Molecular Cancer Therapeutics最新文献

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.

Despite new therapies, many patients with non-Hodgkin lymphoma (NHL) relapse and need more effective salvage therapies. This study (NCT02483000) evaluated the safety of B9E9-FP, a tetrameric single-chain anti-CD20-streptavidin fusion protein used in pretargeted radioimmunotherapy, when combined with BEAM and autologous stem cell transplantation (ASCT) for patients with NHL. Patients with high-risk NHL received B9E9-FP on day -17, clearing agent on day -15, and DOTA-biotin (DOTA-Bt) equally divided and labeled with dose-escalated yttrium-90 (90Y) or with indium-111 (for imaging) on day -14. BEAM chemotherapy started at day -7 before stem cell infusion. Three patients with NHL (mantle cell lymphoma, transformed diffuse large B-cell lymphoma, and de novo diffuse large B-cell lymphoma), ages 52 to 62 years, were treated with 30, 50, or 70 mCi (1,110, 1,850, or 2,590 MBq) 90Y/m2 before ASCT without any dose-limiting toxicity. One case of diarrhea (grade 2) and one case of rash (grade 1) were possibly associated with B9E9-FP or DOTA-Bt, respectively. Pharmacokinetic studies showed peak blood biological percent injected dose per gram blood (% ID/g) of 90Y-DOTA-Bt at 15 minutes after infusion (14.8%-49.4% ID), with only 0.82% to 2.59% ID after 72 hours. Uptake was preferential at bone marrow (1.73-5.96 cGy/mCi injected) and spleen (2.4-4.17 cGy/mCi injected) compared with lungs (0.19-0.48 cGy/mCi). Unbound 90Y-DOTA-Bt was excreted renally without any renal dysfunction noted up to 2 years later. Two of the three enrolled patients are alive and in remission 3.5 to 4.9 years after transplant. Pharmacokinetic, dosimetry, and outcome data support that B9E9-FP pretargeted radioimmunotherapy combined with 90Y-augmented ASCT DOTA-Bt is feasible.

Epigenetic aberrations are key drivers of multiple myeloma (MM), yet targeted therapies exploiting epigenetic alterations have not been established. By integrating clinical and molecular MM patient data sets with an unbiased genetic in vivo screen, we identified KAT8 regulatory NSL complex subunit 2 (KANSL2) as a histone posttranslational modification (PTM)-associated candidate oncogene. High expression of KANSL2 was associated with adverse prognosis in MM patients. Genetic gain and loss of function models identified a protective role of KANSL2 towards genotoxic stress. By transcriptomics, proteomics and quantitative acetylome profiling, we identified a KANSL2-dependent specific molecular program targetable by acetylation-related modifiers. High KANSL2 levels increased sensitivity to the histone deacetylase (HDAC) inhibitor panobinostat and bromodomain and extra-terminal motif (BET) inhibitor OTX-015 and their combination. Ex vivo drug response profiling in relapsed/refractory MM patient samples confirmed that high KANSL2 expression is associated with selective MM cell killing by HDAC and BET inhibitors. Collectively, these findings position KANSL2 as a mediator of chemotherapy resistance and actionable biomarker for response to drugs targeting its epigenetic program.

Breast cancer brain metastasis (BCBM) remains a clinical challenge marked by limited therapeutic options and poor survival rates. Approximately 30% of all metastatic breast cancer patients develop BCBM, with the highest incidence in patients with aggressive molecular subtypes, including triple-negative breast cancer (TNBC). TNBC patients with brain metastasis experience rapid disease progression and significantly reduced survival times due to a lack of targeted treatments that can penetrate the blood-brain barrier (BBB) and effectively control metastatic expansion. Current treatment options, such as whole-brain radiotherapy and chemotherapy, offer limited efficacy and are associated with significant toxicities, underscoring the urgent need for novel therapeutics that can target BCBM directly. We developed innovative colchicine binding site inhibitors (CBSIs) targeting tubulin, SB-216 and SP-1-39, that show potent preclinical efficacy against brain and extracranial metastases in BCBM models. Both CBSIs cross the BBB, inhibit cell growth and migration, and induce apoptosis with low nM potencies, similar to Azixa (MPC-6827), another CBSI previously evaluated in clinical trials. SB-216 reduced brain and concurrent extracranial metastases in a preventive dosing paradigm, extending overall survival. SB-216 also suppressed the expansion of pre-established brain lesions. In a taxane-refractory TNBC PDX model, SP-1-39 therapy markedly reduced brain and extracranial tumor burden. Together, these results highlight the promising therapeutic potential of SB-216 and SP-1-39 in treating taxane-sensitive or -resistant BCBM, filling a critical gap in TNBC management by offering targeted treatments that can cross the BBB and combat chemorefractory disease.

AXL is an important negative regulator of type I interferon (IFN) responses during viral infections. In the context of tumors, AXL is associated with driving tumor progression, spread, immune evasion, and therapy resistance. AXL regulation of tumor cell intrinsic IFN responses remains unexplored. We show that AXL suppresses tumor intrinsic IFN responses by inhibiting the cytosolic DNA sensor cGAS via an AKT-dependent pathway. AXL inhibition in combination with chemo-immunotherapy demonstrated potent anti-tumor effects in poorly immunogenic tumors that are refractory to immunotherapy. The inhibition of AXL correlated with increased cGAMP levels, activation of IFN, and enhanced infiltration of T cells and NK cells into the tumor microenvironment. These findings reveal a novel role for AXL in suppressing IFN within tumors and support AXL targeting as a promising strategy in conjunction with chemo-immunotherapy for treating therapy-resistant tumors.