Molecular Cancer Therapeutics最新文献

Advances in tumor molecular profiling have uncovered shared genomic and proteomic alterations across tumor types that can be exploited therapeutically. A biomarker-driven, disease-agnostic approach to oncology drug development can maximize the reach of novel therapeutics. To date, eight drug-biomarker pairs have been approved for the treatment of patients with advanced solid tumors with specific molecular profiles. Emerging biomarkers with the potential for clinical actionability across tumor types include gene fusions involving NRG1, FGFR1/2/3, BRAF, and ALK and mutations in TP53 Y220C, KRAS G12C, FGFR2/3, and BRAF non-V600 (class II). We explore the growing evidence for clinical actionability of these biomarkers in patients with advanced solid tumors.

Triple negative breast cancer (TNBC) represents a therapeutic challenge in which standard chemotherapy is limited to paclitaxel. MBQ167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ167 in combination with paclitaxel in TNBC preclinical models, as a prelude to safety trials of this combination in patients with advanced breast cancer. Individual MBQ167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared with paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB231 and MDA-MB468), individual MBQ167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, whereas MBQ167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ167 and paclitaxel decreased established lung metastases by ∼80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ167 and paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action.

The emergence of trastuzumab deruxtecan (T-DXd), a new-generation antibody-drug conjugate (ADC), has profoundly altered the therapeutic paradigm for HER2-positive solid tumors, demonstrating remarkable clinical benefits. However, the combined outcomes of T-DXd with immunotherapy agents remain ambiguous. In this study, we introduce Tras-DXd-MTL1, an innovative HER2 targeting ADC that integrates the topoisomerase inhibitor DXd and a toll like receptor 7 (TLR7) agonist MTT5, linked to trastuzumab via a GGFG tetrapeptide linker. Mechanistically, Tras-DXd-MTL1 retains the DNA-damaging and cell-killing properties of topoisomerase inhibitors while simultaneously enhancing the immune response within the tumor microenvironment. This is achieved by promoting immune cell infiltration and activating dendritic cells and CD8+T cells via MTT5. In vivo evaluation of Tras-DXd-MTL1's antitumor potency revealed a notably superior performance compared with the T-DXd (Tras-DXd) or Tras-MTL1 in immunocompetent mice with trastuzumab-resistant EMT6-HER2 tumor and immunodeficient mice with JIMT-1 tumor. This improved efficacy is primarily attributed to its dual functions of immune stimulation and cytotoxicity. Our findings highlight the potential of incorporating immunostimulatory agents into ADC design to potentiate antitumor effects and establish durable immune memory, thereby reducing tumor recurrence risks. Therefore, our study offers a novel strategy for the design of immune-activating ADCs and provides a potential approach for targeting solid tumors with different levels of HER2 expression.

The human CMG helicase (Cdc45-MCM-GINS) is a novel target for anticancer therapy. Tumor-specific weaknesses in the CMG are caused by oncogene-driven changes that adversely affect CMG function, and CMG activity is required for recovery from replicative stresses such as chemotherapy. Herein, we developed an orthogonal biochemical screening approach and identified CMG inhibitors (CMGi) that inhibit ATPase and helicase activities in an ATP-competitive manner at low micromolar concentrations. Structure-activity information, in silico docking, and testing with synthetic chemical compounds indicate that CMGi require specific chemical elements and occupy ATP-binding sites and channels within minichromosome maintenance (MCM) subunits leading to the ATP clefts, which are likely used for ATP/ADP ingress or egress. CMGi are therefore MCM complex inhibitors (MCMi). Biologic testing shows that CMGi/MCMi inhibit cell growth and DNA replication using multiple molecular mechanisms distinct from other chemotherapy agents. CMGi/MCMi block helicase assembly steps that require ATP binding/hydrolysis by the MCM complex, specifically MCM ring assembly on DNA and GINS recruitment to DNA-loaded MCM hexamers. During the S-phase, inhibition of MCM ATP binding/hydrolysis by CMGi/MCMi causes a "reverse allosteric" dissociation of Cdc45/GINS from the CMG that destabilizes replisome components Ctf4, Mcm10, and DNA polymerase-α, -δ, and -ε, resulting in DNA damage. CMGi/MCMi display selective toxicity toward multiple solid tumor cell types with K-Ras mutations, targeting the CMG and inducing DNA damage, Parp cleavage, and loss of viability. This new class of CMGi/MCMi provides a basis for small chemical development of CMG helicase-targeted anticancer compounds with distinct mechanisms of action.

The persistence of cancer stem cells (CSC) is believed to contribute to resistance to platinum-based chemotherapy and disease relapse in ovarian cancer, the fifth leading cause of cancer-related death among US women. HOXC transcript antisense RNA (HOTAIR) is a long, noncoding RNA (lncRNA) overexpressed in high-grade serous ovarian cancer and linked to chemoresistance. However, HOTAIR impacts chromatin dynamics in ovarian CSCs. Oncogenic lncRNA's contributions to drug-resistant disease are incompletely understood. Here, we generated HOTAIR knockout (KO) high-grade serous ovarian cancer cell lines using paired CRISPR guide RNA design to investigate the function of HOTAIR. We show the loss of HOTAIR function resensitized ovarian cancer cells to platinum treatment and decreased the population of ovarian CSCs. Furthermore, HOTAIR KO inhibited the development of stemness-related phenotypes, including spheroid formation ability and expression of key stemness-associated genes ALDH1A1, NOTCH3, SOX9, and PROM1. HOTAIR KO altered the cellular transcriptome and chromatin accessibility landscape of multiple oncogenic-associated genes and pathways, including the NF-kB pathway. HOTAIR functions as an oncogene by recruiting enhancer of zeste homolog 2 (EZH2) to catalyze H3K27 trimethylation to suppress downstream tumor suppressor genes, and it was of interest to inhibit both HOTAIR and EZH2. In vivo, combining a HOTAIR inhibitor with an EZH2 inhibitor and platinum chemotherapy decreased tumor formation and increased survival. These results suggest a key role for HOTAIR in ovarian CSCs and malignant potential. Targeting HOTAIR in combination with epigenetic therapies may represent a therapeutic strategy to ameliorate ovarian cancer progression and resistance to platinum-based chemotherapy.

Improvement of outcome in patients with pancreatic ductal adenocarcinoma (PDAC) requires exploration of novel therapeutic targets. Thus far, most studies of PDAC therapies, including those inhibiting small ubiquitin-like modifications (SUMOylation), have focused on PDAC epithelial cell biology, yet SUMOylation occurs in a variety of cell types. The mechanisms by which SUMOylation impacts PDAC in the context of its tumor microenvironment are poorly understood. We used clinically relevant orthotopic PDAC mouse models to investigate the effect of SUMOylation inhibition using a specific, clinical-stage compound, TAK-981. In contrast to its inhibition of PDAC cell proliferation in vitro, the survival benefit conferred by TAK-981 in vivo is dependent on the presence of T cells, suggesting that induction of adaptive antitumor immunity is an important antitumor effect of SUMOylation inhibition in vivo. To understand how this adaptive antitumor immunity is promoted, we investigated how SUMOylation inhibition in vivo alters major cell types/subtypes and their communications in the PDAC tumor microenvironment by performing transcriptomic analyses at single-cell resolution, which allowed mapping of cells in our orthotopic mouse model to cells in human PDAC tumors based on gene expression profiles. Findings are further validated by flow cytometry, immunofluorescence, IHC, western blots, and qPCR. The single-cell transcriptome dataset provided here suggests several combination strategies to augment adaptive immune responses that are necessary for durable disease control in patients with PDAC.

The p53 pathway plays an important role in role in cancer immunity. Mutation or downregulation of the proteins in the p53 pathway are prevalent in many cancers, contributing to tumor progression and immune dysregulation. Recent findings suggest that the activity of p53 within tumor cells, immune cells, and the tumor microenvironment can play an important role modulating natural killer (NK) cell-mediated immunity. Consequently, efforts to restore p53 pathway activity are being actively pursued to modulate this form of immunity. This review focuses on p53 activity regulating the infiltration and the activation of NK cells in the tumor immune microenvironment, which are illustrated in the Graphical Abstract for this review. Furthermore, impact of p53 and its regulation of NK cells on immunogenic cell death within solid tumors and the abscopal effect is reviewed. Finally, future avenues for therapeutically restoring p53 activity to improve NK cell-mediated anti-tumor immunity and optimize the effectiveness of cancer therapies are discussed.

CD47 is a cell surface glycoprotein that is expressed on normal human tissues and has a key role as a marker of self. Tumor cells have coopted CD47 overexpression to evade immune surveillance and thus blockade of CD47 is a highly active area of clinical exploration in oncology. However, clinical development of CD47-targeted agents has been complicated by its robust expression in normal tissues and the toxicities that arise from blocking this inhibitory signal. Further, pro-phagocytic signals are not uniformly expressed in tumors and antibody blockade alone is often not sufficient to drive antitumor activity. The inclusion of an IgG1 antibody backbone into therapeutic design has been shown to serve as an additional pro-phagocytic signal but also exacerbates toxicities in normal tissues. Therefore, a need persists for more selective therapeutic modalities targeting CD47. To address these challenges, we developed SGN-CD47M, a humanized anti-CD47 IgG1 monoclonal antibody linked to novel masking peptides through linkers designed to be cleaved by active proteases enriched in the tumor microenvironment. Masking technology has the potential to increase the amount of drug that reaches the tumor microenvironment, while concomitantly reducing systemic toxicities. We demonstrate that SGN-CD47M is well tolerated in cynomolgus monkeys and displays a 20-fold improvement in tolerability to hematologic toxicities when compared to the unmasked antibody. SGN-CD47M also displays preferential activation in the tumor microenvironment that leads to robust single-agent antitumor activity. For these reasons, SGN-CD47M may have enhanced antitumor activity and improved tolerability relative to existing therapies that target the CD47-SIRPα interaction.