Molecular Cancer Therapeutics最新文献

Prostate cancers harboring alterations of genes involved in DNA damage response and repair tend to be more aggressive and are associated with poorer survival outcomes. The application of poly (ADP-ribose) polymerase (PARP) enzyme inhibitors (PARPi) improves the survival of patients with prostate cancer carrying germline or somatic BRCA1 or BRCA2 gene mutations, whereas their role in tumors with alterations of DNA repair genes other than BRCA1/2 and proteins remains controversial, as inhibitors of such targets are currently in clinical development. In this study, we provide an overview of the most frequently observed genomic aberrations affecting DNA repair pathways in prostate cancer and discuss how patient selection needs improvement to identify the population that will eventually benefit from PARPi treatment beyond BRCA1/2 deficiency. Further, we explore emerging treatment approaches with novel DNA repair pathway inhibitors, highlighting the biological rationale and how they are believed to overcome current challenges posed by primary and secondary treatment resistance in this heterogeneous disease.

The deregulation of histone methylation has been implicated in the pathogenesis of multiple diseases, including ovarian cancer (OC), one of the most lethal gynaecological malignancies worldwide. The roles of the H3K27 demethylases UTX and JMJD3- key regulators of epigenetic homeostasis- remain incompletely characterised in OC. Here, we used the demethylase inhibitor GSK-J4 and siRNA-mediated knockdown of UTX and JMJD3 to investigate the functional impact of altered H3K27 methylation in OC in vitro models. Pharmacological modulation of H3K27me2/3 induced distinct cell type-specific phenotypes, including reduced proliferation, apoptosis and alterations in 3D spheroid architecture. These effects were accompanied by transcriptional downregulation of EMT- and ECM-associated genes. Notably, we identified the androgen receptor (AR) as a key upstream regulator of H3K27 methylation. In AR-expressing OC cells, AR inhibition increased H3K27me2/3 levels, revealing a novel epigenetic axis linking nuclear receptor signalling with histone methylation dynamics. Together, our findings uncover context-dependent vulnerabilities in OC cells and highlight a potential therapeutic interplay between AR signalling and epigenetic modulation.

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-HER2 antibody and a cytotoxic topoisomerase I inhibitor, is approved for the treatment of HER2-positive and HER2-low breast cancer as well as HER2-high gastric and HER2-mutant lung cancer tumours. The AKT inhibitor capivasertib is approved for the treatment of HER2- ER+ breast cancer with alterations in PIK3CA, PTEN and AKT-1. The potential for the combination of T-DXd with AKT inhibition to enhance anti-tumour activity was explored in HER2+ or HER2-low preclinical models. In vitro, combination activity was observed in both HER2-high and HER2-low expressing breast cancer as well as in gastric, endometrial and ovarian models, irrespective of HER2 expression level or PI3K-AKT status pathway alterations. The T-DXd-capivasertib combination effect translated in vivo with increased anti-tumour benefit in HER2 expressing, PI3K-AKT pathway altered tumour xenografts when compared to the combination of trastuzumab and capivasertib. In cell lines sensitive to the combination, combining T-DXd with capivasertib targeted complimentary pathways which resulted in disruption of the cell cycle and increased cell death. These results suggest that T-DXd combined with capivasertib has the potential to be active in HER2-positive as well as HER2-low tumours independent of PI3K pathway alteration status.

One of the many barriers to successful chimeric antigen receptor (CAR) T-cell immunotherapy against solid tumors is the scarcity of targetable molecules common to multiple types of cancer. The purpose of this study was to determine the efficacy of αvβ3 CAR-T cells against solid tumors, particularly melanoma and triple-negative breast cancer, two malignancies recognized for dependence on the αvβ3 pathway for tumor progression and metastases. A novel αvβ3 CAR-T cell developed in our lab and demonstrated to be effective and safe in preclinical models of glioblastoma and pediatric diffuse intrinsic pontine glioma was utilized in this study. Two versions of the αvβ3 CAR-T construct, containing either a CD28 or 4-1BB co-stimulation domain, were tested here. Multiple xenograft studies consisting of melanoma and orthotopic breast tumor models were conducted to evaluate the efficacy of systemically administered αvβ3 CAR-T cells. In this study, we demonstrate that the integrin αvβ3 is a highly attractive target for CAR-T cells as we found it to be highly expressed on various cancer types, including melanoma and triple-negative breast cancer, and susceptible to CAR-T cell-mediated control in multiple xenograft models. In vivo antitumor efficacy of αvβ3 CAR-T cells was underscored by the ability of CARs to circumvent tumor metastasis and to persist long term. Surprisingly, co-stimulation provided by CD28, rather than 4-1BB, led to more robust antitumor efficacy typified by superior long-term control, better persistence, and improved durability against continuous antigen exposure. These results strengthen the rationale for clinical translation and deployment of αvβ3 CAR-T cells against multiple cancer types.

Metastasis remains a major challenge in cancer treatment due to the lack of effective targeted therapies. MBQ-167, a first-in-class dual Rac/Cdc42 inhibitor currently in a Phase 1 clinical trial, has demonstrated promising activity in preclinical breast cancer models by reducing tumor burden and preventing metastasis. To characterize its metabolism, we conducted liver microsome assays and identified several MBQ-167 metabolites. Of these, M6 was the primary metabolite from dog and human plasma following oral administration of MBQ-167. The M6 pharmacokinetics profile parallels that of MBQ-167 in human plasma from advanced breast cancer patients enrolled in the clinical trial. In metastatic breast cancer cell lines (HER2-BM, MDA-MB-231, MDA-MB-468), M6 exhibited minimal effects on cell viability and apoptosis, but strongly inhibited Rac1 activation without affecting Cdc42 activation. M6 also inhibited phosphorylation of Group 1 p21-activated kinases (PAKs) more effectively than MBQ-167 and significantly reduced breast cancer cell migration in wound healing and Transwell assays. In vivo studies with immunocompromised mice bearing HER2-BM tumors demonstrated that M6 inhibits tumor growth and metastasis to the lungs, livers, and kidneys by ~90%, comparable to MBQ-167. These findings suggest that M6 exhibits potent anticancer properties both in vitro and in vivo, potentially contributing to the sustained efficacy of MBQ-167 in metastatic breast cancer.

T-lineage acute lymphoblastic leukemia (T-ALL) lacks effective targeted therapies, with poor outcomes in relapsed/refractory disease. HOXA-high T-ALL is biologically aggressive and often resistant to standard therapy. Menin inhibitors, recently approved for KMT2A-rearranged leukemias, may be effective in T-ALL, but biomarkers of response remain undefined. This study aims to evaluate the efficacy of menin inhibition in T-ALL and identify molecular predictors of sensitivity. We tested menin inhibitors (ziftomenib, revumenib, VTP-50469) in 14 primary T-ALL samples and 8 cell lines, representing HOXA-high and HOXA-low genotypes. In vitro sensitivity assays, xenograft mouse models, transcriptomics, proteomics, and phosphoproteomics were used to characterize drug response. MEF2C modulation experiments and combination studies with CDK1/2 and ERK1/2 inhibitors were performed in vitro and in vivo. Menin inhibitors suppressed leukemic growth in a subset of HOXA-high and HOXA-low primary human T-ALL samples. Similarly, ziftomenib was effective in reducing tumor burden in xenografts without major toxicity. Upon treatment, we observed down-regulation of canonical menin targets (HOXA, MEIS1, MEF2C) and upregulation of T-cell differentiation programs. Phosphoproteomic studies identified MEF2C S222 phosphorylation-mediated by CDK1/2 and ERK1/2-as a predictor of ziftomenib sensitivity in T-ALL. MEF2C overexpression promoted proliferation and ziftomenib resistance, while knockdown impaired growth. Ziftomenib synergized with CDK1/2 and ERK1/2 inhibitors in vitro and improved survival in xenografted mice. In conclusion, a subset of T-ALL, defined by high p-MEF2C S222, is sensitive to menin inhibition. Combining ziftomenib with CDK or ERK inhibition offers synergistic efficacy, supporting biomarker-driven clinical trials of this strategy in relapsed/refractory T-ALL.

Estrogen receptor-positive (ER+) breast cancers (BC) comprise over 70% of breast cancers and are the leading cause of BC-related deaths in women worldwide. Despite available therapies that target ER, recurrence occurs in many patients due to therapeutic resistance. Semaphorin 7a (SEMA7A) is emerging as a biomarker associated with poor prognosis and endocrine therapy resistance in BC patients. Survival analyses of ER+ BC patients treated with endocrine therapy suggest early recurrence in patients with SEMA7A+ tumors. Thus, establishing novel treatment strategies could improve outcomes for patients with ER+ SEMA7A+ BC. In this paper, we investigate mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ BC. Our results suggest that SEMA7A forms a protein complex with integrins B1 and B4, which results in AKT-mediated pro-survival signaling via its RGD domain. Using mouse models of ER+BC (FVB/N mice, TC11 tumor model), we show reduced growth of SEMA7A+ tumors with PI3K inhibitors (GCT-007:10 mg/kg daily, alpelisib: 20mg/kg daily), alone or in combination with tamoxifen (0.5mg/100uL, every 3rd day). Combination of an anti-SEMA7A antibody (SmAbH1) (100-250 ug/100uL, every other day) and fulvestrant (83 mg/kg, every 5 days) also revealed that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A-expressing tumors, and that the efficacy of SmAbH1 is not diminished by the standard of care, fulvestrant. Overall, our studies suggest that patients with ER+SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy.

Mesothelin (MSLN) is a cell-membrane-anchored glycoprotein overexpressed in several cancers including pancreatic cancer, ovarian cancer, and mesothelioma. MSLN is protease-cleaved at the membrane-proximal region, releasing shed MSLN (sMSLN) into the tumor microenvironment, leaving behind a membrane-bound stub. sMSLN in the tumor microenvironment is hypothesized to create a 'sink' that could limit tumor binding of MSLN-targeted anticancer therapies. We describe JNJ-79032421, a bispecific antibody targeting cluster of differentiation (CD)3 on T cells and the membrane-restricted, non-shed region of full-length MSLN on cancer cells. Crystal structure analysis confirmed JNJ-79032421 binding to the membrane-restricted, non-shed C-terminal region of MSLN. Using Western blot, enzyme-linked immunosorbent assay, fluorescence-activated cell sorting, and immunohistochemistry, elevated levels of sMSLN were detected in blood, serosal fluids, and tumor tissue of patients and tended to increase with MSLN tumor expression. Binding and cytotoxicity of JNJ-79032421 against cancer cell lines was unaffected by the presence of sMSLN. In cancer cell lines and cell-line-derived and patient-derived xenograft mouse models, increasing levels of MSLN expression led to increased JNJ-79032421 potency. In contrast, MSLNxCD3 bispecific antibodies whose binding is non membrane restricted demonstrated a loss of cytotoxicity in the presence of sMSLN. This 'sink' effect was most pronounced for high-affinity non-membrane-restricted bispecific antibodies. Increases of CD45+ and CD8+ T-cell infiltrates, as well as CD8+ T-cell activation, observed in xenograft tumor tissues were time and JNJ-79032421 dose dependent. Overall, these data suggest that JNJ-79032421 may offer meaningful clinical activity by avoiding binding to sMSLN.

Integrin αvβ3, absent in most normal cells, has emerged as both a marker and a driver of tumor stemness and drug resistance in epithelial cancers, making it an attractive therapeutic target. The humanized IgG1 anti-αvβ3 antibody etaracizumab was originally developed to exploit NK cell-mediated cytotoxicity against αvβ3-positive tumors. However, despite its favorable safety profile and clinical efficacy, its impact was insufficient for further development. We previously discovered that αvβ3-positive epithelial tumors exhibit a tumor-associated macrophage (TAM)-rich microenvironment with limited NK-cell infiltration, potentially limiting the effectiveness of etaracizumab. In this study, we hypothesized that re-engineering the anti-αvβ3 antibody to activate TAM-mediated cytotoxicity would enhance its antitumor activity. We developed a fully human IgG4 variant of etaracizumab (anti-αvβ3 G4) with identical affinity for integrin αvβ3, but optimized for activation of CD64, an immune effector cell-activating receptor, selectively expressed on macrophages. In organotypic cultures of patients with lung cancer and mouse lung cancer xenografts, anti-αvβ3 G4 demonstrated superior antitumor activity compared with its IgG1 counterpart. Mechanistically, this enhancement was driven by CD64 activation in TAMs, leading to robust upregulation of inducible nitric oxide synthase, a pivotal enzyme for immune effector-mediated cytotoxicity. Our findings reveal a powerful strategy for targeting highly aggressive, drug-resistant integrin αvβ3-positive tumors by harnessing TAMs for antibody-mediated cancer therapy and demonstrate that this Fc switch approach may be broadly applicable to other targets in TAM-enriched tumor microenvironments.