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EP-4740951-A2 - IGH REARRANGEMENTS AND USES THEREOF

EP4740951A2EP 4740951 A2EP4740951 A2EP 4740951A2EP-4740951-A2

Abstract

Provided herein are methods related to detecting overexpression of an oncogene through translocations in the immunoglobulin heavy (IGH) locus, as well as methods of treatment, uses, and kits related thereto. As demonstrated herein, IGH translocations lead to oncogene overexpression when the distance from a breakpoint of the translocation to the transcription start site (TSS) of an oncogene is within 0-1.3 Mb. As such, detecting IGH translocations in which a breakpoint is 1.3Mb or less from an oncogene TSS may find use, e.g., in detecting oncogene overexpression, providing assessment/diagnosis, identifying individuals for treatment, selecting therapies, identifying treatment options, and treating or delaying progression of cancer, e.g., using relevant targeted and/or non-targeted therapies.

Inventors

  • ROSENZWEIG, MARK
  • ZHONG, LEI
  • ERBACH, Rachel

Assignees

  • Foundation Medicine, Inc.

Dates

Publication Date
20260513
Application Date
20211221

Claims (15)

  1. A method of detecting overexpression of an oncogene, the method comprising detecting in a sample from an individual a presence of a translocation comprising a first breakpoint in the immunoglobulin heavy (IGH) locus and a second breakpoint, wherein the second breakpoint of the translocation is 1.3Mb or less from a transcription start site (TSS) of the oncogene.
  2. A method of identifying one or more treatment options for an individual having cancer, the method comprising: a) acquiring knowledge of a translocation comprising a first breakpoint in the IGH locus and a second breakpoint in a sample from an individual, wherein the second breakpoint is 1.3Mb or less from a TSS of an oncogene; and b) generating a report comprising one or more treatment options identified for the individual based at least in part on said knowledge, wherein the one or more treatment options comprise a targeted therapy that inhibits expression and/or activity of a protein product of the oncogene.
  3. A method of identifying an individual having cancer who may benefit from a treatment comprising a targeted therapy, the method comprising acquiring knowledge of a translocation comprising a first breakpoint in the IGH locus and a second breakpoint in a sample from the individual, wherein the second breakpoint is 1.3Mb or less from a TSS of an oncogene, and wherein presence of the second breakpoint 1.3Mb or less from the TSS of the oncogene in the sample identifies the individual as one who may benefit from a targeted therapy comprising an agent that inhibits expression and/or activity of a protein product of the oncogene.
  4. A method of selecting a therapy for an individual having cancer, the method comprising acquiring knowledge of a translocation comprising a first breakpoint in the IGH locus and a second breakpoint in a sample from the individual, wherein the second breakpoint is 1.3Mb or less from a TSS of an oncogene, and wherein the detection of the second breakpoint 1.3Mb or less from the TSS of the oncogene in the sample identifies the individual as one who may benefit from a targeted therapy comprising an agent that inhibits expression and/or activity of a protein product of the oncogene.
  5. The method according to any one of claims 2 to 4, wherein the acquiring knowledge of the translocation comprises detecting the presence of the translocation in a sample from the individual.
  6. The method according to any one of claims 2 to 5, wherein the targeted therapy comprises (a) an antibody that specifically binds a protein product of the oncogene, (b) a compound that inhibits an activity of a protein product of the oncogene, or (c) a nucleic acid that inhibits expression of a protein product of the oncogene.
  7. The method according to claim 6 wherein the targeted therapy comprises: a) an antibody that inhibits expression and/or activity of a protein product of the oncogene; b) a compound that inhibits an enzymatic activity of the protein product of the oncogene, optionally wherein the compound is a competitive inhibitor of the protein product or wherein the compound is a non-competitive inhibitor of the protein product; or c) an antisense nucleic acid, ribozyme, siRNA, shRNA, miRNA, gRNA, or triple helix nucleic acid that inhibits expression of a protein product of the oncogene.
  8. A method for generating a personalized cancer treatment report, comprising: (a) obtaining a sample from an individual; (b) detecting a presence of a translocation comprising a first breakpoint in the IGH locus and a second breakpoint in the sample, wherein the second breakpoint is 1.3Mb or less from a TSS of an oncogene; and (c) providing a report comprising information on the oncogene, the translocation, or both.
  9. The method according to any one of claims 1 to 8, wherein the oncogene is CCND1, MYEOV, MYC, MAF, MAFB, BCL6, BCL2, FGFR3, WHSC1, BCL3, NBEAP1, BCL10, BCL11A, CCND2, CCND3, CCNE1, CD44, CDK6, CEBPA, CEBPB, CEBPD, CEBPE, CRLF2, ID4, DDX6, DUX4, EPOR, GPR34, FCRL4, FCGR2B, IRF4, IRF8, CD274, PDCD1LG2, LHX2, LHX4, PAX5, IGF2BP1, TNFSF13, MALT1, FOXP1, IL3, miR-125b-1, MUC1, SOX5 or MYCN.
  10. The method according to any one of claims 2 to 9, wherein the cancer is multiple myeloma (MM), B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma unclassified, acute myeloid leukemia (AML), follicular lymphoma (FL), Burkitt lymphoma, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphoma (NHL), B-cell non-Hodgkin's lymphoma (B-NHL), Waldenstroms lymphoma, extranodal lymphoma, mantle cell lymphoma (MCL), mature B cell neoplasm, hairy cell leukemia (HCL), hairy cell leukemia variant (HCL-v), splenic marginal zone lymphoma (SMZL), nodal marginal zone lymphoma, extranodal marginal zone lymphoma, MALT lymphoma, myeloproliferative neoplasm (MPN), skin lymphoma, lymphoproliferative disease, primary mediastinal large B-cell lymphoma (PMBCL), plasmablastic lymphoma, chronic lymphocytic leukemia (CLL), small cell lymphoma (SLL), Hodgkin's lymphoma (HL), bone marrow lymph proliferative disease, myelodysplastic syndrome, or angioimmunoblastic T-cell lymphoma (AITL).
  11. The method according to any one of claims 2 to 10, wherein: a) the oncogene is MYC, the targeted therapy comprises a MYC inhibitor, and the cancer is DLBCL, B-cell lymphoma, Burkitt lymphoma, multiple myeloma, ALL, B-ALL, NHL, MCL, mature B cell neoplasm, MPN, skin lymphoma, CLL, or lymphoproliferative disease; b) the oncogene is BCL2, the targeted therapy comprises a BCL2 inhibitor, and the cancer is DLBCL, FL, B-cell lymphoma, ALL, CLL, HL, NHL, bone marrow lymph proliferative disease, or lymphoproliferative disease; c) the oncogene is BCL6, the targeted therapy comprises a BCL6 inhibitor, and the cancer is DLBCL, FL, multiple myeloma, SMZL, NHL, PMBCL, or plasmablastic lymphoma; d) the oncogene is CCND1, the targeted therapy comprises a CDK inhibitor, and the cancer is multiple myeloma, B-cell lymphoma, AML, DLBCL, or FL; e) the oncogene is MAF, the targeted therapy comprises a MAF inhibitor, and the cancer is multiple myeloma, CLL, ALL, AITL, or DLBCL; f) the oncogene is MAFB, the targeted therapy comprises a MAFB inhibitor, and the cancer is multiple myeloma, ALL, B-ALL, or DLBCL; or g) the oncogene is WHSC1 or FGFR3, the targeted therapy comprises a WHSC1 inhibitor, an FGFR3 inhibitor, or a pan-FGFR inhibitor, and the cancer is multiple myeloma or DLBCL
  12. The method according to any one of claims 1 to 11, wherein the translocation results in at least a 2-fold increase, at least a 5-fold increase, or at least a 20-fold increase in expression of the oncogene, as compared to a reference.
  13. The method according to any one of claims 1, or 5 to 12, wherein the translocation is detected in the sample by one or more methods selected from the group consisting of next-generation sequencing (NGS), a nucleic acid hybridization assay, an amplification-based assay, a PCR-RFLP assay, real-time or quantitative PCR, sequencing, a screening analysis, FISH, spectral karyotyping or MFISH, comparative genomic hybridization, in situ hybridization, sequence-specific priming (SSP) PCR, HPLC, and mass-spectrometric genotyping.
  14. The method according to any one of claims 1, or 5 to 13, wherein the sample: a) is a nucleic acid sample; b) is a nucleic acid sample and comprises cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA); c) comprises fluid, protein, cells, or tissue; d) is from a tumor biopsy or specimen; or e) the sample comprises a circulating tumor cell.
  15. The method according to any one of claims 1 to 14, wherein the translocation comprises translocation of one or more enhancers of the IGH locus with a different region of the genome.

Description

CROSS-REFERENCE TO RELATED APPLICATION This application claims the benefit of U.S. Provisional Application 63/129,286, filed December 22, 2020, which is hereby incorporated by reference in its entirety. FIELD Provided herein are methods related to detecting overexpression of an oncogene through translocations in the immunoglobulin heavy (IGH) locus, as well as methods of diagnosis/treatment, uses, and kits related thereto. BACKGROUND Translocations involving the immunoglobulin heavy (IGH) locus at the chromosome band 14q32 have been reported in a wide range of hematological malignancies, most frequently in B-cell lymphomas (Küppers, R. (2005) Nat. Rev. Cancer 5:251-262) and multiple myeloma (MM) (Jiménez, C. et at (2016) J. Mol. Diagnostics 19:1-8; Kuehl, W.M. and Bergsagel, P.L. (2002) Nat. Rev. Cancer 2:175-187), and less commonly, but recurrently, in acute lymphoblastic leukemia (ALL) (Jeffries, S.J. et al. (2014) Haematologica 99:1334-1342; Chapiro, E. et al (2013) Cancer Genet. 206:162-173; Woo, J.S. et al. (2014) Exp. Hematol. Oncol. 3:16). Juxtaposition of oncogenes to the IGH locus is thought to drive oncogene overexpression due to the influence of strong IGH transcriptional enhancers, which is essential for oncogenesis. Multiple IGH rearrangements have established diagnostic, prognostic, and/or therapeutic roles in the routine clinical management of a variety of hematological malignancies (Dupain, C. et at (2017) Mol. Ther. Nucleic Acid 6:315-326; Copie-Bergman, C. et al. (2015) Blood 126:2466-2474; Xu-Monette, Z.Y. et al. (2015) Mod. Pathol. 28:1555-1573; De Braekeleer, M. et al. (2016) Mod. Clin. Oncol. 4:682-694; Manier, S. et al (2016) Nal. Rev. Clin. Oncol doi:10.1038/nrclinonc.2016.122; Sawyer, J. R. (2011) Cancer Genet. 204:3-12). For example, t(8;14)(q24;q32) (IGH-MYC) is the diagnostic chromosomal translocation in Burkitt lymphoma, observed in ~80% of these tumors (Hecht, J.L. et al. (2000) J. Clin, Oncol. 18:3707-3721). The t(X;14)(p22;q32) (IGH-CRLF2) is associated with poor prognosis in patients with ALL (Moorman, A.V. et al. (2012) J. Clin. Oncol. 30:3100-3108; Russell, L.I. et al. (2014) J. Clin. Oncol. 32:1453-1462), whereas co-occurrence of IGH-MYC with IGH-BCL2 and/or IGH-BCL6 translocations, known as "double hit" or "triple hit," correlates with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) (Zelenetz, A.D. et al. (2016) J. Natl. Compr. Canc. Netw. 14:196-231). Moreover, the presence of IGH translocations may suggest different treatment options. For example, t(4;14) (IGH-FGFR3/MMSET), t(14;16) (IGH-MAF), or t(14;20) (IGH-MAFB) translocations define a subgroup of high-risk MM patients with poor prognosis using conventional therapies, whereas patients with t(4;14) have been reported to achieve better outcome with bortezomib- or lenalidomide-containing regimens (Kalff, A. et al. (2012) Blood Cancer J.. 2:e89-8). Patients with t(11;14)(q13;q32) (IGH-CCND1)-positive mantle cell lymphoma (MCL) have benefitted from the CDK4/6 inhibitor palbociclib (Leonard, J.P. et al. (2013) Blood 119:4597-4607). IGH translocation with 18q21 may result in upregulation of either BCL2 (Nunez, G. et al. (1989) Proc. Natl. Acad. Sci. 86:4589-4593; Han, Y. et al. (2013) Zhonghua Yi Xue Yi Chuan Xue Za Zhi 30:143-147; Monni, O. et al. (1999) Leuk. Lymphoma 34:45-52; Maeshima, A.M. et al. (2013) Cancer Sci. 104:952-957), which may suggest increased sensitivity to BCL2 inhibitors such as venetoclax (Souers, A.J. et al. (2013) Nat. Med. 19:202-208; Ross, J. et al. (2015) Blood 126:2975), or of MALT1 (Sanchez-Izquierdo, D. et al. (2003) Blood 101:4539-4546; Ye, H. et al. (2005) J. Pathol. 205:293-301), a positive regulator of NF-kB signaling (Ho, L. et al. (2005) Blood doi:10.1182/blood-2004-06-2297; Du, M.Q. (2017) Best Pract. Res. Clin. Haematol.. doi:10.1016/j.beha.2016.09.002; Schulze-Luehrmann, J. and Ghosh, S. (2006) Immunity 25:701-715) located 4.5 Mb from BCL2 and not appreciably linked to venetoclax sensitivity. Therefore, accurate and consistent detection and description of IGH translocations is of special clinical importance in disease diagnosis, classification, and management. Currently, fluorescence in situ hybridization (FISH) is routinely used in clinical care to detect chromosomal translocations. This technique involves sequential use of several commercially available break-apart fluorescent probes, followed by expert interpretation of the signals. Although FISH has high sensitivity and specificity, dependency on probes restricts the analysis to the translocations for which specific probes are designed, and only a limited number of translocations can be assessed at a time (Gozzetti, A. and Le Beau, M.M. (2000) Semin. Hematol. 37:320-333). FISH does not provide precise breakpoint information, due to the low-resolution nature of hybridization, and limited data suggests that not all observed IGH translocations lead to oncogene overexpression (Santra, M. et al. (2003) Blood 101: