Targeting Oncogenic Wnt/β-Catenin Signaling in Adrenocortical Carcinoma Disrupts ECM Expression and Impairs Tumor Growth.

Adrenocortical carcinoma (ACC) is a rare but highly aggressive cancer with limited treatment options and poor survival for patients with advanced disease. An improved understanding of the transcriptional programs engaged in ACC will help direct rational, targeted therapies. Whereas activating mutations in Wnt/β-catenin signaling are frequently observed, the β-catenin-dependent transcriptional targets that promote tumor progression are poorly understood.

Preclinical efficacy of the Wnt/β-catenin pathway inhibitor BC2059 for the treatment of desmoid tumors.

Mutation in the CTNNB1 gene, leading to a deregulation of the WTN/β-catenin pathway, is a common feature of desmoid tumors (DTs). Many β-catenin inhibitors have recently been tested in clinical studies; however, BC2059 (also referred as Tegavivint), a selective inhibitor of nuclear β-catenin that works through binding TBL-1, is the only one being evaluated in a clinical study, specifically for treatment of desmoid tumor patients. Preclinical studies on BC2059 have shown activity in multiple myeloma, acute myeloid leukemia and osteosarcoma.

In vivo evaluation of the lysine-specific demethylase (KDM1A/LSD1) inhibitor SP-2577 (Seclidemstat) against pediatric sarcoma preclinical models: A report from the Pediatric Preclinical Testing Consortium (PPTC).

SP-2577(Seclidemstat), an inhibitor of lysine-specific demthylase KDM1A (LSD1) that is overexpressed in pediatric sarcomas, was evaluated against pediatric sarcoma xenografts. SP-2577 (100 mg/kg/day × 28 days) statistically significantly (p < .05) inhibited growth of three of eight Ewing sarcoma (EwS), four of five rhabdomyosarcoma (RMS), and four of six osteosarcoma (OS) xenografts.

Transducin β-like protein 1 controls multiple oncogenic networks in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma and is characterized by a remarkable heterogeneity with diverse variants that can be identified histologically and molecularly. Large-scale gene expression profiling studies have identified the germinal center B-cell (GCB-) and activated B-cell (ABC-) subtypes. Standard chemo-immunotherapy remains standard front line therapy, curing approximately two thirds of patients.

Tegavivint and the β-Catenin/ALDH Axis in Chemotherapy-Resistant and Metastatic Osteosarcoma.

Background: The Wnt/β-catenin pathway is closely associated with osteosarcoma (OS) development and metastatic progression. We investigated the antitumor activity of Tegavivint, a novel β-catenin/transducin β-like protein 1 (TBL1) inhibitor, against OS employing in vitro, ex vivo, and in vivo cell line and patient-derived xenograft (PDX) models that recapitulate high risk disease.

Methods: The antitumor efficacy of Tegavivint was evaluated in vitro using established OS and PDX-derived cell lines.

Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment.

This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively.

MEK1/2 inhibition suppresses tamoxifen toxicity on CNS glial progenitor cells.

It is increasingly apparent that treatment with a variety of anticancer agents often is associated with adverse neurological consequences. Clinical studies indicate that exposure even to tamoxifen (TMX), a putatively benign antihormonal agent widely used in breast cancer treatment, causes cognitive dysfunction and changes in CNS metabolism, hippocampal volume, and brain structure. We found that TMX is toxic for a variety of CNS cell populations in vitro and also increased cell death in the corpus callosum and reduced cell division in the mouse subventricular zone, the hippocampal dentate gyrus, and the corpus callosum.

Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system.

Background: Cancer treatment with a variety of chemotherapeutic agents often is associated with delayed adverse neurological consequences. Despite their clinical importance, almost nothing is known about the basis for such effects. It is not even known whether the occurrence of delayed adverse effects requires exposure to multiple chemotherapeutic agents, the presence of both chemotherapeutic agents and the body's own response to cancer, prolonged damage to the blood-brain barrier, inflammation or other such changes.

CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo.

Background: Chemotherapy in cancer patients can be associated with serious short- and long-term adverse neurological effects, such as leukoencephalopathy and cognitive impairment, even when therapy is delivered systemically. The underlying cellular basis for these adverse effects is poorly understood.

Results: We found that three mainstream chemotherapeutic agents--carmustine (BCNU), cisplatin, and cytosine arabinoside (cytarabine), representing two DNA cross-linking agents and an antimetabolite, respectively--applied at clinically relevant exposure levels to cultured cells are more toxic for the progenitor cells of the CNS and for nondividing oligodendrocytes than they are for multiple cancer cell lines.