Journal: Molecular Cancer Therapeutics

Abbreviation

Mol Cancer Ther

Publisher

American Association for Cancer Research

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ISSN

1535-7163
1538-8514

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Publications1 - 10 of 12
  • Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade
    Item type: Journal Article
    Hooper, Andrea T.; Marquette, Kimberly; Chang, Chao-Pei Betty; et al. (2022)
    Molecular Cancer Therapeutics
    Extra domain B splice variant of fibronectin (EDB+FN) is an extracellular matrix protein (ECM) deposited by tumor-associated fibroblasts, and is associated with tumor growth, angiogenesis, and invasion. We hypothesized that EDB+FN is a safe and abundant target for therapeutic intervention with an antibody-drug conjugate (ADC). We describe the generation, pharmacology, mechanism of action, and safety profile of an ADC specific for EDB+FN (EDB-ADC). EDB+FN is broadly expressed in the stroma of pancreatic, non-small cell lung (NSCLC), breast, ovarian, head and neck cancers, whereas restricted in normal tissues. In patient -derived xenograft (PDX), cell-line xenograft (CLX), and mouse syngeneic tumor models, EDB-ADC, conjugated to auristatin Aur0101 through site-specific technology, demonstrated potent antitumor growth inhibition. Increased phospho-histone H3, a pharmacodynamic biomarker of response, was observed intumor cells distal to the target site of tumor ECM after EDB-ADC treatment. EDB-ADC potentiated infiltration of immune cells, including CD3+ T lymphocytes into the tumor, providing rationale for the combination of EDB-ADC with immune check-point therapy. EDB-ADC and anti-PD-L1 combination in a syngeneic breast tumor model led to enhanced antitumor activity with sustained tumor regressions. In nonclinical safety studies in nonhuman primates, EDB-ADC had a well-tolerated safety profile without signs of either on-target toxicity or the off -target effects typically observed with ADCs that are conjugated through conventional conjugation methods. These data highlight the potential for EDB-ADC to specifically target the tumor microenvironment, provide robust therapeutic benefits against multiple tumor types, and enhance activity antitumor in com-bination with checkpoint blockade.
  • Potency-matched Dual Cytokine–Antibody Fusion Proteins for Cancer Therapy
    Item type: Journal Article
    De Luca, Roberto; Soltermann, Alex; Pretto, Francesca; et al. (2017)
    Molecular Cancer Therapeutics
  • Development of Multivalent FAP-Targeted Small Molecule–Drug Conjugates with Tailored MMAE Release Kinetics
    Item type: Journal Article
    Bocci, Matilde; Principi, Lucrezia; Neri, Dario; et al. (2025)
    Molecular Cancer Therapeutics
    Antibody–drug conjugates are one of the most diffused targeted therapeutic modalities for cancer treatment and consist of a tumor-targeted monoclonal antibody connected to a cytotoxic payload, which is released selectively at the tumor site. Small molecule–drug conjugates (SMDC) represent an alternative approach, in which the antibody is replaced by a tumor-homing small organic ligand. Thanks to their small molecular size, SMDCs are characterized by rapid extravasation and enhanced penetration in solid tumors compared with antibody–drug conjugates. We recently developed SMDCs targeting fibroblast activation protein (FAP), a cell surface endopeptidase abundant in the tumor microenvironment, using the highly specific FAP inhibitor OncoFAP as a targeting moiety. In this study, we compared the tumor-targeting properties and in vivo activity of SMDCs based on OncoFAP against products based on a stronger FAP inhibitor (i.e., trivalent OncoFAP), aiming to tune the release kinetic of the cytotoxic payload to the neoplastic site. We compared the kinetic profiles of the monovalent and trivalent derivatives of OncoFAP through in vivo and ex vivo biodistribution and therapy studies. The distinct in vivo monomethyl auristatin E (MMAE) release obtained for OncoFAP–GlyPro–MMAE and TriOncoFAP–GlyPro–MMAE did not lead to substantial differences in therapeutic efficacy in a preclinical FAP-positive cancer model.
  • Molecular Dosimetry of Temozolomide: Quantification of Critical Lesions, Correlation to Cell Death Responses, and Threshold Doses
    Item type: Journal Article
    Stratenwerth, Björn; Geisen, Susanne M.; He, Yang; et al. (2021)
    Molecular Cancer Therapeutics
    Temozolomide (TMZ) is a DNA-methylating agent used in cancer chemotherapy, notably for glioblastoma multiforme (GBM), where it is applied as a front-line drug. One of the DNA alkylation products of TMZ is the minor lesion O6-methylguanine (O6MeG), which is responsible for nearly all genotoxic, cytotoxic, and cytostatic effects induced in the low-dose range relevant for cancer therapy. Here, we addressed the question of how many O6MeG adducts are required to elicit cytotoxic responses. Adduct quantification revealed that O6MeG increases linearly with dose. The same was observed for DNA double-strand breaks (DSB) and p53ser15. Regarding apoptosis, hockeystick modeling indicated a possible threshold for A172 cells at 2.5 μmol/L TMZ, whereas for LN229 cells no threshold was detected. Cellular senescence, which is the main cellular response, also increased linearly, without a threshold. Using a dose of 20 μmol/L, which is achievable in a therapeutic setting, we determined that 14,000 adducts give rise to 32 DSBs (γH2AX foci) in A172 cells. This leads to 12% cell death and 35% of cells entering senescence. In LN229 cells, 20 μmol/L TMZ induced 20,600 O6MeG adducts, 66 DSBs (γH2AX foci), 24% apoptosis, and 52% senescence. The linear dose response and the genotoxic and cytotoxic effects observed at therapeutically relevant dose levels make it very likely that the TMZ target concentration triggers a significant cytotoxic and cytostatic effect in vivo. Despite a linear increase in the O6MeG adduct level, DSBs, and p53 activation, the low curative effect of TMZ results presumably from the low rate of apoptosis compared to senescence.
  • PSMA-Targeted Small Molecule–Drug Conjugates Based on a Postprolyl Peptidase–Cleavable Linker for the Treatment of Prostate Cancer
    Item type: Journal Article
    Georgiev, Tony; Puglioli, Sara; Principi, Lucrezia; et al. (2025)
    Molecular Cancer Therapeutics
    Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on the surface of cancerous prostate cells both in primary tumors and in metastases. Small organic ligands targeting PSMA have been broadly and successfully used to deliver radionuclide payloads to prostate cancer lesions. 177Lu-PSMA-617 (Pluvicto, a Novartis product) is a PSMA-targeted product that has been recently approved for the treatment of metastatic castration-resistant prostate cancer. By contrast, no small molecule–drug conjugates (SMDC) directed against PSMA have gained marketing authorization yet. In this article, we present the development of novel SMDCs generated by conjugating the tumor-targeting moiety of Pluvicto (here named “OncoPSMA”) to highly cytotoxic auristatin payloads through cleavable linkers, including valine–citrulline, disulfide bridges, and a recently described postprolyl peptidase–cleavable linker [glycine–proline (Gly-Pro)]. The efficiency of payload release at the cancer site and in healthy tissues was assessed via biodistribution studies using mass spectrometry quantification upon systemic administration in tumor-bearing mice. SMDCs based on the Gly-Pro linker mediated the highest payload release in solid tumors compared with widely utilized cathepsin B–cleavable and disulfide linkers. The in vivo efficacy of OncoPSMA-Gly-Pro-monomethyl auristatin E and OncoPSMA-Gly-Pro-monomethyl auristatin F was tested in therapy studies alone and in combination with an antibody–IL2 fusion protein, capable of preferential homing to solid tumors. Combination treatments resulted in complete and durable responses, highlighting the potential benefit of this therapeutic modality to patients with metastatic prostate cancer.
  • Differential antiproliferative mechanisms of novel derivative of benzimidazo[1,2-{alpha}]quinoline in colon cancer cells depending on their p53 status
    Item type: Journal Article
    Sedic, Mirela; Poznic, Miroslav; Gehrig, Peter; et al. (2008)
    Molecular Cancer Therapeutics
  • Selective Photodetection and Photodynamic Therapy for Prostate Cancer through Targeting of Proteolytic Activity
    Item type: Journal Article
    Zuluaga, M.F.; Sekkat, N.; Gabriel, D.; et al. (2013)
    Molecular Cancer Therapeutics
  • Optimizing the design and geometry of T cell engaging bispecific antibodies targeting CEA in colorectal cancer
    Item type: Journal Article
    Elsayed, Abdullah; Plüss, Louis; Nideroest, Larissa; et al. (2024)
    Molecular Cancer Therapeutics
    Metastatic colorectal cancer remains a leading cause of cancer-related deaths, with a 5-year survival rate of only 15%. T cell–engaging bispecific antibodies (TCBs) represent a class of biopharmaceuticals that redirect cytotoxic T cells toward tumor cells, thereby turning immunologically “cold” tumors into “hot” ones. The carcinoembryonic antigen (CEA) is an attractive tumor-associated antigen that is overexpressed in more than 98% of patients with colorectal cancer. In this study, we report the comparison of four different TCB formats employing the antibodies F4 (targeting human CEA) and 2C11 (targeting mouse CD3ε). These formats include both antibody fragment–based and IgG-based constructs, with either one or two binding specificities of the respective antibodies. The 2 + 1 arrangement, using an anti-CEA single-chain diabody fused to an anti-CD3 single-chain variable fragment, emerged as the most potent design, showing tumor killing at subnanomolar concentrations across three different CEA+ cell lines. The in vitro activity was three times greater in C57BL/6 mouse colon adenocarcinoma cells (MC38) expressing high levels of CEA compared with those expressing low levels, highlighting the impact of CEA density in this assay. The optimal TCB candidate was tested in two different immunocompetent mouse models of colorectal cancer and showed tumor growth retardation. Ex vivo analysis of tumor infiltrates showed an increase in CD4+ and CD8+ T cells upon TCB treatment. This study suggests that bivalent tumor targeting, monovalent T-cell targeting, and a short spatial separation are promising characteristics for CEA-targeting TCBs.
  • Immunotherapy with Immunocytokines and PD-1 Blockade Enhances the Anticancer Activity of Small Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX
    Item type: Journal Article
    Millul, Jacopo; Krudewig, Christiane; Zana, Aureliano; et al. (2021)
    Molecular Cancer Therapeutics
    Small molecule–drug conjugates (SMDCs) represent an alternative to conventional antitumor chemotherapeutic agents, with the potential to improve the therapeutic window of cytotoxic payloads through active delivery at the site of the disease. In this article, we describe novel combination therapies consisting of anti-carbonic anhydrase IX SMDCs combined with different immunomodulatory products. The therapeutic effect of the SMDCs was potentiated by combination with PD-1 blockade and with tumor-homing antibody–cytokine fusions in mouse models of renal cell carcinoma and colorectal cancer. The combination with L19-IL12, a fusion protein specific to the alternatively spliced EDB domain of fibronectin containing the murine IL12 moiety, was also active against large established tumors. Analysis of the microscopic structures of healthy organs performed 3 months after tumor eradication confirmed absence of pathologic abnormalities in the healthy kidney, liver, lung, stomach, and intestine. Our findings may be of clinical significance as they provide motivation for the development of combinations based on SMDCs and immunotherapy for the treatment of renal cell carcinoma and hypoxic tumors. © 2020 American Association for Cancer Research
  • Therapeutic Targeting of EZH2 and BET BRD4 in Pediatric Rhabdoid Tumors
    Item type: Journal Article
    Ishi, Yukitomo; Zhang, Yongzhan; Zhang, Ali; et al. (2022)
    Molecular Cancer Therapeutics
    Aberrant activity of the H3K27 modifiers EZH2 and BRD4 is an important oncogenic driver for atypical teratoid/rhabdoid tumor (AT/RT), and each is potentially a possible therapeutic target for treating AT/RT. We, therefore, determined whether targeting distinct histone modifier activities was an effective approach for treating AT/RT. The effects of EZH2 and BRD4 inhibition on histone modification, cell proliferation, and cell invasion were analyzed by immunoblotting, MTS assay, colony formation assay, and cell invasion assay. RNA- and chromatin immunoprecipitation-sequencing were used to determine transcriptional and epigenetic changes in AT/RT cells treated with EZH2 and BRD4 inhibitors. We treated mice bearing human AT/RT xenografts with EZH2 and BRD4 inhibitors. Intracranial tumor growth was monitored by bioluminescence imaging, and the therapeutic response was evaluated by animal survival. AT/RT cells showed elevated levels of H3K27 trimethylation (H3K27me3) and H3K27 acetylation (H3K27ac), with expression of EZH2 and BRD4, and lack of SMARCB1 proteins. Targeted inhibition of EZH2 and BRD4 activities reduced cell proliferation and invasiveness of AT/RT in association with decreasing H3K27me3 and H3K27ac. Differential genomic occupancy of H3K27me3 and H3K27ac regulated specific gene expression in response to EZH2 and BRD4 inhibitions. A combination of EZH2 and BRD4 inhibition increased the therapeutic benefit in vitro and in vivo, outperforming either monotherapy. Overall, histones H3K27me3 and H3K27ac were elevated in AT/RT cells and distributed in distinct chromatin regions to regulate specific gene expression and to promote AT/RT growth. Targeting EZH2 and BRD4 activity is, therefore, a potential combination therapy for AT/RT.
Publications1 - 10 of 12