IP Library › Granted Patent US 8,716,233
Granted Patent B2
US 8,716,233 · App. 12/453,833 · Granted May 6, 2014

NOTCH mutations leading to increased receptor signaling

Inventors: Jon C. Aster (Lexington, MA); Stephen C. Blacklow (Cambridge, MA); A. Thomas Look (North Reading, MA); Adolfo A. Ferrando (New York, NY); Andrew P. Weng (Vancouver, CA)
Assignees: The Brigham and Women's Hospital, Inc.; Dana-Farber Cancer Institute, Inc.
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Quick Facts
Patent No.
US 8,716,233
App. No.
12/453,833
Granted
May 6, 2014
Kind
B2
Abstract

The present invention is based upon the identification of regions within the NOTCH-1 receptor that, when mutated, lead to increase receptor signaling. The mutations are associated with uncontrolled cellular growth and this growth may be arrested using agents that interfere with NOTCH-1 activity, such as inhibitors of gamma-secretase. Assays for the NOTCH-1 mutations may be used diagnostically or as part of a treatment regimen for cancer patients.

Claims (22)

1. A method of treating a patient for T-cell acute lymphoblastic leukemia (T-ALL) comprising: administering an effective amount of a gamma-secretase inhibitor to said patient, wherein prior to treatment, said patient has been found to have cancer cells with a mutant NOTCH-1 receptor comprising the amino acid sequence of SEQ ID NO:1 except for one or more mutations which:

a) are associated with increased receptor signaling in response to gamma-secretase, and

b) are in the region of SEQ ID NO:1 from amino acid 2311 to amino acid 2556.

2. The method of claim 1 , wherein, except for said one or more mutations, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

3. The method of claim 1 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

4. The method of claim 3 , wherein, except for said one or more mutations, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

5. A method of treating a patient for T-cell acute lymphoblastic leukemia (T-ALL) comprising: administering an effective amount of a gamma-secretase inhibitor to said patient, wherein prior to treatment, said patient has been found to have cancer cells with a mutant NOTCH-1 receptor comprising the amino acid sequence of SEQ ID NO:1 except that the portion of said amino acid sequence from amino acid 2311 to amino acid 2556 is replaced with a sequence selected from the group consisting of: SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:34; SEQ ID NO:35; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:41; SEQ ID NO:42; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:46; SEQ ID NO:47; SEQ ID NO:48; SEQ ID NO:49; SEQ ID NO:50; SEQ ID NO:51; SEQ ID NO:52; SEQ ID NO:53; SEQ ID NO:54; SEQ ID NO:55; SEQ ID NO:56; SEQ ID NO:57; SEQ ID NO:58; SEQ ID NO:59; SEQ ID NO:138; SEQ ID NO:139; SEQ ID NO:140; SEQ ID NO:141; SEQ ID NO:142; SEQ ID NO:143; and SEQ ID NO:144.

6. The method of claim 5 , wherein, except for the replacement of the portion of said amino acid sequence from amino acid 2311 to amino acid 2556, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

7. The method of claim 5 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

8. The method of claim 7 , wherein, except for said one or more mutations, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

9. The method of claim 5 , wherein, in addition to the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 in said mutant NOTCH-1 receptor, the portion of the amino acid sequence of SEQ ID NO:1 from amino acid 1571 to amino acid 1618 is replaced with a sequence selected from the group consisting of: SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:102; SEQ ID NO:103; SEQ ID NO:104; SEQ ID NO:105; SEQ ID NO:106; SEQ ID NO:107; SEQ ID NO:108; SEQ ID NO:109; SEQ ID NO:110; SEQ ID NO:111; SEQ ID NO:112; SEQ ID NO:113; SEQ ID NO:114; SEQ ID NO:115; SEQ ID NO:116; SEQ ID NO:117; SEQ ID NO:118; and SEQ ID NO:145.

10. The method of claim 9 , wherein, except for the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 and for the replacement of the sequence from amino acid 1571 to amino acid 1618, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

11. The method of claim 9 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

12. The method of claim 5 , wherein, in addition to the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 in said mutant NOTCH-1 receptor, the portion of the amino acid sequence of SEQ ID NO:1 from amino acid 1571 to amino acid 1622 is replaced with a sequence selected from the group consisting of: SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:29; SEQ ID NO:119; SEQ ID NO:120; SEQ ID NO:121; SEQ ID NO:122; SEQ ID NO:123; SEQ ID NO:124; SEQ ID NO:125; SEQ ID NO:126; and SEQ ID NO:127.

13. The method of claim 12 , wherein, except for the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 and for the replacement of the sequence from amino acid 1571 to amino acid 1622, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

14. The method of claim 12 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

15. The method of claim 5 , wherein, in addition to the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 in said mutant NOTCH-1 receptor, the portion of the amino acid sequence of SEQ ID NO:1 from amino acid 1674 to amino acid 1730 is replaced with a sequence selected from the group consisting of: SEQ ID NO:70; SEQ ID NO:71; SEQ ID NO:72; SEQ ID NO:73; SEQ ID NO:74; SEQ ID NO:75; SEQ ID NO:128; SEQ ID NO:129; SEQ ID NO:130; SEQ ID NO:131; SEQ ID NO:132; SEQ ID NO:133; SEQ ID NO:134; SEQ ID NO:135; SEQ ID NO:136; and SEQ ID NO:137.

16. The method of claim 15 , wherein, except for the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 and for the replacement of the sequence from amino acid 1674 to amino acid 1730, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

17. The method of claim 15 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

18. The method of claim 5 , wherein in addition to the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 in said mutant NOTCH-1 receptor, said mutant NOTCH-1 receptor is mutated at one or more amino acid positions selected from the group consisting of: 1571; 1573; 1575; 1576; 1578; 1579; 1583; 1586; 1588; 1590; 1593; 1594; 1595; 1598; 1600-1607; 1610-1618; 1674; 1675; 1677; 1679-1684; 1686; 1695; 1696; 1703; 1706; 1715; 1720; 1725; and 1728.

19. The method of claim 18 , wherein, except for the replacement of the sequence of SEQ ID NO:1 from amino acid 2311 to amino acid 2556 and for the mutation of one or more amino acid positions selected from the group consisting of: 1571; 1573; 1575; 1576; 1578; 1579; 1583; 1586; 1588; 1590; 1593; 1594; 1595; 1598; 1600-1607; 1610-1618; 1674; 1675; 1677; 1679-1684; 1686; 1695; 1696; 1703; 1706; 1715; 1720; 1725; and 1728, said mutant NOTCH-1 receptor consists of the amino sequence of SEQ ID NO:1.

20. The method of claim 18 , wherein said gamma-secretase inhibitor is selected from the group consisting of: III-31-C; N-[N-(3,5-difluorophenacetyl)-L-alanyl]S-phenylglycine t-butyl ester) (DAPT); compound E; D-helical peptide 294; isocoumarins; BOC-Lys(Cbz)Ile-Leu-epoxide; and (Z-LL) 2 -ketone.

Assignments (3)
CONFIRMATORY LICENSE Recorded Jan 14, 2021
From: DANA-FARBER CANCER INST
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 054998/0777 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 6, 2012
From: LOOK, A. THOMAS; FERRANDO, ADOLFO A.
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 028329/0801 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 5, 2012
From: ASTER, JON C.; BLACKLOW, STEPHEN C.; WENG, ANDREW P.
To: THE BRIGHAM AND WOMEN'S HOSPITAL, INC.
Reel/Frame 028319/0752 →
Continuity (4)
Continuation 11194913 · Aug 2, 2005
Provisional Application 60598546 · Aug 4, 2004
Provisional Application 60672053 · Apr 18, 2005
Related Publication 20100087358A1 · Apr 8, 2010