one of  claims 64 - 73 , wherein the reagents comprise one or more aptamers. 
     
     
         77 . The kit of any one of  claims 64 - 73 , wherein the reagents measure the DNA copy number alteration, or the RNA transcript levels, or the protein levels of the selected DETERMINANTS. 
     
     
         78 . A method of identifying a compound capable of reducing the risk of cancer reoccurrence or development of metastatic cancer, comprising:
 (a) providing a cell expressing a DETERMINANT selected from the group consisting of the DETERMINANTS listed on Table 2, 3, and 5;   (b) contacting the cell with a candidate compound; and   (c) determining whether the candidate compound alters the expression or activity of the selected DETERMINANT;   whereby the alteration observed in the presence of the compound indicates that the compound is capable of reducing the risk of cancer reoccurrence or development of metastatic cancer.   
     
     
         79 . A method of identifying a compound capable of treating cancer, comprising:
 (a) providing a cell expressing a DETERMINANT selected from the group consisting of the DETERMINANTS listed on Table 2, 3, and 5;   (b) contacting the cell with a candidate compound; and   (c) determining whether the candidate compound alters the expression or activity of the selected DETERMINANT;   whereby the alteration observed in the presence of the compound indicates that the compound is capable of treating cancer.   
     
     
         80 . A method of identifying a compound capable of reducing the risk of cancer occurrence or development of cancer, comprising:
 (a) providing a cell expressing a DETERMINANT selected from the group consisting of the DETERMINANTS listed on Table 2, 3, and 5;   (b) contacting the cell with a candidate compound; and   (c) determining whether the candidate compound alters the expression or activity of the selected DETERMINANT;   whereby the alteration observed in the presence of the compound indicates that the compound is capable of reducing the risk of cancer occurrence or development of cancer.   
     
     
         81 . A mouse wherein the genome of at least one prostate epithelial cell contains a homozygous inactivation of the endogenous PTEN gene, p53 gene, and TERT gene, and the TERT gene can be inducibly re-activated and therefore expressed, and wherein the mouse exhibits an increased susceptibility to development of metastatic prostate cancer upon expression of the TERT gene. 
     
     
         82 . A mouse wherein the genome of at least one prostate epithelial cell contains a homozygous inactivation of the endogenous PTEN gene, p53 gene, and SMAD4 gene, and wherein the mouse exhibits an increased susceptibility to development of metastatic prostate cancer. 
     
     
         83 . A cell from the mouse of  claim 81  or  82 . 
     
     
         84 . The cell of  claim 83 , wherein said cell is an epithelial cancer cell. 
     
     
         85 . A method for treating a cancer patient in need thereof, comprising:
 a) measuring the level of a DETERMINANT selected from the group consisting of the DETERMINANTS listed on Table 2, 3, and 5; and   b) administering an agent that modulates the level of the selected DETERMINANT.   
     
     
         86 . The method of  claim 85 , wherein the administered agent is a small molecule modulator, a small molecule inhibitor, siRNA, or an antibody or fragment thereof. 
     
     
         87 . A method for treating a cancer patient in need thereof, comprising:
 a) measuring the level of a DETERMINANT selected from the group consisting of AGPAT6, ATAD2, ATP6V1C1, AZIN1, COX6C, CPNE3, DPYS, EBAG9, EFR3 A, EXT1, GRINA, HRSP12, KIAA0196, MAL2, MTDH, NSMCE2, NUDCD1, PDE7A, POLR2K, POP1, PTK2, SPAG1, SQLE, SRI, STK3, TAF2, TGS1, TMEM65, TMEM68, TOP1MT, UBR5, WDYHV1, WWP1, and YWHAZ; and   b) administering an agent that modulates the level of the selected DETERMINANT.   
     
     
         88 . The method of  claim 87 , wherein the administered agent is a small molecule modulator, a small molecule inhibitor, siRNA, or an antibody or fragment thereof. 
     
     
         89 . The method of  claim 87 , wherein the selected DETERMINANT is AGPAT6, AZIN1, CPNE3, DPYS, NSMCE2, NUDCD1, SR1, TGS1, UBR5, or WDYHV1.
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