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Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors

ABSTRACT: This phase I/II trial evaluates the highest safe dose, side effects, and possible benefits of tegavivint in treating patients with solid tumors that has come back (recurrent) or does not respond to treatment (refractory). Tegavivint interferes with the binding of beta-catenin to TBL1, which may help stop the growth of tumor cells by blocking the signals passed from one molecule to another inside a cell that tell a cell to grow.

DISEASE(S): Sarcoma, Ewing,Carcinoma,Refractory Desmoid Fibromatosis,Solid Pseudopapillary Neoplasm Of The Pancreas,Recurrent Desmoid Fibromatosis,Neuroblastoma,Endometrial Neoplasms,Fibroma,Pancreatic Ductal Adenocarcinoma,Neoplasms,Colorectal Carcinoma,Refractory Hepatocellular Carcinoma,Recurrent Hepatoblastoma,Recurrent Malignant Solid Neoplasm,Fibromatosis, Aggressive,Osteosarcoma,Ovarian Carcinoma,Colorectal Neoplasms,Recurrent Ewing Sarcoma,Pancreatic Neoplasms,Hepatoblastoma,Refractory Non-hodgkin Lymphoma,Refractory Osteosarcoma,Refractory Hepatoblastoma,Sarcoma,Melanoma,Recurrent Hepatocellular Carcinoma,Refractory Malignant Solid Neoplasm,Lymphoma,Recurrent Non-hodgkin Lymphoma,Recurrent Osteosarcoma,Refractory Ewing Sarcoma,Lymphoma, Non-hodgkin,Wilms Tumor,Carcinoma, Hepatocellular,Endometrial Carcinoma

PROVIDER: 2374785 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Constitutive activation of the anti-apoptotic NF-ÎºB signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL) that is characterized by adverse survival. Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-ÎºB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 mutants in the NF-ÎºB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of Î²-Catenin and its destruction complex consisting of APC, AXIN1, CK1Î± and GSK3Î² to oncogenic CARMA1. Recruitment of the Î²-Catenin destruction complex was independent of CARMA1-BCL10-MALT1 (CBM) complex formation or constitutive NF-ÎºB activation and promoted the stabilization of Î²-Catenin. Elevated Î²-Catenin expression was detected in cell lines and biopsies from ABC DLBCL that rely on chronic BCR signaling. Increased Î²-Catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF dependent transcriptional activation in response to WNT signaling. In conjunction with NF-ÎºB, Î²-Catenin enhanced expression of immune suppressive IL-10 and repressed anti-tumoral CCL3, indicating that Î²-Catenin may induce a favorable tumor microenvironment. Thus, parallel activation of NF-ÎºB and Î²-Catenin signaling by gain-of-function mutations in CARMA1 can augment WNT stimulation and is required for maintaining high expression of distinct NF-ÎºB target genes and can thereby trigger cell intrinsic and extrinsic processes that promote DLBCL lymphomagenesis. CARMA1 mutants were expressed in BJAB, an NF-ÎºB negative GCB DLBCL lymphoma cell line. Gene expression induced by GCB DLBCL derived CARMA1 L225LI mutant was compared with the empty vector (mock) control, CARMA1 WT, CARMA1 point mutant R35A and with CARMA1 double mutant R35A/L225LI.

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Tegavivint for the Treatment of Recurrent or Refractory Solid Tumors, Including Lymphomas and Desmoid Tumors

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