Molecular Cancer Therapeutics最新文献

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce anti-tumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FoxP3+CD4+ T cells than either monotherapy alone. Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of Tregs through innate immune cells, potentially by activation of type I interferon responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.

In chordoma, epidermal growth factor receptor (EGFR) blockade shows significant but incomplete anti-tumor activity, suggesting that inhibition of other tumor growth promoting pathways is required for enhanced efficacy. Here, we detected high expression of cyclin-dependent kinase (CDK) 7 and 9 in both sacral and clival chordomas, and subsequently explored the efficacy of the CDKs inhibitors THZ1 and TG02, both as single agents and in combination with EGFR inhibitor afatinib in preclinical chordoma models. Monotherapy with THZ1, TG02, and afatinib led to decreased cell viability, proliferative capacity, colony formation and induced cell apoptosis across multiple chordoma cell lines, and enhanced activity was observed with THZ1/afatinib and TG02/afatinib co-treatments. Mechanistically, THZ1 and TG02 attenuated phosphorylation of POL II, leading to transcriptional inhibition of the chordoma driver gene brachyury, which was enhanced when combined with afatinib. Both CDK inhibitors also reduced expression of MCL1 which was further suppressed with combination therapy. Importantly, co-treatments exhibited greater inhibition of tumor growth than single treatments in cell line- and patient-derived xenograft models. Taken together, our data revealed that THZ1 or TG02 enhanced in vitro and in vivo efficacy of afatinib, suggesting a potential novel combination therapeutic strategy for patients with chordoma.

The therapeutic benefit of the combination of the first generation BRAFi encorafenib and the EGFR blocking antibody cetuximab in second line metastatic colorectal cancers (CRC) harboring BRAF V600E mutations remains limited and short lived. Here, we present the preclinical characterization of the next generation BRAF inhibitor mosperafenib (RG6344/RO7276389) in colorectal cancer (CRC) models. Mosperafenib was designed as a MAPK paradox breaker. Since it does not trigger P-ERK over-activation in BRAF WT contexts we hypothesized that it may lead to an improved safety profile while reaching higher target coverage in the clinic. In in vivo experiments conducted in BRAFi naïve xenograft models, mosperafenib monotherapy outperformed encorafenib/cetuximab at clinically relevant doses indicating higher activity of mosperafenib. Combination of mosperafenib and cetuximab demonstrated potent activity with tumor regression and long survival benefits in BRAFi naïve models and in PDX models derived from patients that progressed to encorafenib/cetuximab therapy supporting the activity of mosperafenib even in BRAFi experienced patients. Additional combination studies of mosperafenib with FOLFOX resulted in tumor regression and superior activity compared to the same combination with encorafenib. Collectively these data provide a strong preclinical rationale for the potentially transformative activity of mosperafenib as monotherapy and as a preferred backbone BRAFi for combinatorial regimen for BRAF mutated CRC.

Antibody-drug conjugates (ADCs) have recently emerged as an effective treatment option for cancer. While 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 anti-tumor 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 IL-10RA. 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 anti-tumor response mediated by memory CD8+ T cells were crucial for the formation of immunological memory induced by both ADCs. Therefore, our findings reveal that, after ADC-mediated tumor cytotoxicity, different ADC payloads elicit distinct immunological responses characterized by varying levels of myeloid cell activation within the TME.

OBI-992, a novel TROP2-targeted antibody-drug conjugate (ADC), is composed of an anti-TROP2 antibody conjugated to exatecan, a topoisomerase 1 inhibitor, via an enzyme-cleavable hydrophilic linker. The stability, pharmacokinetics, pharmacodynamics, and off-target toxicity of OBI-992 were evaluated and compared with a benchmark ADC, datopotamab deruxtecan (Dato-DXd). OBI-992 exhibited better stability in human and monkey serum than Dato-DXd, which was further supported by in vivo PK study in rats. OBI-992 displayed a favorable pharmacokinetic profile compared with Dato-DXd in non-small cell lung cancer cell line-derived xenograft mouse models (NCI-H1975 and NCI-H1975/C797S), with lower clearance, longer half-lives of ADC in serum, and higher exposure of payload in tumor. The higher level of breast cancer resistance protein expression was detected in NCI-H1975/C797S cells, which may contribute better antitumor activity of OBI-992 compared with Dato-DXd as DXd is a much better substrate to breast cancer resistance protein than exatecan. The levels of the payload of OBI-992 in nontarget organs were lower or comparable with Dato-DXd. In addition, OBI-992 exhibited lower toxicity compared with Dato-DXd in the monocytic cell line THP-1 and differentiated neutrophils. Furthermore, in the Good Laboratory Practice toxicity study with cynomolgus monkeys, the highest nonseverely toxic dose was determined to be ≥60 mg/kg. Major toxicities were target-related skin lesions and reduced reticulocytes, which were reversible during recovery period. These results support further clinical development of OBI-992 for the treatment of TROP2-expressing cancers, which is currently in a phase 1 clinical trial (NCT06480240).

Ferroptosis has recently been described as an iron-dependent subroutine of programmed cell death. Cancers driven by oncogenic Ras mutations, such as pancreatic ductal adenocarcinoma, are particularly vulnerable to ferroptosis and are thus promising candidates for antineoplastic drugs targeting this unique form of programmed cell death. Our group has developed a cancer-specific drug conjugate (ACXT-3102), consisting of a proapoptotic sigma-2 ligand as a delivery moiety (SV119), linked to an inhibitor of the cystine antiporter xCT (dm-erastin), an established inducer of ferroptosis. We hypothesized that ACXT-3102 would trigger apoptosis and ferroptosis via its discrete chemical components, representing a new approach to clinical therapy for pancreatic ductal adenocarcinoma. In vitro cell viability assays corroborated our earlier findings that ACXT-3102 is a potent inducer of cancer cell death. The sigma-2 delivery component of ACXT-3102 induced canonical markers of apoptosis, including cleaved caspase-3/7 and PARP, whereas the dm-erastin cargo component induced canonical markers of ferroptosis, including lipid peroxidation and consumption of glutathione peroxidase 4. These changes resulted in the accumulation of reactive oxygen species. Subsequently, we found that ACXT-3102-mediated cell death was accompanied by the activation of MAPK/ERK signaling, presumably via the reactive oxygen species-dependent degradation of dual-specificity phosphatase 6, a negative regulator of MAPK/ERK phosphorylation. We suspected that this was a compensatory reaction and that ACXT-3102-induced cancer cell death would be augmented by inhibition of MAPK/ERK signaling. We successfully combined ACXT-3102 with trametinib (MEK inhibitor) to enhance the overall efficacy of treatment in vitro and in vivo, presumably by targeting ACXT-3102-induced upregulation of MAPK/ERK.

Glioblastoma, the most aggressive primary brain tumor, carries a dismal prognosis, with median survival remaining under 15 months despite standard therapies. This is largely because of the tumor's infiltrative nature, the restrictive blood-brain barrier, and intratumoral heterogeneity. Chlorotoxin (CTX), a 36-amino acid peptide derived from scorpion venom, has emerged as a promising multifunctional agent with high specificity for neuroectodermal tumors. In this comprehensive review, we highlight CTX's potential to address critical limitations of current glioma treatments by bridging diagnostic and therapeutic modalities. Diagnostic advancements include CTX-conjugated near-IF fluorophores and nanoparticles for fluorescence-guided surgery and multimodal imaging to enhance intraoperative accuracy. On the therapeutic front, CTX enables targeted delivery of siRNA, radioisotopes, and novel immunotherapies such as CTX-directed chimeric antigen receptor T cells. We also examine emerging clinical data supporting the safety and preliminary efficacy of CTX-based interventions. Collectively, CTX represents a paradigm shift in neuro-oncology, offering a single molecule with both diagnostic and therapeutic capabilities. Its utility may also extend beyond gliomas to metastases and other malignancies within and beyond the central nervous system.

Glioblastoma (GB) is the most common and aggressive brain-derived tumor. It often shows genetic alterations in kinase signaling pathways, such as the Pi3K/mTOR and RAS/MAPK pathways, which frequently converge onto oncogenic processes. However, it is unknown to what extend co-vulnerabilities exist within this network and which kinase drug targets are promising for GB treatment. We investigated the drug sensitivity of GB cell line models to monotherapy and synergy effects in dual combination therapy to targeting components of Pi3K/mTOR and RAS/MAPK pathways. In addition, we examined cell line drug sensitivities in relation to their individual genetic tumor-driving lesions [i.e., neurofibromin 1 (NF1) alterations as well as transcriptomic defined GB subtypes]. Synergy levels were correlated to in-lab generated phosphoproteomic data. Lastly, serial or simultaneous addition of MEK and mTOR inhibitors was investigated in longitudinal experiments. Dual inhibition of MEK and mTOR resulted in synergistic effects, which were associated with NF1 deficiency. Strong synergy effects were also associated with the mesenchymal subtype. Dual inhibition of MEK and mTOR led to prolonged growth inhibition in GB spheroids. In addition, sequential drug treatment resulted in similar growth inhibitory effects compared with simultaneous combination therapies. Our findings highlight the potential of dual inhibition strategies targeting multiple kinases for the treatment of GB, particularly in NF1-deficient and mesenchymal tumors, the most lethal subtype of GB.

Myeloid cells are key mediators of immunosuppression and treatment resistance in primary brain tumors, including glioblastoma (GBM). This study aims to eradicate CD11b+ immunosuppressive cells at the tumor site to enhance overall survival in a model of GBM using an α-emitting radiopharmaceutical therapy targeted to tumor-associated myeloid cells as a monotherapy or in combination with immune checkpoint inhibitors. An anti-CD11b (αCD11b) antibody was modified for radiolabeling with diagnostic (zirconium-89) or therapeutic (actinium-225) radioisotopes. Initial PET imaging and biodistribution studies using 89Zr-αCD11b found that an antibody concentration of ∼5 mg/kg of αCD11b (100 μg) was effective in saturating on-target/off-site sinks, such as the spleen, but effective in increasing tumor accumulation. The estimated maximum tolerable activity of [225Ac]Ac-DOTA-αCD11b (225Ac-αCD11b) was determined by biodistribution and dosimetry studies, including the free in vivo-generated decay daughters. The dose-limiting tissue was the bone marrow, and an estimated maximum tolerable activity (∼0.55 kBq, 100 μg) was determined. The therapeutic efficacy of 225Ac-αCD11b was evaluated by survival studies, both as a monotherapy and in combination with immune checkpoint inhibitors. Combination therapy resulted in increased survival in the GBM model compared with the monotherapy and controls; in addition, long-term survival was observed in 50% of the mice receiving combination therapy as well as in a single mouse receiving 225Ac-αCD11b alone. No long-term surviving mice were observed in the control groups. Long-term surviving mice were rechallenged, and potential antitumor immunity was observed, as no tumors developed over 120 days after rechallenge. Overall, these results validate the preclinical relevance of CD11b-targeted image-guided α-emitting radiopharmaceutical therapy.

Targeting PIK3CA-mutant colorectal cancers with precision medicine strategies is of great clinical interest. However, resistance to single-agent PI3K pathway inhibitors has been observed across multiple clinical trials, necessitating the identification of combination therapies that overcome or prevent resistance to precision medicine strategies. Previously, our group identified that inhibition of mTORC1/2 is necessary to induce a response in PIK3CA-mutant colorectal cancers. The PI3K/mTORC1/2 inhibitor copanlisib has demonstrated some clinical activity in PIK3CA-mutant solid tumors as part of the NCI-MATCH trial. In this study, we evaluate potential combination therapies that could enhance the efficacy of copanlisib and other similar inhibitors in PIK3CA-mutant colorectal cancers. Using a novel high-throughput drug screen method in Apc- and Pik3ca-mutant mouse-derived cancer organoids, we identify navitoclax, a BCL-2 family inhibitor, as a drug that could potentially enhance the response to copanlisib. Across multiple in vitro and in vivo colorectal cancer models, navitoclax enhanced PI3K/mTOR inhibition (copanlisib, sapanisertib, and dactolisib) and induced apoptosis. Furthermore, we examine these combination therapies across a panel of patient-derived cancer organoids with a range of mutation profiles. These studies indicate that KRAS mutations could confer resistance. Furthermore, we identify BCL-xL as the major BCL-2 family target important for the response to this combination in this setting. This provides a strong rationale for mTORC1/2 and BCL-2 family inhibition as a potential treatment strategy for PIK3CA-mutant colorectal cancers.