Molecular Cancer Therapeutics最新文献

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.

Metastatic prostate cancer (mPC) is a lethal disease; most therapeutic options focus on androgen receptor signaling inhibition, but resistance eventually arises. Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have shown antitumor efficacy in mPC preclinical models, but their efficacy in mPC clinical trials has been limited. We hypothesize that novel combination therapies designed leveraging mPC adaptation to CDK4/6i could lead to increased and sustained antitumor effect. In this study, we demonstrate in a range of in vitro and in vivo prostate cancer models, including patient-derived xenografts, that prostate cancer cells adopt a senescent phenotype upon CDK4/6 inhibition that can be selectively targeted using senolytic compounds. Notably, interrupting CDK4/6 inhibition in intermittent drug schedules prompts a rapid bypass of the senescent phenotype that is associated with a temporal downregulation of replisome proteins in Rb-proficient but not in Rb-deficient models, leading to DNA damage accumulation and replication stress following treatment withdrawal. This effect opens a window of opportunity for treatment with PARP inhibitors (PARPi): Although upfront combined inhibition of CDK4/6 and PARP1 had no antitumor effect, their sequential use adding PARPi upon CDK4/6i withdrawal and cell-cycle reentry results in major antitumor activity. Our findings underscore the potential of CDK4/6i in prostate cancer therapy, particularly when administered under biology-driven sequential use of senolytic therapy or PARPi. Such strategic interventions hold promise in overcoming resistance and enhancing treatment outcomes for patients with advanced prostate cancer and open avenues for repurposing CDK4/6i therapy in mPC.

Precision medicine is a likely future for all cancer treatment but may have its greatest impact on less common, high-mortality, and molecularly heterogeneous cancers. TFCP2-rearranged rhabdomyosarcoma (RMS) is a rare, aggressive cancer with poor survival due to the lack of effective therapies and relevant models to facilitate research. In this study, we establish the first matched patient-derived xenograft and cell line model for TFCP2-rearranged intraosseous RMS, coupled with comprehensive multiomic and functional analyses, to discover and preclinically validate novel actionable molecular targets for this malignancy. Sequencing analyses of matched patient tumor and xenograft material revealed alterations in gene networks associated with the oncogenic, potentially targetable PI3K/AKT pathway. Preclinical assessments revealed that targeting the pathway with a small-molecule PI3K/mTOR inhibitor dactolisib presents a promising treatment approach for this rare cancer, decreasing cancer cell viability in vitro and significantly reducing tumor growth in vivo. Parallel identification of the codeletion of adjacent genes cyclin-dependent kinase inhibitor 2A and methylthioadenosine phosphorylase in these tumors led us to further explore protein arginine methyltransferase 5 inhibition as a potential therapeutic approach. Strikingly, combined inhibition of protein arginine methyltransferase 5 and PI3K/mTOR signaling synergistically enhanced antitumor response and significantly improved survival in vivo. This study highlights the importance of new patient-derived models for the elucidation of the biology of rare cancers and identification of new therapeutic entry points, with clear implications for the future treatment of TFCP2-rearranged intraosseous RMS.

The oncofetal antigen 5T4 is expressed in many solid tumors, making it an attractive antitumor target. XB010 is a novel, 5T4-targeted, antibody-drug conjugate developed using the SMARTag platform to optimize tolerability. We describe the development, design, and preclinical characterization of XB010. In vitro and in vivo efficacy of XB010 was assessed in cell-derived xenograft breast cancer cell lines (MCF-7 and MDA-MB-468) and in patient-derived xenograft tumor models (squamous cell carcinoma of the head and neck, non-small cell lung cancer, and breast cancer). Additionally, the in vivo combinatorial efficacy of XB010 + anti-PD-1 antibody was assessed in an MC38-h5T4 syngeneic colon cancer xenograft model. The toxicity profile of XB010 was evaluated in both Sprague-Dawley rats and cynomolgus monkeys. XB010 demonstrated in vitro cytotoxic effects with sub-nanomolar potency in the MCF-7 and MDA-MB-468 breast cancer cell lines and in vivo tumor growth inhibition (80%-99%) compared with vehicle-treated animals in xenograft and patient-derived xenograft models at doses of 5 to 10 mg/kg XB010. In the syngeneic MC38-h5T4-expressing colon cancer xenograft model, XB010 + anti-PD-1 showed improved efficacy compared with either agent administered alone. XB010 safety assessments demonstrated tolerability of doses up to 60 mg/kg in rats and up to 25 mg/kg in nonhuman primates. XB010 is a novel anti-5T4 antibody-drug conjugate that exhibits potent antitumor activity, inhibiting cancer cell growth in vitro and tumor growth in various in vivo models, with an acceptable toxicity profile. These findings support the evaluation of XB010 in clinical studies.

CanAg (CA242) is a carbohydrate antigen highly overexpressed in most gastrointestinal cancers, with minimal expression in normal tissue, making it an attractive target for antibody-drug conjugate (ADC) therapeutics in these cancers. Previous efforts to target CanAg with ADCs have shown limited clinical efficacy, possibly due to resistance to the tubulin inhibitor payloads used. IKS04 is a novel CanAg-targeting ADC comprising an anti-CanAg humanized mAb Isumab04 and a highly potent pyrrolobenzodiazepine prodrug payload. However, the use of potent payloads such as pyrrolobenzodiazepines can limit the maximum tolerated dose of ADCs, which in turn limits tumor tissue penetration and efficacy, particularly for high-expression targets such as CanAg. Coadministration of unconjugated antibody can potentially improve tumor tissue penetration, resulting in increased ADC efficacy. In this study, we evaluated the impact of Isumab04 coadministration on the distribution and efficacy of IKS04 in human tumor xenograft mouse models with different CanAg expression levels. Although the addition of the Isumab04 antibody showed minimal impact on IKS04 cell-killing activity in vitro in cells with moderate and high CanAg expression, coadministration of Isumab04 with IKS04 improved tumor tissue distribution of the ADC in both tumor spheroids and in vivo tumor models. This improved distribution correlated with increased efficacy in vivo, in which increasing doses of unconjugated antibody resulted in greater efficacy until apparent tumor saturation was reached. These results support the use of antibody coadministration to improve the efficacy of ADCs targeting high-expression antigens with highly potent payloads.

Metabolic reprogramming constitutes a key mechanism driving immunotherapy resistance in colorectal cancer although the immunomodulatory role of L-arginine metabolism remains poorly defined. Through metabolomic profiling, we identified aldehyde dehydrogenase 2 (ALDH2) as a critical regulator depleting intracellular L-arginine pools in colorectal cancer cells. High-performance liquid chromatography analysis of cell supernatants further demonstrated that ALDH2 overexpression significantly diminishes extracellular L-arginine availability. Functionally, this arginine deficiency suppressed CD8+ T-cell proliferation while inducing the attenuation of antitumor efficacy. Mechanistic studies revealed that ALDH2 upregulates pre-B-cell leukemia homeobox 3 (PBX3), which enhances arginase 2 (ARG2) transcription to promote L-arginine catabolism. This process suppresses glycolysis in CD8+ T cells, ultimately compromising their effector functions. Notably, ALDH2-high tumors exhibited resistance to immune checkpoint blockade (ICB), whereas combinatorial ARG2 inhibition and ICB therapy synergistically restored antitumor immunity. These findings nominate ARG2 as a novel therapeutic target and propose dual metabolic-immunologic intervention as a promising strategy for ICB-resistant colorectal cancer.

PIK3CA and KRAS are among the most frequently mutated oncogenes and often co-mutated in colorectal cancers. Understanding the impact of KRAS codon-specific mutations on cross-talks between the PI3K and MAPK pathways and response to targeted therapies, such as the p110α-specific inhibitor inavolisib (GDC-0077), is critical for advancing precision oncology. Focusing on colorectal PIK3CA + KRAS co-mutated models, we found that KRASG12D-mutated cells were more sensitive to inavolisib than models with KRASG13D, or other MAPK pathway mutations, even though the PI3K and MAPK pathways were active in both genotypes. In most co-mutated models, regardless of the type of KRAS alteration, the combination of inavolisib with MAPK pathway inhibitors showed synergy in vitro and in vivo. Our work highlights how specific codon substitutions in KRAS differentially toggle pathway activity and alter sensitivity to inavolisib, which could inform whether patients would benefit more from single-agent inavolisib or combination with MAPK pathway inhibitors.