Molecular Cancer Therapeutics最新文献

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging types of cancer with little or no response to immune checkpoint inhibitors (ICIs). Photodynamic therapy (PDT) has been shown to ablate tumors and induce an immune response. In our study, we investigated the effect of photodynamic therapy (PDT), using the photosensitizer Bremachlorin, in its ability to reduce tumor burden and to sensitize immunologically T-cell high and T-cell low murine PDAC tumors to the ICI that blocks programmed cell death-1 (PD-1) immune checkpoint. In addition, we monitored the effect on survival and investigated if there was a response in PDT-treated and non PDT-treated distant tumors. Our results showed that Bremachlorin PDT induces direct tumor killing which increased survival in both 'hot' T-cell high and 'cold' T-cell low PDAC tumors and that it can make the T-cell high tumors more sensitive to ICI blocking PD-1. We found that T-cell high tumor bearing mice had an overall greater response to therapy than T-cell low tumor bearing mice. One mouse with T-cell high tumors exhibited complete tumor regression in both the treated and non-treated distant tumor 90 days after treatment. These results indicate that combining immune checkpoint inhibitors (ICIs) with Bremachlorin PDT could be a promising therapeutic intervention for enhancing PDAC's response to therapy.

Inactivation of the Hippo tumor suppressive pathway is frequently observed in mesothelioma, which leads to the activation of YAP and TAZ (YAP/TAZ) transcriptional coactivators. YAP/TAZ form complexes with TEAD family members, DNA-binding proteins, to activate transcription, which promotes cancer cell growth and proliferation. Recently developed TEAD inhibitors exhibit antitumor activity by inhibiting the formation of the transcription complex through binding to TEAD; however, the antitumor activity of TEAD inhibitors against mesothelioma remains to be fully elucidated. Here, we show that the TEAD inhibitor K-975 acts as a pan-TEAD inhibitor and selectively inhibits the binding of TEAD-binding proteins, especially YAP/TAZ, in mesothelioma cells. In studies using a panel of mesothelioma cell lines, K-975 showed a significant growth inhibitory effect on Hippo-inactivated mesothelioma cells, but some of these cell lines exhibited primary resistance to K-975. Differential gene expression analysis revealed that cells resistant to K-975 exhibited activation of MYC signaling in the presence of K-975, and cells overexpressed with MYC showed strong drug resistance, both in vitro and in vivo. Our study revealed the features of a subset of mesothelioma cells that proliferate in a TEAD-independent manner and provides important insights for the successful development of therapeutic strategies for mesothelioma with Hippo pathway inactivation.

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Notably, Platinum-based chemotherapy induces resistance of EOC to poly (ADP-ribose) polymerase (PARP) inhibition. However, therapeutic approaches targeting PARP inhibitors (PARPi) resistance remain to be explored. Here, we show that all-trans retinoic acid (ATRA) reduces PARPi resistance-associated EOC cells induced by cisplatin (CDDP) treatment. Clinically applicable ATRA suppressed the outgrowth of CDDP-treated EOC cells both in vitro and in vivo. Moreover, a CDDP treatment followed by niraparib maintenance therapy in combination with ATRA improved the survival of EOC-bearing mice. These phenotypes correlated with PARPi resistant EOC signature, which consists of elevated expression of ALDH1A1, NAMPT, PARP1 and Chk1, as well as elevated NAD+ level-mediated high activity of ALDH1A1 and PARP1. Mechanistically, ATRA down-regulates the expression of these genes and level of intracellular NAD+. Our results suggest that ATRA in conjunction with PARPi represents a promising maintenance therapeutic strategy for EOC.

Androgen receptor (AR) signaling is the principal driver of prostate cancer, and drugs that target this pathway (e.g., abiraterone and enzalutamide) are standard treatments for metastatic hormone-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). However, continual evolution during prostate cancer progression can result in AR alterations (e.g., mutation, amplification, splicing) that can cause tumors to become resistant to these therapies. Bavdegalutamide (ARV-110) is a PROteolysis TArgeting Chimera (PROTAC®) protein degrader that recruits the cereblon-containing E3 ubiquitin ligase to direct the polyubiquitination and subsequent proteasomal degradation of AR. Bavdegalutamide selectively degrades wild-type AR and most clinically relevant mutants with low nanomolar potency. The superiority of the degradation mechanism of action is demonstrated by bavdegalutamide's higher activity relative to the AR antagonist enzalutamide in cell-based systems that assess effects on prostate-specific antigen (PSA) synthesis, prostate cancer cell proliferation, and induction of apoptosis. In an AR-expressing patient-derived xenograft mouse model, bavdegalutamide showed substantial AR degradation and greater tumor growth inhibition compared with enzalutamide. Bavdegalutamide also showed robust tumor growth inhibition in enzalutamide- and abiraterone-resistant prostate cancer animal models and enhanced activity in combination with abiraterone. These promising preclinical data supported clinical development of bavdegalutamide as a potential treatment for patients with prostate cancer. Bavdegalutamide was the first PROTAC protein degrader to enter human clinical trials, specifically in patients with mCRPC in a phase 1/2 study (NCT03888612).

Radiation-induced fibrosis (RIF) is a progressive pathology deleteriously impacting cancer survivorship. CXCL12 is an immune-stromal signal implicated in fibrosis and innate response. We hypothesised that modulation of CXCL12 would phenotypically mitigate RIF. CXCL12 expression was characterised in a rodent model of RIF and its expression modulated by the intravascular delivery of lentiviral vectors encoding small hairpin RNA to silence (LVShCXCL12) or overexpress (LVOeCXCL12) CXCL12. Multi-modal fibrotic outcomes were quantified, flow cytometry and Y-chromosome lineage-tracking studies performed to examine cellular recruitment and activation post-radiotherapy (post-RT). Whole-tissue RNA-seq was used to examine matrisomal response. MATBIII tumours were engrafted within tissues with differing levels of CXCL12 expression and tumoral response to RT evaluated. CXCL12 was upregulated in irradiated fibroblasts demonstrating DNA-damage post-RT and led to the recruitment of CD68+ macrophages. Silencing Cxcl12 with LVShCXCL12 demonstrated reduced RIF phenotype as a result of decreased macrophage recruitment. Transcriptomic profiling identified osteopontin (SPP1) as being highly differentially expressed in LVShCXCL12-treated tissues. Tumours growing in tissues devoid of CXCL12 expression responded better following RT due to reductions in peri-tumoural fibrosis as a result of decreased CXCL12 and OPN expression at the tumour/normal tissue interface. This was also associated with greater CD8+ T cell infiltration in tumours with less fibrosis. Antibody-mediated OPN blockade slowed tumour growth by increased intra-tumoral CD8+ T cell activation. The CXCL12/OPN axis is an important node of immune/matrisomal cross-talk in the development of fibrosis. Therapeutic manipulation of this axis may offer greater anti-tumour efficacy whilst also reducing adverse effects.

Src homology-2 domain-containing phosphatase 2 (SHP2) promotes RAS-MAPK signaling and tumorigenesis and is a promising therapeutic target for multiple solid tumors. Migoprotafib is a potent and highly selective SHP2 inhibitor designed for the treatment of RAS-MAPK driven cancers, particularly in combination with other targeted agents. Here we report first-in-human study results of single agent migoprotafib in advanced solid tumor patients. We conducted a phase 1a, open-label, multi-center, dose-escalation and expansion study in adult patients with locally advanced or metastatic solid tumors. The key objectives were to evaluate safety, pharmacokinetics, pharmacodynamics (peripheral blood pERK) and preliminary anti-tumor activity. Fifty-six heavily pre-treated patients were treated with migoprotafib (10-150 mg QD). Migoprotafib had a rapid absorption rate (~0.5-2 hours) with dose-dependent increases in exposure and pathway modulation (pERK changes). The maximum tolerated dose was 100 mg and the recommended phase 2 dose (RP2D) was 60 mg daily (QD) based on safety, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity. Migoprotafib was generally well tolerated with the most frequent adverse events of diarrhea, peripheral edema, dyspnea, anemia, constipation, fatigue, AST increase and platelet count decrease. Stable disease was observed in 10 patients (18%). Migoprotafib had predictable, dose-dependent PK with an effective half-life that supports QD dosing and demonstrated promising safety, tolerability, and clinical activity at the RP2D. Further clinical testing of migoprotafib in combination with other targeted agents is warranted.

Lurbinectedin is a selective inhibitor of oncogenic transcription approved for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. Preclinical data provide evidence for lurbinectedin exerting its actions in a unique manner that involves oncogenic transcription inhibition, DNA damage, reshaping of the tumor microenvironment, and inducing anticancer immunity. Understanding the mechanism of action (MoA) has facilitated the rational combination of lurbinectedin and anticancer therapies with complementary modes of action, in order to obtain synergistic effects that could potentially lead to improved efficacy. This review evaluates the MoA for lurbinectedin and provides an overview of the therapeutic landscape with regards to lurbinectedin combination therapies for the treatment of SCLC based on data from preclinical and clinical studies.

Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutical limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances the anti-tumor effects when combined with anti-PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with NSCLC. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating the NLRP3 inflammasome formation. This leads to macrophage activation via the NF-kB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knock-out mice confirmed that AXL inhibition by denfivontinib enhances the anti-tumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk-RNA sequencing data from 21 NSCLC patients undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for NLRP3 inflammasome in activating immune responses during treatment.

Proteasomes generate antigenic peptides that are presented on the tumor surface to cytotoxic T-lymphocytes. Immunoproteasomes are highly specialized proteasome variants that are expressed at higher levels in antigen-presenting cells and contain replacements of the three constitutive proteasome catalytic subunits to generate peptides with a hydrophobic C-terminus that fit within the groove of MHC class I (MHC-I) molecules. A hallmark of cancer is the ability to evade immunosurveillance by disrupting the antigen presentation machinery and downregulating MHC-I antigen presentation. High-throughput screening was performed to identify compound A, a novel molecule that selectively increased immunoproteasome activity and expanded the number and diversity of MHC-I-bound peptides presented on multiple myeloma cells. Compound A increased the presentation of individual MHC-I-bound peptides by >100-fold and unmasked tumor-specific neoantigens on myeloma cells. Global proteomic integral stability assays determined that compound A binds to the proteasome structural subunit PSMA1 and promotes association of the proteasome activator PA28α/β (PSME1/PSME2) with immunoproteasomes. CRISPR/Cas9 silencing of PSMA1, PSME1, or PSME2 as well as treatment with immunoproteasome-specific suicide inhibitors abolished the effects of compound A on antigen presentation. Treatment of multiple myeloma cell lines and patient bone marrow-derived CD138+ cells with compound A increased the anti-myeloma activity of allogenic and autologous T cells. Compound A was well-tolerated in vivo and co-treatment with allogeneic T cells reduced the growth of myeloma xenotransplants in NOD/SCID gamma mice. Taken together, our results demonstrate the paradigm shifting impact of immunoproteasome activators to diversify the antigenic landscape, expand the immunopeptidome, potentiate T-cell-directed therapy, and reveal actionable neoantigens for personalized T-cell immunotherapy.

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard-of-care androgen deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as an mCRPC tumor antigen with overexpression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids into proteins at selected sites, we have developed ARX517, an antibody-drug conjugate composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a noncleavable polyethylene glycol linker and stable oxime conjugation enabled via synthetic amino acid protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice and dose-dependent antitumor activity in both enzalutamide-sensitive and -resistant cell line-derived xenograft and patient-derived xenograft models of prostate cancer. Repeat-dose toxicokinetic studies in nonhuman primates demonstrated that ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a phase I clinical trial (NCT04662580).