Molecular Cancer Therapeutics最新文献

Cancer immunotherapy has been revolutionized through the implementation of the state-of-the-art "chimeric antigen receptor" (CAR)-mediated therapies. CAR-based technologies, which encompass CAR T cells, CAR macrophages, and CAR-NK cells, show great promise in the treatment of various cancers. Despite the success of CAR-based therapies in treating malignancies, they face numerous challenges, including dysfunction of effector innate and adaptive immune cells, immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and on-target/off-tumor bio-toxicity. The CD47/SIRPα axis is recognized as a critical innate immune checkpoint and is important in regulating myeloid-derived clearance of tumor cells and the innate-adaptive cells' cross-talk in cancer immunity. This signaling axis has risen as a promising target to boost the CAR-based immunotherapies by overcoming phagocytic inhibition and modulating immune evasion. This narrative review explores the integration of CD47/SIRPα modulation as an adjunct to CAR therapies. CD47/SIRPα immune-modulation revealed its potential to boost infiltration, persistence, and phagocytic activity of the immune cells. However, its blockade also poses challenges, including hematologic toxicities, CAR T cell clearance, and compensatory escape pathways. Future work will depend on selective targeting, combinatorial checkpoint modulation, and engineered CAR designs that preserve safety while unlocking durable responses. Herein, we discuss pre-clinical and clinical advancements, safety considerations, and cutting-edge advancements.

Due to the paucity of validated cell surface osteosarcoma-specific targets, patients with this condition have long been excluded from the benefits of antibody-drug conjugate (ADC) therapy observed in patients with several solid and hematologic malignancies. Our comprehensive surfaceome profiling approach previously identified osteosarcoma-specific cell-surface antigens that are highly expressed in osteosarcomas but minimally expressed in normal tissues. As a result, one such antigen, CADM1, was selected for the generation of an ADC. We tested a CADM1-targeting ADC with a tesirine payload (SG3249) in vitro in osteosarcoma, rhabdomyosarcoma, and neuroblastoma patient-derived xenograft cell lines. In vivo, we tested six CADM1-expressing osteosarcoma patient-derived xenograft models. The CADM1 ADC demonstrated significant antitumor activity in vitro across the osteosarcoma, rhabdomyosarcoma, and neuroblastoma cell lines. Additionally, it effectively reduced tumor volume and extended event-free survival in all six osteosarcoma PDX models tested. Notably, the CADM1 ADC achieved a major complete response in one model (OS2), complete responses in two models (OS1 and OS33), and partial responses in three models (OS9, OS17, and OS31). Based on these results, clinical development of CADM1-targeted therapies for osteosarcoma and other CADM1-expressing pediatric solid tumors may be warranted.

As many as 90% of human pancreatic ductal adenocarcinoma (PDAC) tumors harbor gain-of-function mutations in the KRAS oncogene. Recently, inhibitors of the most common KRAS mutation, KRASG12D, have entered the clinical arena. However, early evidence suggests that as monotherapy, KRASG12D inhibitors such as MRTX1133 at best provide brief periods of disease stabilization. Hence, there is a growing interest in understanding the mechanisms through which tumors acquire resistance to KRAS inhibition. In the present study, we generated in vitro models of MRTX1133 resistance and subjected parental and drug-resistant cell lines to RNA sequencing. This suggested that MRTX1133-resistant tumor cells undergo a global shift toward histone acetylation. Inhibition of the histone acetyltransferase EP300 reversed the drug-resistant phenotype in vitro, which subsequent RNA sequencing experiments determined was associated with the suppression of pro-survival FOSL1 signaling. Accordingly, siFOSL1 reversed the MRTX1133-resistant phenotype with similar effects on pro-survival signaling. Given the lack of clinically useful EP300 or FOSL1 inhibitors, we next explored whether inhibitors of the acetylation scanning BET proteins would be similarly effective. The addition of BET inhibitors re-sensitized several resistant cell lines to MRTX1133 and impaired FOSL1-mediated survival signaling in vitro. In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition.

PROTACs are bivalent molecules that simultaneously bind to proteins of interest and cellular ubiquitin E3 ligases to promote target degradation. Tumor-specific expression of E3 should increase therapeutic efficacy and reduce toxicity in cancer therapy applications. The E3 ligases currently employed during PROTAC design such as CRBN, VHL, c-IAP and MDM2 are ubiquitously expressed and not considered tumor-specific. However, MDM2 is part of the p53 negative feedback loop and is dynamically regulated at transcriptional and post-translational levels. MDM2 gene amplification occurs at 4-20% frequency in multiple tumor types. To investigate whether MDM2 can serve as tumor-specific PROTAC E3 in certain setting, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. The results showed that A1874 activity is dependent on p53-mediated induction of MDM2 expression and is inactive in cells with mutant p53. Importantly, A1874 showed on average ~12-fold higher potency in tumor cells with MDM2 amplification compared to non-amplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using PROTAC approach.

Effective treatment for metastatic cancer has remained elusive due to the persistence of drug-resistant metastasis stem cells (MetSCs) that drive relapse. MetSCs are tumor cell subpopulations enriched for their ability to reinitiate and sustain metastatic growth, displaying phenotypic plasticity and resistance to chemotherapy. These cells express the L1 cell adhesion molecule (L1CAM), a transmembrane protein detected in numerous human solid tumor types and at multiple disseminated organ sites. As a selective surface marker of MetSCs, L1CAM is a promising candidate for molecularly targeted drugs aimed at eliminating metastases, yet strategies to date have not achieved clinical success. Here, we develop antibody-drug conjugates (ADCs) to deliver highly toxic PNU-159682 payloads to L1CAM-expressing cells. We report the generation of monoclonal antibodies (mAb) with high binding affinity, specificity and selectivity for the human L1CAM extracellular domain. Optimized L1CAM-targeting mAbs were conjugated to PNU-159682 to generate ADC variants with both cleavable and non-cleavable linkers, with an average drug-antibody-ratio (DAR) of four. ADCs derived from three antibodies targeting various epitopes of the L1CAM extracellular portion potently killed cells exhibiting varying levels of surface L1CAM expression. L1CAM ADCs given as monotherapy resulted in robust tumor control and extended survival in mice harboring subcutaneous L1CAM+ xenografts or L1CAM+ lung metastases from triple-negative basal breast cancer and lung adenocarcinoma. Safety analyses with mouse cross-reactive antibodies indicate a feasible therapeutic window. Our findings offer strong proof-of-concept to support the preclinical development of these novel L1CAM ADCs as therapeutic agents for advanced solid tumors.

Radiation remains a primary treatment for glioblastoma (GBM), yet tumors frequently recur within 2 years. In this study, orthotopic xenografts initiated from glioma stem-like cells (GSC) 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 and olfactory bulb (OB), whereas postirradiation 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 with untreated tumors. A total of 463 genes were differentially expressed, and gene set enrichment analysis revealed significant enrichment of pathways related to cell-cycle regulation in the recurrent as compared with 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 with 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. Whereas ixazomib had no effect on untreated tumors, its administration after 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.

The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria for trastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY® domain-based HER2-targeting, T cell receptor (TCR)αβ-based T cell engager (TCE) molecule-TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma (GEJ) cancers. TPP-45142 mediated potent T cell-dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favourable therapeutic index as per a cytokine release assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.

RAS genes encode small GTPases essential for mammalian cell proliferation, differentiation, and survival. RAS gene mutations are associated with 20% to 30% of all human cancers. Based on earlier reports of extremely high Ras binding affinities for GTP, Ras proteins were previously considered undruggable. Using three independent techniques, we report binding affinities of K-Ras and several K-Ras mutants for GTP in the 250 to 400 nmol/L range, orders of magnitude lower than previously reported (∼10 pmol/L). This discovery suggests that K-Ras and other small-GTPase proteins may indeed be druggable targets. We identified more than 400 small molecules that compete non-covalently with GTP binding to K-Ras. Focusing on two inhibitors, we demonstrate the inhibition of K-Ras in downstream signaling and cellular proliferation in human pancreatic and non-small cell lung cancer cells expressing wild-type or mutant K-Ras. These two compounds represent novel pan-Ras superfamily inhibitors as they also inhibited GTP binding to other members such as RAB5A and RAB35.

Proteolysis-targeting chimeras (PROTACs) leverage the ubiquitin-proteasome system to selectively degrade oncogenic proteins, including such previously seen as undruggable. Recent preclinical studies indicate that PROTACs may come as novel therapeutic strategy in lymphoma and myeloma. Indeed, preclinically, PROTACs have high efficacy and remarkable selectivity, favorable safety profile and lower toxicity compared to conventional therapies. Their catalytic, reusable mechanism enables drug dosing and offers the perspective of a long-term low dose treatment. PROTACs demonstrated their ability to overcome drug resistance by targeting and degrading overexpressed or mutant proteins, which are responsible for refractory disease. This review aims to offer a comprehensive evaluation of the current existing PROTACs that have been tested in Lymphoma and Myeloma, to highlight the need for drug optimization and further translational research that could translate PROTACs to clinical trials.

Tumor-associated mucin-1 (TA-MUC1) is a glycoform of the MUC1 protein that is aberrantly glycosylated and is primarily observed in cancer cells. TA-MUC1 is highly expressed in various human epithelial cancers, making it an attractive target for cancer therapies. In this study, we describe the development of DS-3939a, a novel TA-MUC1-targeting antibody-drug conjugate that utilizes the potent DNA topoisomerase I inhibitor DXd, and evaluation of its pharmacologic activity in preclinical in vitro and in vivo models. IHC of clinical tumor tissue microarrays of various cancer types exhibited positive staining for TA-MUC1 in a number of samples, with a particularly high positive rate in bladder, lung, and breast cancers. In vitro profiling of DS-3939a confirmed that it could specifically bind to TA-MUC1 and inhibit the growth of TA-MUC1-positive cancer cells by inducing DNA damage and apoptosis. DS-3939a also exhibited significant antitumor effects in multiple TA-MUC1-positive cell line-derived and patient-derived xenograft models. Moreover, DS-3939a elicited strong tumor regression in several xenograft models even following treatment with other cytotoxic antibody-drug conjugates, likely through its efficient payload delivery. Overall, these data provide evidence for the potential utility of DS-3939a for the treatment of TA-MUC1-expressing tumors and support the rationale for the ongoing phase I/II clinical study (NCT05875168).