This study will be conducted in 2 parts. The first part is a phase 1 single-agent dose escalation,optimization, and expansion study of tegavivint in patients with advanced HCC after failure of at least one line of prior systemic therapy. In the second part of the study, the combination of tegavivint plus pembrolizumab will be assessed with a limited dose escalation followed by a randomized dose optimization.

Start Date13 Sep 2023

Sponsor / Collaborator

Iterion Therapeutics, Inc.

NCT03459469 / CompletedPhase 1

Phase 1 Trial of BC2059 (Tegavivint) in Patients With Unresectable Desmoid Tumor

Phase I, open-label, non-randomized study to evaluate safety of BC2059 administered intravenously to subjects with proven primary or recurrent desmoid tumor that is unresectable and symptomatic or progressive.

Start Date15 Jul 2018

Sponsor / Collaborator

Iterion Therapeutics, Inc.

100 Clinical Results associated with Iterion Therapeutics, Inc.

0 Patents (Medical) associated with Iterion Therapeutics, Inc.

Literatures (Medical) associated with Iterion Therapeutics, Inc.

10 Jul 2023·Cancers

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

Article

Author: Mohan, Dipika R ; Lerario, Antonio M ; Penny, Morgan K ; Chukkapalli, Sahiti ; Converso-Baran, Kimber ; Giordano, Thomas J ; Rey, Carmen González Del ; Han, Ruolan ; Hammer, Gary D ; Basham, Kaitlin J ; LaPensee, Chris ; Hoenerhoff, Mark J ; Newman, Erika A ; Suárez-Fernández, Laura

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. To address this question, we analyzed ACC transcriptome data and identified a novel Wnt/β-catenin-associated signature in ACC enriched for the extracellular matrix (ECM) and predictive of poor survival. This suggested an oncogenic role for Wnt/β-catenin in regulating the ACC microenvironment. We further investigated the minor fibrillar collagen, collagen XI alpha 1 (COL11A1), and found that COL11A1 expression originates specifically from cancer cells and is strongly correlated with both Wnt/β-catenin activation and poor patient survival. Inhibition of constitutively active Wnt/β-catenin signaling in the human ACC cell line, NCI-H295R, significantly reduced the expression of COL11A1 and other ECM components and decreased cancer cell viability. To investigate the preclinical potential of Wnt/β-catenin inhibition in the adrenal microenvironment, we developed a minimally invasive orthotopic xenograft model of ACC and demonstrated that treatment with the newly developed Wnt/β-catenin:TBL1 inhibitor Tegavivint significantly reduced tumor growth. Together, our data support that the inhibition of aberrantly active Wnt/β-catenin disrupts transcriptional reprogramming of the microenvironment and reduces ACC growth and survival. Furthermore, this β-catenin-dependent oncogenic program can be therapeutically targeted with a newly developed Wnt/β-catenin inhibitor. These results show promise for the further clinical development of Wnt/β-catenin inhibitors in ACC and unveil a novel Wnt/β-catenin-regulated transcriptome.

15 Aug 2020·Cancer Research

Abstract 3955: The role of the Wnt/Beta-catenin pathway in adrenocortical carcinoma

Author: Giordano, Thomas J. ; Penny, Morgan K. ; Lerario, Antonio M. ; Hammer, Gary D. ; LaPensee, Chris ; Newman, Erika A. ; Han, Ruolan

AbstractAdrenocortical carcinoma (ACC) is an aggressive cancer that affects 1-2 people per million in the United States annually. The only option for cure is surgical resection, and the 5-year survival rate for ACC remains low at 35%. Improved understanding of this disease is needed to develop rational therapies. Genomic alterations activating Wnt/Beta-catenin signaling occur in approximately 40% of ACCs and are associated with poor prognosis. However, the biologic consequences of constitutive Wnt/Beta-catenin activation in ACC are poorly understood. Treatment with Beta-catenin inhibitors BC2059 and PKF115-584 decreases viability in the NCI-H295R ACC cell line, which harbors an activating CTNNB1 (Beta-catenin) mutation. In addition, BC2059 significantly inhibits NCI-H295R tumor growth in an orthotopic xenograft model. Our data supports the hypothesis that Wnt/Beta-catenin regulates ACC cell growth and survival. To better characterize transcriptional programs engaged by Wnt/Beta-catenin signaling in ACC, we performed independent component analysis on The Cancer Genome Atlas (TCGA) ACC transcriptome dataset to identify components of coordinately expressed genes. One component is significantly enriched for Wnt signaling activity and is strongly associated with somatic CTNNB1 (Beta-catenin) mutation. The Wnt-enriched component is also enriched for extracellular matrix (ECM)-receptor interaction, including (but not restricted to) expression of COL11A1 (Collagen alpha-1(XI)), COL26A1 (Collagen alpha-1(XXVI)), LAMC3 (Laminin, gamma 3), and ITGA2 (Integrin, alpha 2), suggesting that Wnt/Beta-catenin is regulating composition of the ACC microenvironment. Current literature supports that ACC has relatively low contribution from stromal cells, suggesting that tumor-cell-derived ECM may have substantial biologic effect in the tumor microenvironment. To follow up on these observations, we performed immunohistochemical staining on tissue microarrays containing 97 ACC samples. We observed a strong correlation of COL11A1 expression and nuclear Beta-catenin localization, suggesting COL11A1 may be regulated by Wnt/Beta-catenin. Furthermore, COL11A1 expression is significantly associated with decreased overall survival and decreased event-free survival. Cell culture studies confirm that expression of COL11A1, COL26A1, and LAMC3 is significantly reduced in NCI-H295R cells treated with PKF115-584 or BC2059, consistent with our hypothesis that Wnt/Beta-catenin regulates expression of ECM components in ACC. These results illustrate a novel role for Wnt/Beta-catenin activity in ACC, and suggest that Beta-catenin-associated expression of ECM components may contribute to cancer cell survival and disease progression.Citation Format: Morgan K. Penny, Antonio M. Lerario, Chris LaPensee, Thomas J. Giordano, Ruolan Han, Erika A. Newman, Gary D. Hammer. The role of the Wnt/Beta-catenin pathway in adrenocortical carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3955.

01 Jul 2019·Cancer Research

Abstract 3036: BRD4 degrader and inhibitor of beta catenin-TCF7L2 are synergistically active against human AML cells resistant to BET inhibitor

Author: Khoury, Joseph D. ; Manshouri, Taghi ; Soldi, Raffaella ; Bhalla, Kapil N. ; Horrigan, Steve ; Saenz, Dyana T. ; Mill, Christopher P. ; Fiskus, Warren C. ; Sharma, Sunil ; Verstovesek, Srdan

AbstractTreatment with bromodomain and extra-terminal protein inhibitor (BETi) reduces in vivo AML cell burden, inducing clinical remissions in AML. Yet, resistance to BETi treatment develops uniformly. Here, following at least 10 exposures of secondary (s) AML control (parental) SET2 and HEL92.1.7 cells to 1.0 µM of the BETi OTX015 for 48 hours followed by full recovery, we generated BETi persister-resistant (BETi-P/R) SET2-P/R and HEL-P/R cells. These cells showed > 10-fold resistance to OTX015 and cross-resistance to other BETis. Compared to the controls, SET2-P/R and HEL-P/R cells lacked additional genetic alterations or altered levels of TRIM33, SPOP, DUB3 or phosphorylated BRD4 (previously described mechanisms of BETi-resistance). However, SET2-P/R and HEL-P/R cells demonstrated significantly higher nuclear levels of β-catenin, the transcription factor TCF7L2 and adaptor protein TBL1X (TBL1), associated with increased expression of TCF7L2 targets, including c-Myc, Cyclin D1, TERT and Survivin. ATAC-Seq and ChIP-Seq (H3K27Ac mark) analyses showed significant gain of peaks and active enhancers in HEL-P/R over HEL92.1.7 cells, with enrichment of STAT5, MYC, PU.1 and GATA2 binding sites, as well as newly gained peaks in the enhancers of JAK1/2, RUNX1, PU.1, MYC, BCL2L1 and CTNNB1. RNA-Seq analysis showed significant increase/decrease in mRNA expressions (340/247), with induction of gene-sets involving MYC/MAX, STAT5, NFkB and TCF7L2 targets. QPCR and Western analyses confirmed increase in the mRNA and protein levels of TCF7L2, c-Myc, Survivin and PIM1 in HEL-P/R over HEL92.1.7 cells. Also, confocal microscopy demonstrated increased binding of β-catenin with TBL1 and TCF7L2 in the nucleus in BETi-P/R sAML cells. β-catenin inhibitor BC2059, which disrupts binding of nuclear β-catenin with TBL1 and TCF7L2 and depletes β-catenin levels, exerted similar lethality in BETi-P/R sAML and control sAML cells. Both shRNA-mediated knockdown of BRD4 and BRD4-PROTAC (proteolysis-targeting chimera) ARV-771 (Arvinas, Inc.), which degrades BRD4/3/2, induced similar level of apoptosis in BETi-P/R and control sAML cells. Co-treatment with ARV-771 and BC2059 synergistically induced lethality in BETi-P/R sAML cells as well as in patient-derived, CD34+ sAML BPCs (combination indices < 1.0). This was associated with marked attenuation of c-Myc, TCF4, Survivin, CDK6, PIM1 and Bcl-xL levels. Also, compared to each agent alone, in vivo treatment with ARV-771 (30 mg/kg SQ daily x 5, per week) and BC2059 (30 mg/kg IP BIW, per week) for 3 weeks, significantly reduced sAML burden and improved survival of NSG mice engrafted with HEL-P/R cells (p < 0.01). Thus, increased levels and activity of β-catenin-TCF7L2-MYC axis is mechanistically responsible for BETi-P/R, and co-targeting with BRD4 degrader and β-catenin-TCF7L2 inhibitor is a promising therapeutic strategy against BETi-P/R sAML BPCs.Citation Format: Dyana T. Saenz, Warren C. Fiskus, Taghi Manshouri, Christopher P. Mill, Steve Horrigan, Raffaella Soldi, Joseph D. Khoury, Sunil Sharma, Srdan Verstovesek, Kapil N. Bhalla. BRD4 degrader and inhibitor of beta catenin-TCF7L2 are synergistically active against human AML cells resistant to BET inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3036.

News (Medical) associated with Iterion Therapeutics, Inc.

20 Feb 2024

·www.prnewswire.com

Iterion Therapeutics Announces First Patient Dosed in Phase 1b/2a Clinical Trial of Tegavivint in Patients with Advanced Hepatocellular Carcinoma Who Have Failed One or More Systemic Treatments

HOUSTON, Feb. 20, 2024 /PRNewswire/ -- Iterion Therapeutics, an oncology-focused biopharmaceutical company developing small molecule inhibitors of Transducin beta-like protein 1 (TBL1), a downstream target in the Wnt/beta-catenin signaling pathway, announced today it is actively enrolling a Phase 1b/2a clinical trial of its lead molecule, tegavivint, in patients with advanced hepatocellular carcinoma (HCC) that have failed at least one line of systemic therapy. Activation of the Wnt/beta-catenin pathway is a hallmark of several forms of cancer, including HCC, in which approximately half of patients have tumors with Wnt-activating mutations. Unfortunately, key members of this pathway (including beta-catenin) have either been resistant to conventional drug development or plagued with off-target toxicities. Extensive pre-clinical study results across multiple tumor types suggest that TBL1 is a downstream target that is necessary for Wnt/beta-catenin-activated oncogenesis. TBL1 binds nuclear beta-catenin thus stabilizing the transcription complex necessary to turn on cancer-causing genes. Tegavivint's direct binding to TBL1 displaces beta-catenin and disrupts this complex, allowing the degradation of free nuclear beta-catenin and preventing downstream oncogenic gene transcription. "By targeting TBL1, tegavivint promotes potent inhibition of nuclear beta-catenin oncogenic activity without inducing toxicities observed for other drugs that are upstream in the Wnt-pathway" stated Rahul Aras, Ph.D., President & CEO for Iterion Therapeutics. "HCC is a devastating cancer with a high prevalence of Wnt-activated tumors, and we are committed to developing tegavivint for this patient population that otherwise has very few therapeutic options". HCC is the sixth most commonly diagnosed cancer and the third leading cause of cancer death globally. In 2023, the National Cancer Institute (NCI) estimated 41,210 new HCC cases diagnosed in the US, with 29,380 deaths. The overall prognosis is poor, with a 5-year survival rate of 21.6%. Wnt-activation plays multiple roles in the pathogenesis of HCC by initiating tumorigenesis, promoting metastasis, and enhancing an immunosuppressive tumor microenvironment. Patients with elevated nuclear beta-catenin and TBL1 demonstrate particularly poor outcomes. Despite this, there are no FDA-approved therapies targeting this pathway. "There is a desperate need for novel targeted therapies to address the large unmet clinical need in HCC" expressed Casey Cunningham, M.D., Chief Medical Officer for Iterion Therapeutics. "Tegavivint has demonstrated excellent tolerability and has the potential to address a large portion of this population by directly inhibiting beta-catenin's oncogenic activity". The ongoing clinical trial will enroll approximately 35 patients in dose escalation and optimization cohorts of patients with unresectable locally advanced or metastatic HCC that have failed at least one line of systemic treatment. The study will evaluate safety and clinical efficacy in addition to pharmacokinetic and pharmacodynamic markers to determine a Recommended Phase 2 Dose (RP2D) in HCC. Tegavivint has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 clinical study of patients with desmoid tumors. For more information about this Phase 1b/2a clinical trial of tegavivint in patients with advanced HCC, please visit using the identifier NCT05797805. About Iterion Therapeutics Iterion Therapeutics is a clinical-stage biotechnology company developing novel cancer therapeutics. The company's lead product, tegavivint, is a potent and selective small molecule that binds to Transducin beta-like protein 1 (TBL1), a newly characterized target in the Wnt/beta-catenin pathway. TBL1 binds to nuclear beta-catenin, forming an active transcription complex that prevents nuclear degradation of beta-catenin and activates genes necessary for the Wnt/beta-catenin oncogenic activity. Tegavivint binds to TBL1 and disrupts the interaction between beta-catenin and TBL1, thus promoting the degradation of nuclear beta-catenin and preventing the transcription of Wnt/beta-catenin targeted oncogenes. Iterion is currently advancing multiple clinical programs investigating tegavivint in cancer indications where nuclear beta-catenin overexpression is a known factor. These include Iterion-sponsored programs in hepatocellular carcinoma (HCC), as well as investigator-sponsored programs in non-small cell lung cancer (NSCLC), diffuse large B-cell lymphomas (DLBCL), and pediatric solid tumors. Iterion is the recipient of combined a $18.9 million in Product Development Awards from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information on Iterion, please visit . SOURCE Iterion Therapeutics

Phase 1

16 May 2023

·www.prnewswire.com

Iterion Therapeutics Announces the Initiation of a Phase 1 Clinical Trial for Tegavivint in Patients with c-Myc-overexpressing Relapsed or Refractory Large B-Cell Lymphomas

HOUSTON, May 16, 2023 /PRNewswire/ -- Iterion Therapeutics, a leading biopharmaceutical company dedicated to the development of innovative treatments for cancer, announced today its collaboration in a Phase 1 clinical trial for tegavivint in patients with relapsed or refractory c-Myc-overexpressing large B-cell lymphomas. The first patient has been enrolled to this National Cancer Institute-funded study, which is being conducted at The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus, Ohio. Continue Reading Diffuse large B-cell lymphomas (DLBCL) are a type of Non-Hodgkin lymphoma (NHL) that originates from white blood cells. It is estimated that each year there are more than 20,000 patients diagnosed with DLBCL resulting in greater than 7,000 deaths annually. In a subset of DLBCL, the oncogene c-MYC is overexpressed through genetic mechanisms. Patients with c-Myc-overexpressing DLBCL are less likely to respond to currently available therapies, with an overall survival (OS) rate of 30% at 2 years compared to 76% in c-MYC negative patients. Patients with relapsed/refractory c-MYC-overexpressing DLBCL represent a significant unmet clinical as their prognosis is particularly poor with very limited effective treatment options. Iterion Therapeutics Announces the Initiation of a Phase 1 Clinical Trial for Tegavivint in Patients with c-Myc-overexpressing Relapsed or Refractory Large B-Cell Lymphomas Tweet this Tegavivint is a first-in-class small molecule inhibitor of Transducin beta-like protein 1 (TBL1), that has demonstrated safety, clinical and pharmacodynamic activity in a Phase 1 study of patients with desmoid tumors. TBL1 is an exchange adaptor protein known to regulate protein stability and acts as a master regulator of the Wnt-signaling pathway by binding to nuclear beta-catenin to protect it from degradation and promote its downstream transcriptional activity. TBL1 is highly expressed in DLBCL compared to normal B cells, with expression inversely correlated with OS in DLBCL patients treated with standard first-line treatment. Pre-clinical studies have shown tegavivint promotes DLBCL cell death in vitro and in vivo through modulating stability of key oncogenic proteins, including c-Myc. "TBL1 and MYC have long been therapeutic targets of interest in DLBCL" states Lapo Alinari, MD, PhD, a hematologist with the OSUCCC – James and assistant professor at The Ohio State University College of Medicine. "Tegavivint provides the first opportunity to treat DLBCL patients with a targeted therapy toward TBL1 and the pre-clinical data suggests that by doing so, we can also impact MYC protein levels resulting in anti-tumor activity". The Phase 1 dose-escalation study will enroll up to 20 patients with relapsed or refractory c-Myc-overexpressing DLBCL, who have failed at least two lines of prior treatment. The primary endpoint for the study will be to assess safety, measure dose limiting toxicities (DLTs), and define a recommended phase 2 dose (RP2D). Patients will also be followed for clinical responses, pharmacokinetics and changes in pharmacodynamic markers. "While there have been significant advances in treatment of DLBCL, the patients targeted in this study are known to have poor prognosis and poor response to the current standard of care", states Casey Cunningham, MD, Chief Medical Officer at Iterion. "The pre-clinical data suggests that tegavivint may provide a therapeutic option where one does not currently exist" For more information about the Phase 1 clinical trial of tegavivint in patients with large B-cell lymphomas, please visit ClinicalTrials.gov using the identifier NCT05755087. This trial is funded by the National Cancer Institute with additional support from Iterion, manufacturer of the study drug, Tegavivint. Patients on this study receive the study drug at no cost while on the clinical trial. About Iterion Therapeutics Iterion Therapeutics is a clinical-stage biotechnology company developing novel cancer therapeutics. The company's lead product, tegavivint, is a potent and selective small molecule that binds to Transducin Beta-Like Protein 1 (TBL1) in the nucleus, inhibiting nuclear beta-catenin signaling and oncogenic activity. Increased expression of beta-catenin and TBL1 are associated with metastasis and poor prognosis in a broad range of tumor types, making TBL1 an emerging, high-value cancer target of interest. Iterion is currently advancing multiple clinical programs investigating tegavivint in cancer indications where nuclear beta-catenin overexpression is a known factor. These include Iterion-sponsored programs in hepatocellular cancer (HCC), as well as investigator-sponsored programs in acute myeloid leukemia (AML), non-small cell lung cancer (NSCLC), and solid tumors. Iterion is the recipient of an up to $18.9 million Product Development Award from the Cancer Prevention and Research Institute of Texas (CPRIT). For more information on Iterion, please visit . SOURCE Iterion Therapeutics

Phase 1

100 Deals associated with Iterion Therapeutics, Inc.

100 Translational Medicine associated with Iterion Therapeutics, Inc.

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