Molecular Cancer Therapeutics最新文献

This study evaluates PM534, a novel colchicine-binding domain inhibitor, for its potential in cancer therapy. PM534 exhibited potent in vitro efficacy against a panel of fourteen human cancer cell lines, including breast, ovarian, and prostate cancers, with GI50 values in the low nanomolar range. Both continuous (72 hours) and short-term (1-24 hours) exposure led to irreversible effects, inducing G2/M cell cycle arrest and multinucleation. Additionally, PM534 also impaired angiogenic process. It effectively inhibited HUVEC cell functions, including adhesion with an IC50 of 2.3 nM, markedly more potent than colchicine (IC50 = 1,800 nM). At concentrations as low as 1.6 nM, PM534 delayed wound closure in migration assays, completely inhibiting migration above 4 nM. Additionally, PM534 abrogated invasion and disrupted capillary-like network formation at concentrations starting from 0.5 nM, without inducing cytotoxicity. In vivo PM534 demonstrated robust antitumor efficacy across six xenograft models, including ovarian (A2780, ES-2), triple-negative breast (MDA-MB-231, HCC-1937), and prostate (VCaP, 22Rv1) tumors. This treatment also led to statistically significant increases in median survival times across all models, without inducing signs of systemic toxicity. Mechanistically, PM534 induced apoptosis, mitotic catastrophe, and necrosis in tumor tissues. Importantly, PM534 retained efficacy in models overexpressing multidrug resistance proteins P-glycoprotein or β-III tubulin, overcoming common resistance mechanisms that limit the effectiveness of other tubulin-binding agents. Collectively, these findings highlight PM534 as a promising antitumor agent with potent activity against diverse and treatment-resistant malignancies. A Phase I clinical trial (NCT05835609) is underway to assess the therapeutic potential of PM534 in patients with advanced solid tumors.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal form of pancreatic cancer, with poor prognosis driven by late diagnosis, therapeutic resistance, and an immunosuppressive tumor microenvironment. Interactions between tumor cells and immune cells promote immune evasion and tumor progression, limiting the efficacy of immune checkpoint blockade and other immunotherapies. Given the high expression of TROP2 in PDAC, we developed a TROP2-targeted TLR7 agonist (E104) designed for selective accumulation within the tumor microenvironment to activate antitumor immunity. Although antibody bioactivity is traditionally linked to Fcγ receptor (FcγR) engagement and recruitment of effector cells, our legumain-cleavable, non-glycosylated immune-stimulating antibody conjugates (NG-ISACs) induce robust myeloid activation, cytokine release, and tumor regression without FcγR-mediated functions of natural killer cells or macrophages. Rather, NG-anti-TROP2-E104-ISACs depend on tumor antigen recognition and TLR7 activation, not FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP), to elicit tumor regression and adaptive immunity, as evidenced by anti-TROP2 antibody generation in a syngeneic model. By incorporating the cell-permeable E104 payload with bystander activity, NG-ISACs can activate immune responses independently of FcγR binding. In vitro, NG-anti-TROP2-E104-ISACs bypass FcγRIIa-mediated ADCC and FcγRIIIa-mediated ADCP while maintaining potency in co-cultures of TROP2-positive tumor and effector cells. Moreover, NG-anti-TROP2-E104-ISACs display reduced acute toxicity compared to glycosylated counterparts. Together, these findings delineate the bystander mechanism underlying FcγR-independent immune stimulation and establish a framework for designing ISACs with improved safety.

Antibody-drug conjugates (ADCs) have experienced a surge in clinical approvals in the past few years. Despite this success, a major limitation to ADC efficacy in solid tumors is poor tumor penetration, which leaves many cancer cells untargeted. Co-administration of unconjugated antibody can improve tumor penetration and increase efficacy when target receptor expression is high. However, it can also reduce efficacy in low-expression tumors where ADC delivery is limited by insufficient cellular uptake. This creates an intrinsic problem because many patients express different levels of target between and within tumors. Here, we show how unconjugated High-Avidity, Low-Affinity (HALA) antibodies can automatically tune the cellular ADC delivery to match the local expression level. Using HER2 ADCs as a model, the tumor distribution of trastuzumab emtansine and trastuzumab deruxtecan co-administered with the HALA antibody was improved in vivo, translating to equal or greater ADC efficacy across a range of HER2 expression levels. Furthermore, Fc-enhanced HALA antibodies elicited a strong response in an immunocompetent mouse model. These results demonstrate that HALA antibodies can expand treatment ranges beyond high-expression targets and leverage strong immune responses.

Investigating the mechanisms of acquired resistance to antiandrogens remains a critical clinical need as patients with prostate cancer inevitably develop resistance to androgen receptor (AR)-targeted therapies. Previously, we demonstrated that neuregulin 1 (NRG1) derived from cancer-associated fibroblasts (CAF) promotes antiandrogen resistance through human epidermal growth factor receptor 3 (HER3)-AKT signaling. In this study, we sought to further dissect the molecular context in which NRG1-induced PI3K signaling activation plays a dominant role in driving resistance and evaluate whether targeting HER2/3 dimerization can influence sensitivity to AR inhibition. IHC analysis of radical prostatectomy specimens from patients with prostate cancer treated with or without neoadjuvant hormonal therapy shows that NRG1 was significantly upregulated following AR inhibition, independent of PTEN status. However, we found that stimulation with recombinant NRG1 or CAF-conditioned media induced resistance to AR inhibition only in PTEN wild-type prostate cancer cells and not in PTEN-deficient cells. Selective inhibition of NRG1 using the clinical-grade bispecific humanized immunoglobulin G1, zenocutuzumab (Zeno, MCLA-128), restored sensitivity to AR-targeted therapies in PTEN wild-type tumors, demonstrating its efficacy as a potential therapeutic agent to block the effects of NRG1. In the context of PTEN loss and AR inhibitor resistance, Zeno did not restore sensitivity. These findings highlight the critical molecular context in which tumor microenvironment-derived NRG1 affects responsiveness to AR inhibition and suggest that targeting NRG1 is a promising strategy for overcoming resistance to androgen blockade in PTEN wild-type prostate cancers.

Radiation remains a primary treatment for glioblastoma, yet tumors frequently recur within two years. In this study, orthotopic xenografts initiated from glioma stem-like cells (GSCs) implanted into the right striatum of nude mice were used to investigate the biology of recurrent GBM. In this model, untreated tumors showed diffuse growth pattern across the right hemisphere (RH) and olfactory bulb (OB), whereas post-irradiation tumors (10 Gy) regrew predominantly within the OB, exhibiting increased cell density and a well-demarcated border indicative of an altered growth pattern. Transcriptomes of untreated and recurrent tumors were assessed using spatial profiling. Comparison of gene expression across regions of interest revealed that recurrent tumors are less heterogeneous and exhibit a distinct transcriptional profile compared to untreated tumors. 463 genes were differentially expressed and GSEA analysis revealed significant enrichment of pathways related to cell cycle regulation in the recurrent as compared to untreated tumors. Further analysis of those pathways revealed a significant upregulation of 22 proteasome-related genes in recurrent tumors. Moreover, functional assays revealed significantly higher proteasome activity in recurrent compared to untreated tumors, suggesting the proteasome as a potential therapeutic target unique to recurrent GBM. To evaluate the therapeutic relevance, mice were treated with the combination of radiation followed by the proteasome inhibitor ixazomib. While ixazomib had no effect on untreated tumors, its administration post-irradiation significantly prolonged survival in two GSC xenograft models. These results illustrate how defining molecular alterations that develop in recurrent GBM xenografts can lead to the identification of a novel therapeutic target.

Antibody-drug conjugates (ADC) have recently emerged as an effective treatment option for cancer. Although the fundamental mechanisms of direct tumor cell killing by various ADC payloads have been established, their impact on the tumor microenvironment (TME) remains underexplored. To investigate this fundamental question, we generated an immunocompetent murine tumor model that maintains the expression of a clinically validated tumor-associated antigen, human HER2. We evaluated two ADCs with a shared antibody framework: trastuzumab linked to the microtubule inhibitor monomethyl auristatin E (T-MMAE) and the topoisomerase inhibitor deruxtecan (T-DXd). Treatment with T-MMAE led to a significant increase in immune cell infiltration, whereas T-DXd-treated tumors had fewer immune cells albeit comparable tumor cytotoxicity. When combined with anti-PD-1 immunotherapy, similar additive effects on the primary antitumor response were observed for both ADCs. A key qualitative difference between the two ADCs was observed in the phenotypes of myeloid APCs; T-MMAE treatment resulted in greater immune cell infiltration within the tumor, including macrophages that showed increased gene expression of F4/80, CD206, and IL10RA. In contrast, tumors treated with T-DXd exhibited a lower proportion of macrophages, but APCs in these tumors displayed heightened levels of the CD80 costimulatory molecule. The secondary antitumor response mediated by memory CD8+ T cells was crucial for the formation of immunologic memory induced by both ADCs. Therefore, our findings reveal that, after ADC-mediated tumor cytotoxicity, different ADC payloads elicit distinct immunologic responses characterized by varying levels of myeloid cell activation within the TME.

The essential role of mTOR in promoting tumorigenesis of many cancers makes it an attractive therapeutic target. However, catalytic mTOR inhibitors, which block both mTORC1 and mTORC2, result in activation of negative feedback loops as a resistance mechanism. Selective mTORC2 inhibitors are expected to have the desired anti-tumor effects without engaging resistance mechanisms; however, to date, no such mTORC2 inhibitors have been developed. Using in-silico screening and medicinal chemistry optimization, we identified several small molecules that bind to the unique mTORC2 component, SIN1. We demonstrate that this SIN1 inhibitor alters post-translational modification, protein-protein interactions, and blocks mTORC2- and rapamycin sensitive (RS) mTORC1-mediated signaling. The SIN1 inhibitor also inhibits wildtype RAS activation and downstream MAPK signaling, as well as cell proliferation of multiple cancer cell line types. SIN1 inhibition can enhance the efficacy of FDA- approved anti-neoplastic agents in vitro and may provide a novel approach for the treatment of different types of malignancies.

Intratumoral T regulatory cells (Tregs) promote an immunosuppressive tumor microenvironment and are frequently associated with a lack of response to immunotherapy. Selective targeting of intratumoral Tregs while sparing broader Tregs and effector T cell populations is an attractive strategy to enhance antitumor immune responses. CCR8 is a G protein-coupled receptor (GPCR) that is predominantly upregulated on tumor resident Tregs in a range of human solid tumors making it a promising target for their selective depletion. In preclinical studies using the mouse tumor models, anti-mouse CCR8 antibody treatment resulted in depletion of CCR8+ intratumoral Tregs, significant antitumor activity and enhanced survival in combination with anti-PD-1. CHS-114 is a highly selective, afucosylated human anti-CCR8 monoclonal antibody that is being developed as a cancer immunotherapy. CHS-114 selectively binds human CCR8 and potently kills CCR8 expressing cells by inducing antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP). Ex vivo studies evaluating human dissociated tumor cells (DTCs) demonstrated the selectivity of CHS-114 in depleting intratumoral Tregs while sparing CCR8 negative Tregs and effector T cells. Treatment of tumor bearing human CCR8 knock-in (huCCR8KI) mice with CHS-114 resulted in significant tumor growth inhibition (62.6%) accompanied by remodeling of the tumor immune microenvironment and enhanced differentiation of a subset of cytotoxic CD8+ T cells. Based on the promising preclinical data, we are evaluating CHS-114 in clinical trials as an investigational agent for the treatment of solid tumors with and without the anti-PD-1 antibody toripalimab (NCT05635643, NCT06657144).

Statins have been reported to exert anticancer activity, varying with cancer type and specific statins. These findings suggest that more mechanistic insights into the anticancer effects of statins are needed. In this study, we interrogated the ability of statins to induce cell death and ferroptosis in melanoma and colorectal cancer. First, we showed that statins induce cell death in patient-derived melanoma cell lines and that lower expression of mevalonate pathway genes correlates with increased CD8+ T-cell infiltration and improved overall survival in patients with melanoma. We found that lipophilic statins induce cell death with features of ferroptosis. Transcriptional data also revealed system-level changes to a variety of ferroptosis-related pathways. We found that mevalonate rescued statin-induced cell death. Mechanistically, mevalonate-derived isopentyl pyrophosphate is necessary for isopentylation of tRNA [Ser]Sec, which is required for efficient synthesis of the selenoprotein ferroptosis suppressor GPX4. Given the emerging role for ferroptosis in antitumor immunity, we tested lipophilic statins, including simvastatin, alone and in combination with α-PD1 in vivo and found that simvastatin and α-PD1 promoted tumor clearance and extended survival in 20% to 60% of mice alone but in nearly 100% of mice when administered together. Simvastatin also depleted GPX4 in vivo. These results highlight the therapeutic potential of statin use in combination with immunotherapies.

Epigenetic aberrations are key drivers of multiple myeloma, yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular datasets of patients with multiple myeloma with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in patients with multiple myeloma. Genetic gain- and loss-of-function models identified a protective role of KANSL2 toward genotoxic stress. By transcriptomics, proteomics, and quantitative acetylome profiling, we identified a KANSL2-dependent specific molecular program targetable by acetylation-related modifiers. High KANSL2 levels increased sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain and extra-terminal motif (BET) inhibitor OTX-015 and their combination. Ex vivo drug response profiling in samples from patients with relapsed/refractory multiple myeloma confirmed that high KANSL2 expression is associated with selective multiple myeloma cell killing by HDAC and BET inhibitors. Collectively, these findings position KANSL2 as a mediator of chemotherapy resistance and actionable biomarker for response to drugs targeting its epigenetic program.