Anticancer Treatment Strategies Research Articles

A First-in-Human, Open-Label, Phase I Dose Escalation Trial of Daily Oral Nmt Inhibitor Zelenirstat in Patients with Relapsed/Refractory B-Cell Lymphomas and Advanced Solid Tumors

Background Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. Zelenirstat (PCLX-001) is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC 50 of 5nM and 8nM, respectively). In vitro hematologic cancer cell lines were exquisitely sensitive to zelenirstat. Zelenirstat regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient (pt) derived xenograft model. Zelenirstat also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we conducted a phase I dose escalation trial to determine safety, tolerability, maximum tolerated dose (MTD), and pharmacokinetics (PK) of zelenirstat. Methods Pts with relapsed/refractory (R/R) B-cell lymphomas and advanced solid tumors were enrolled in a multicenter, open label, standard phase I dose escalation trial of once daily (OD) oral zelenirstat, administered in 28-day cycles until progressive disease or unacceptable toxicity. Seven dose levels were studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 210 mg, and 280 mg. Dose limiting toxicity (DLT), attributable to zelenirstat during cycle 1, was defined as: grade (Gr) 4 thrombocytopenia, Gr 3 thrombocytopenia with bleeding, Gr 4 neutropenia ≥ 7 days, febrile neutropenia, clinically significant > Gr 3 non-hematologic toxicity, or any significant toxicity warranting a hold of zelenirstat. Plasma PK were obtained on C1D1, C1D15, and trough concentrations C1D2, C1D16 and prior to each subsequent cycle. Response assessments occurred every 2 cycles to determine best overall response. Results Between Sept 2021 and Jul 2023, 21 DLT-evaluable pts [4 R/R B-cell lymphoma (3 DLBCL, 1 FL grade 3b); 17 advanced solid tumor (7 colorectal, 2 pancreas, 2 ovarian, 1 each of sarcoma, NSCLC, pleural mesothelioma, melanoma, CUP, bladder)] received zelenirstat at doses ranging from 20 mg OD to 280 mg OD. Dose escalation occurred without DLT until the 280 mg cohort where two DLTs were reported: a bladder carcinoma pt who developed nausea, vomiting, and drug-induced fever necessitating a hold of zelenirstat and a colorectal cancer (CRC) pt who had Gr 3 dehydration from nausea, vomiting, diarrhea, and oral mucositis. The maximal administered dose was 280 mg OD and the presumptive MTD was 210 mg OD. Drug compliance was high, and of 3 pts within the 210 mg cohort, none required dose reduction. Common treatment-emergent all-grade adverse events (AEs) at doses up to the 210 mg cohort were gastrointestinal and reported in 29% of pts. These were primarily diarrhea, nausea, or vomiting. Gr 2 thrombocytopenia occurred in 17% of patients. No other AEs were seen at a frequency of > 5%. There were no AEs of neuropathy, alopecia, or QT interval prolongation. Noncompartmental PK analyses demonstrated rapid oral absorption, a terminal half-life of approximately 10 hrs, rapid achievement of steady state, and no induction of metabolism. Zelenirstat trough plasma concentrations at 100 mg, 140 mg, and 210 mg doses markedly exceeded the EC 90 required to inhibit cultured cancer cells. Stable disease as best response was seen in five patients (pancreas at 40 mg; CRC at 140 mg; and two ovarian and one CRC at 210 mg). At the 210 mg dose, one of the ovarian cancer pts had a corresponding reduction of CA-125 (20%) while the CRC pt had a reduction in CEA (50%). Conclusions Zelenirstat is safe and well tolerated up to the 210 mg OD dose, which we have established as the presumptive MTD. Additional pts, including a phase IIA study in pts with R/R B-cell NHL, are accruing at this dose for further safety and activity exploration. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of antitumor activity support the ongoing development of zelenirstat for pts with R/R B-cell lymphomas and advanced solid tumors.

Spinning magnetic field patterns that cause oncolysis by oxidative stress in glioma cells

Raising reactive oxygen species (ROS) levels in cancer cells to cause macromolecular damage and cell death is a promising anticancer treatment strategy. Observations that electromagnetic fields (EMF) elevate intracellular ROS and cause cancer cell death, have led us to develop a new portable wearable EMF device that generates spinning oscillating magnetic fields (sOMF) to selectively kill cancer cells while sparing normal cells in vitro and to shrink GBM tumors in vivo through a novel mechanism. Here, we characterized the precise configurations and timings of sOMF stimulation that produce cytotoxicity due to a critical rise in superoxide in two types of human glioma cells. We also found that the antioxidant Trolox reverses the cytotoxic effect of sOMF on glioma cells indicating that ROS play a causal role in producing the effect. Our findings clarify the link between the physics of magnetic stimulation and its mechanism of anticancer action, facilitating the development of a potential new safe noninvasive device-based treatment for GBM and other gliomas.

Super enhancer-driven core transcriptional regulatory circuitry crosstalk with cancer plasticity and patient mortality in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer. Core transcriptional regulatory circuitry (CRC) consists of autoregulated transcription factors (TFs) and their enhancers, which dominate gene expression programs and control cell fate. However, there is limited knowledge of CRC in TNBC. Herein, we systemically characterized the activated super-enhancers (SEs) and interrogated 14 CRCs in breast cancer. We found that CRCs could be broadly involved in DNA conformation change, metabolism process, and signaling response affecting the gene expression reprogramming. Furthermore, these CRC TFs are capable of coordinating with partner TFs bridging the enhancer-promoter loops. Notably, the CRC TF and partner pairs show remarkable specificity for molecular subtypes of breast cancer, especially in TNBC. USF1, SOX4, and MYBL2 were identified as the TNBC-specific CRC TFs. We further demonstrated that USF1 was a TNBC immunophenotype-related TF. Our findings that the rewiring of enhancer-driven CRCs was related to cancer immune and mortality, will facilitate the development of epigenetic anti-cancer treatment strategies.

Early Assessment of Radiation Treatment at Clinical Field Strength by D2O Administration and Deuterium MRI

An accurate and non-invasive assessment of tumor response following treatment is essential. Traditional anatomical imaging techniques are insufficient before a significant morphological change can be observed. Metabolic imaging of molecular processes in the living body is also used. In recent years, deuterium magnetic resonance spectroscopic (MRS) imaging has been demonstrated as an alternative for cancer metabolic imaging by high-field (4-11T) MRI using deuterium-labeled molecules as a contrast agent. The study aim was to evaluate the feasibility of using deuterium MRI 1.5T for tumor visualization and early assessment of the efficacy of three anticancer treatment strategies (radiation and anticancer drugs) in pancreatic cancer model mice given heavy water (D2O) to induce deuterium (2H)-tissue labeling. A MIA PaCa-2 pancreatic cancer model of six BALB/c-nu mice was prepared, and repeated deuterium MRI was performed during the first 10 days after starting free drinking of 30% D2O. We also evaluated 2H accumulation in the tumor after irradiation, bevacizumab administration, or gemcitabine administration of other 20 mice. Additional confirmatory proton MRI, ex vivo metabolic hyperpolarization 13C-MRS and histopathology were performed. The mouse's whole-body distribution of 2H was visible 1 day after drinking, and the signal intensity increased daily. Although the tumor size did not change 1 and 3 days after irradiation, the amount of 2H in the tumor decreased significantly. The 2H image intensity of the tumor also significantly decreased after the administration of bevacizumab or gemcitabine. Metabolic hyperpolarization 13C-MRS, proton MRI and 2H-NMR spectroscopy confirmed the efficacy of the anticancer treatments. Deuterium MRI at 1.5T proved feasibility to track 2H distribution throughout mouse tissues during D2O administration and revealed a higher 2H accumulation in the tumor xenografts. This research demonstrated a promising successful method for early assessment of radiotherapy and chemotherapy of pancreatic cancer.

Identification of Fangchinoline as a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer

Autophagy is a fundamental recycling pathway that enhances cellular resilience, promoting survival. However, this survival mechanism can impede anti-cancer treatment strategies designed to induce cell death. In this study, we identified a novel autophagy inhibitor, Fangchinoline (Fan) isolated from the traditional Chinese medicine Stephania tetrandra. We speculated that when Fan blocks autophagy, cancer cells lose substantial self-preservation abilities during treatment. Firstly, we examined in detail the mechanism through which Fan inhibits autophagy. Specifically, Fan induced a significant increase in autophagosomes, as indicated by GFP-LC3 labeling, confirmed by the up-regulation of LC3-II. The autophagy receptor protein p62 was also up-regulated, suggesting a potential inhibition of autophagy flux. We further ruled out the possibility of fusion barriers between lysosomes and autophagosomes, as confirmed by their co-localization in double fluorescence staining. However, the lysosomal acid environment might be compromised, as suggested by the diminished fluorescence of acidity-sensitive dyes in the lysosomes and the corresponding decrease in mature forms of lysosomal cathepsin. To test the anti-cancer potential of Fan, we combined it with Cisplatin (Cis) or Paclitaxel (PTX) for lung cancer cell treatment. This combined treatment demonstrated a synergistically enhanced killing effect. These promising anti-tumor results were also replicated in a xenografted tumor model. The significance of this research lies in the identification of Fan as a potent autophagy inhibitor and its potential to enhance the efficacy of existing anti-cancer drugs. By unraveling the mechanisms of Fan's action on autophagy and demonstrating its synergistic effect in combination therapies, our study provides valuable insights for developing novel strategies to overcome autophagy-mediated resistance in cancer treatment.

Blocking LTB4 signaling-mediated TAMs recruitment by Rhizoma Coptidis sensitizes lung cancer to immunotherapy

BackgroundImmune checkpoint blockade (ICB) induces durable immune responses across a spectrum of advanced cancers and revolutionizes the oncology field. However, only a subset of patients achieves long-lasting clinical benefits. Tumor-associated macrophages (TAMs) usually secrete immunosuppressive cytokines and contribute to the failure of ICB therapy. Therefore, it is crucial to mechanically manipulate the abundance and function of TAMs in the tumor microenvironment (TME), which can offer a promising molecular basis to improve the clinical response efficacy of ICB in cancer patients. PurposeThis study aims to investigate TAMs in the immunosuppressive microenvironment to identify new therapeutic targets, improve the ability to predict and guide responses to clinical immunotherapy, and develop new strategies for immunotherapy of lung tumors. MethodsLewis lung carcinoma (LLC) xenograft-bearing mouse models were established to analyze the antitumor activity of Rhizoma Coptidis (RC) in vivo. A systems pharmacology strategy was used to predict the correlation between RC and M2 macrophages. The effect of RC on the abundance of M2 macrophages was analyzed by flow cytometry of murine samples. Western blot was performed to analyze the expression of Leukotriene A4 hydrolase (LTA4H) and LTB4 receptor 1 (BLT1) in harvested lung cancer tissues. The impact of blocking leukotriene B4 (LTB4) signaling by RC on the recruitment of M2 macrophages was assessed in vitro and in vivo. Transwell migration assays were conducted to clarify the inhibition of macrophage migration by blocking LTB4. Lta4h−/− mice were used to investigate the sensitivity of immunotherapy to lung cancer by blocking the LTB4 signaling. ResultsHere, we report that RC, an herbal medicine from the family Ranunculaceae, suppresses the recruitment and immunosuppressive function of TAMs, which in turn sensitizes lung cancer to ICB therapy. Firstly, a systems pharmacology strategy was proposed to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype. We predicted and verified that RC significantly inhibits tumor growth and the infiltration of M2-TAMs into TME of LLC tumor-bearing mice. Then, RC inhibits the recruitment of macrophages to the tumor TME via blocking LTB4 signaling, and suppresses the expression of immunosuppressive factors (IL-10, TGF-β and VEGF). As a result, RC enables CD8+ T cells to retain their proliferative and infiltrative abilities within the TME. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumor cells, which is further enhanced by the addition of anti-PD-L1 therapy. Furthermore, we employed LTA4H deficient mice (Lta4h−/− mice) to evaluate the antitumor efficiency, the results showed that the efficacy of immunotherapy was enhanced due to the synergistic effect of LTB4 signaling blockage and ICB inhibition, leading to remarkable inhibition of tumor growth in a mouse model of lung adenocarcinoma. ConclusionsTaken together, these findings suggest that RC enhances antitumor immunity, providing a rationale for combining RC with immunotherapies as a potential anti-cancer treatment strategy.

Intratumoral IL15 Improves Efficacy of Near-Infrared Photoimmunotherapy.

IL15 is a potent inducer of differentiation and proliferation of CD8+ T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL15 suggests the needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anticancer treatment that elicits a massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL15 was more effective than intraperitoneal IL15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL15-secreting MC38 (hIL15-MC38) and parental MC38 tumors, the hIL15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. In addition, the hIL15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8+ T, NK, and natural killer T cells compared with the treated parental line. Furthermore, intratumoral IL15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL15 administration synergistically improves the efficacy of cancer cell-targeted NIR-PIT probably by inducing stronger anticancer immunity, indicating its potential as an anticancer treatment strategy.

A first-in-human, open-label, phase I trial of daily oral PCLX-001, an NMT inhibitor, in patients with relapsed/refractory B-cell lymphomas and advanced solid tumors.

e15094 Background: Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. PCLX-001 is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC50 of 5nM and 8nM, respectively). In vitro, hematologic cancer cell lines were exquisitely sensitive to PCLX-001. PCLX-001 regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient derived xenograft model. PCLX-001 also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we hypothesized that PCLX-001 would be safe, tolerable, and active as a novel oral cancer therapeutic. Methods: Patients with relapsed/refractory B-cell lymphomas and advanced solid tumors are being enrolled in a multicenter, open label, standard phase I dose escalation design to determine feasibility, maximum tolerated dose (MTD), and pharmacokinetics of PCLX-001 monotherapy. Seven dose levels are being studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 200 mg, and 280 mg. Dose limiting toxicity (DLT) is defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, Gr 4 ANC ≥ 7 days, febrile neutropenia, or clinically significant > Gr 3 non-hematologic toxicity. Results: Eighteen evaluable patients (3 relapsed B-cell lymphoma; 15 advanced solid tumor) have been accrued through dose level six (200 mg cohort) without DLT. No attributable Gr 3 or 4 toxicities have been identified. Noncompartmental pharmacokinetic (PK) analyses demonstrate rapid oral absorption, a terminal half-life of approximately 10 hours, rapid achievement of steady state, and no induction of metabolism. PCLX-001 trough plasma concentrations at higher dose cohorts exceed the EC90 required to inhibit cultured cancer cells. Conclusions: PCLX-001 is safe and well tolerated up to the 200 mg daily dose. Our results support the ongoing development of PCLX-001 as an oral daily therapy for the treatment of patients with cancer. Updated study results will be presented, summarizing the safety, MTD, and PK outcomes in PCLX-001 treated patients. Preliminary clinical activity will be determined in 20 patient dose expansion cohorts of relapsed/refractory B-cell lymphomas, and selected advanced solid tumors following the identification of PCLX-001 MTD. Clinical trial information: NCT04836195 .

Targeting Immunosuppressive Adenosine Signaling: A Review of Potential Immunotherapy Combination Strategies.

The tumor microenvironment regulates many aspects of cancer progression and anti-tumor immunity. Cancer cells employ a variety of immunosuppressive mechanisms to dampen immune cell function in the tumor microenvironment. While immunotherapies that target these mechanisms, such as immune checkpoint blockade, have had notable clinical success, resistance is common, and there is an urgent need to identify additional targets. Extracellular adenosine, a metabolite of ATP, is found at high levels in the tumor microenvironment and has potent immunosuppressive properties. Targeting members of the adenosine signaling pathway represents a promising immunotherapeutic modality that can potentially synergize with conventional anti-cancer treatment strategies. In this review, we discuss the role of adenosine in cancer, present preclinical and clinical data on the efficacy adenosine pathway inhibition, and discuss possible combinatorial approaches.

Combination of PEG-b-PAA Carrier and Efficient Cationic Photosensitizers for Photodynamic Therapy.

Photodynamic therapy (PDT) is recognized to be a promising strategy for anticancer treatment. Considering the progressive application of PDT in clinical trials, highly efficient photosensitizers (PSs) are in strong demand. Aggregation-induced emission (AIE) based PSs are promising phototheranostic materials for tumor imaging and PDT due to their high fluorescence and photosensitizing efficiency. Herein, a PS, TPA-2BCP with AIE characteristics is developed by adopting an acceptor-π-donor-π-acceptor (A-π-D-π-A) structure. However, the accumulation of ionic PSs in the tumor is poor due to non-specific interactions with bio-molecules. Therefore, we use a carboxyl-rich polymer material, polyacrylate polyethylene glycol block copolymer (PEG-b-PAA) to encapsulate the cationic PSs into nanoparticles through ionic interactions. The cationic groups are blocked and the generated PS nanoparticles can accumulate well in the tumor site in vivo. Meanwhile, the photosensitizing efficiency of the PS is further enhanced in the nanoparticle format. The tumor growth can be obviously inhibited under 530 nm laser irradiation, demonstrating its potential application in antitumor PDT.

Construction of inflammatory associated risk gene prognostic model of NSCLC and its correlation with chemotherapy sensitivity

Background Inflammation is an important pathogenic factor of most malignant tumors. It is essential to understand mechanism underlying inflammation and cancer development, so as to formulate and develop anti-cancer treatment strategies. However, inflammatory-related gene characterization as well as risk model construction in prognosis and response chemotherapy or immunotherapy in NSCLC are still remain unclear. Methods A total of 1014 lung cancer samples with RNA-seqencing results were download from The Cancer Genome Atlas (TCGA) database. The patient cohort was randomized as a training and test cohorts, and 200 inflammatory-related genes were selected based on previously published data. Consensus clustering and Enrichment and immune function analyses base on Differential expression genes (DEGs) were performed. Prognosis Prediction Model were Constructed and Chemotherapy and immunotherapy sensitivity base on this model were performed. At last, H1299 and HCC827 cells were used to tested the mitoxantrone and oxal iplatin sensitivity after KRT6A knockdown. Results We identified the inflammatory-related genes from NSCLC datasets to build one prognosis prediction signature based on cluster inflammatory-related genes to lay a certain foundation for distinguishing high-risk NSCLC cases with dismal prognostic outcome. The nomogram provides the AUC values for 1-, 3-, and 5-year overall survival were 0.831, 0.853, and 0.86 in validation cohort. Morover, different sensitivity of immunotherapy or chemotherapy also were classified base on the different risk groups in NSCLC patients, which provided potent clinical reference. At last, targeting KRT6A sensitive to mitoxantrone and oxaliplatin in H1299 and HCC827 cells. Conclusions Inflammatory-related gene risk-score is the potential chemotherapeutic and immunotherapeutic biomarker for NSCLC, and targeting KRT6A sensitive to mitoxantrone and oxaliplatin in NSCLC. Highlights Inflammatory-related genes can lay a certain foundation for distinguishing high-risk NSCLC cases with dismal prognostic outcome. Risk-score base on inflammatory-related genes is positive correlated with CD274, TGFBR1 and TGFB1 expression. Targeting KRT6A sensitive to mitoxantrone and oxaliplatin in H1299 and HCC827 cells.

Relationship between anticancer sensitivities and cellular respiration properties in 5-fluorouracil-resistant HCT116 human colorectal cancer cells.

5-Fluorouracil (5-FU) is widely used for colorectal cancer (CRC) treatment; however, continuous treatment of CRC cells with 5-FU can result in acquired resistance, and the underlying mechanism of 5-FU resistance remains unclear. We previously established an acquired 5-FU-resistant CRC cell line, HCT116RF10 , and examined its biological features and 5-FU resistance mechanisms. In this study, we evaluated the 5-FU sensitivity and cellular respiration dependency of HCT116RF10 cells and parental HCT116 cells under conditions of high- and low-glucose concentrations. Both HCT116RF10 and parental HCT116 cells were more sensitive to 5-FU under low-glucose conditions compared with high-glucose conditions. Interestingly, HCT116RF10 and parental HCT116 cells exhibited altered cellular respiration dependence for glycolysis and mitochondrial respiration under high- and low-glucose conditions. Additionally, HCT116RF10 cells showed a markedly decreased ATP production rate compared with HCT116 cells under both high- and low-glucose conditions. Importantly, glucose restriction significantly reduced the ATP production rate for both glycolysis and mitochondrial respiration in HCT116RF10 cells compared with HCT116 cells. The ATP production rates in HCT116RF10 and HCT116 cells were reduced by approximately 64% and 23%, respectively, under glucose restriction, suggesting that glucose restriction may be effective at enhancing 5-FU chemotherapy. Overall, these findings shed light on 5-FU resistance mechanisms, which may lead to improvements in anticancer treatment strategies.

Acetyl-Click Screening Platform Identifies Small-Molecule Inhibitors of Histone Acetyltransferase 1 (HAT1).

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H4. To ascertain whether targeting HAT1 is a viable anticancer treatment strategy, we sought to identify small-molecule inhibitors of HAT1 by developing a high-throughput HAT1 acetyl-click assay. Screening of small-molecule libraries led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity. Compounds were refined by synthesis and testing of over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl side chain improved enzymatic potency and cellular growth suppression. One compound (JG-2016 [24a]) showed relative specificity toward HAT1 compared to other acetyltransferases, suppressed the growth of human cancer cell lines, impaired enzymatic activity in cellulo, and interfered with tumor growth. This is the first report of a small-molecule inhibitor of the HAT1 enzyme complex and represents a step toward targeting this pathway for cancer therapy.

Targeted Epigenetic Interventions in Cancer with an Emphasis on Pediatric Malignancies.

Over the past two decades, novel hallmarks of cancer have been described, including the altered epigenetic landscape of malignant diseases. In addition to the methylation and hyd-roxymethylation of DNA, numerous novel forms of histone modifications and nucleosome remodeling have been discovered, giving rise to a wide variety of targeted therapeutic interventions. DNA hypomethylating drugs, histone deacetylase inhibitors and agents targeting histone methylation machinery are of distinguished clinical significance. The major focus of this review is placed on targeted epigenetic interventions in the most common pediatric malignancies, including acute leukemias, brain and kidney tumors, neuroblastoma and soft tissue sarcomas. Upcoming novel challenges include specificity and potential undesirable side effects. Different epigenetic patterns of pediatric and adult cancers should be noted. Biological significance of epigenetic alterations highly depends on the tissue microenvironment and widespread interactions. An individualized treatment approach requires detailed genetic, epigenetic and metabolomic evaluation of cancer. Advances in molecular technologies and clinical translation may contribute to the development of novel pediatric anticancer treatment strategies, aiming for improved survival and better patient quality of life.

Phospho-heavy-labeled-spiketide FAIMS stepped-CV DDA (pHASED) provides real-time phosphoproteomics data to aid in cancer drug selection

Global high-throughput phosphoproteomic profiling is increasingly being applied to cancer specimens to identify the oncogenic signaling cascades responsible for promoting disease initiation and disease progression; pathways that are often invisible to genomics analysis. Hence, phosphoproteomic profiling has enormous potential to inform and improve individualized anti-cancer treatment strategies. However, to achieve the adequate phosphoproteomic depth and coverage necessary to identify the activated, and hence, targetable kinases responsible for driving oncogenic signaling pathways, affinity phosphopeptide enrichment techniques are required and often coupled with offline high-pressure liquid chromatographic (HPLC) separation prior to nanoflow liquid chromatography–tandem mass spectrometry (nLC-MS/MS). These complex and time-consuming procedures, limit the utility of phosphoproteomics for the analysis of individual cancer patient specimens in real-time, and restrict phosphoproteomics to specialized laboratories often outside of the clinical setting. To address these limitations, here we have optimized a new protocol, phospho-heavy-labeled-spiketide FAIMS stepped-CV DDA (pHASED), that employs online phosphoproteome deconvolution using high-field asymmetric waveform ion mobility spectrometry (FAIMS) and internal phosphopeptide standards to provide accurate label-free quantitation (LFQ) data in real-time. Compared with traditional single-shot LFQ phosphoproteomics workflows, pHASED provided increased phosphoproteomic depth and coverage (phosphopeptides = 4617 pHASED, 2789 LFQ), whilst eliminating the variability associated with offline prefractionation. pHASED was optimized using tyrosine kinase inhibitor (sorafenib) resistant isogenic FLT3-mutant acute myeloid leukemia (AML) cell line models. Bioinformatic analysis identified differential activation of the serine/threonine protein kinase ataxia-telangiectasia mutated (ATM) pathway, responsible for sensing and repairing DNA damage in sorafenib-resistant AML cell line models, thereby uncovering a potential therapeutic opportunity. Herein, we have optimized a rapid, reproducible, and flexible protocol for the characterization of complex cancer phosphoproteomes in real-time, a step towards the implementation of phosphoproteomics in the clinic to aid in the selection of anti-cancer therapies for patients.

Multifunctional Bi NSs@BSA Nanoplatform Guided by CT Imaging for Effective Photothermal Therapy.

Photothermal therapy (PTT) has attracted great attention as an anticancer treatment strategy. With the rapid development of nanomedicine, multifunctional inorganic nanophotothermal agents provide a new way to improve the effect of PTT. Herein, bovine serum albumin (BSA)-modified Bi nanosheets (Bi NSs) with good biocompatibility were synthesized by a facile redox and ball milling method and applied as a photothermal agent for the enhancement of PTT. Owing to the strong near-infrared absorption, Bi NSs exhibit high photothermal conversion efficiency (η = 36.17%) under 808 nm laser irradiation and can serve as a nanotherapeutic agent for cancer therapy. In addition, in vitro cell safety analysis also suggests that the toxicity of BSA-modified Bi NSs is negligible. Upon 808 nm irradiation, the uptake ability of tumor cells to Bi NSs@BSA has been improved. Moreover, Bi NSs@BSA also can be used as a good contrast agent for CT imaging and then to observe the distribution of materials in the tumor site. Finally, Bi NSs@BSA-mediated PTT results show a high ablation rate of A549 tumor cells both in vitro and in vivo. All results reveal that Bi NSs@BSA is a promising nanotherapeutic platform for PTT.

What Are the Reasons for Continuing Failures in Cancer Therapy? Are Misleading/Inappropriate Preclinical Assays to Be Blamed? Might Some Modern Therapies Cause More Harm than Benefit?

Over 50 years of cancer research has resulted in the generation of massive amounts of information, but relatively little progress has been made in the treatment of patients with solid tumors, except for extending their survival for a few months at best. Here, we will briefly discuss some of the reasons for this failure, focusing on the limitations and sometimes misunderstanding of the clinical relevance of preclinical assays that are widely used to identify novel anticancer drugs and treatment strategies (e.g., "synthetic lethality"). These include colony formation, apoptosis (e.g., caspase-3 activation), immunoblotting, and high-content multiwell plate cell-based assays, as well as tumor growth studies in animal models. A major limitation is that such assays are rarely designed to recapitulate the tumor repopulating properties associated with therapy-induced cancer cell dormancy (durable proliferation arrest) reflecting, for example, premature senescence, polyploidy and/or multinucleation. Furthermore, pro-survival properties of apoptotic cancer cells through phoenix rising, failed apoptosis, and/or anastasis (return from the brink of death), as well as cancer immunoediting and the impact of therapeutic agents on interactions between cancer and immune cells are often overlooked in preclinical studies. A brief review of the history of cancer research makes one wonder if modern strategies for treating patients with solid tumors may sometimes cause more harm than benefit.

Platelet-promoting drug delivery efficiency for inhibition of tumor growth, metastasis, and recurrence.

Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.

All-in-one microfluidic design to integrate vascularized tumor spheroid into high-throughput platform.

The development of a scalable and highly reproducible in vitro tumor microenvironment (TME) platform still sheds light on new insights into cancer metastasis mechanisms and anticancer therapeutic strategies. Here, we present an all-in-one injection molded plastic array three-dimensional culture platform (All-in-One-IMPACT) that integrates vascularized tumor spheroids for highly reproducible, high-throughput experimentation. This device allows the formation of self-assembled cell spheroids on a chip by applying the hanging drop method to the cell culture channel. Then, when the hydrogel containing endothelial cells and fibroblasts is injected, the spheroid inside the droplet can be patterned together in three dimensions along the culture channel. In just two steps above, we can build a vascularized TME within a defined area. This process does not require specialized user skill and minimizes error-inducing steps, enabling both reproducibility and high throughput of the experiment. We have successfully demonstrated the process, from spheroid formation to tumor vascularization, using patient-derived cancer cells (PDCs) as well as various cancer cell lines. Furthermore, we performed combination therapies with Taxol (paclitaxel) and Avastin (bevacizumab), which are used in standard care for metastatic cancer. The All-in-One IMPACT is a powerful tool for establishing various anticancer treatment strategies through the development of a complex TME for use in high-throughput experiments.

Bioactive Microbial Metabolites in Cancer Therapeutics: Mining, Repurposing, and Their Molecular Targets.

The persistence and resurgence of cancer, characterized by abnormal cell growth and differentiation, continues to be a serious public health concern critically affecting public health, social life, and the global economy. Hundreds of putative drug molecules of synthetic and natural origin were approved for anticancer therapy in the last few decades. Although conventional anticancer treatment strategies have promising aspects, several factors such as their limitations, drug resistance, and side effects associated with them demand more effort in repositioning or developing novel therapeutic regimens. The rich heritage of microbial bioactive components remains instrumental in providing novel avenues for cancer therapeutics. Actinobacteria, Firmicutes, and fungi have a plethora of bioactive compounds, which received attention for their efficacy in cancer treatment targeting different pathways responsible for abnormal cell growth and differentiation. Yet the full potential remains underexplored to date, and novel compounds from such microbes are reported regularly. In addition, the advent of computational tools has further augmented the mining of microbial secondary metabolites and identifying their molecular targets in cancer cells. Furthermore, the drug-repurposing strategy has facilitated the use of approved drugs of microbial origin in regulating cancer cell growth and progression. The wide diversity of microbial compounds, different mining approaches, and multiple modes of action warrant further investigations on the current status of microbial metabolites in cancer therapeutics. Hence, in this review, we have critically discussed the untapped potential of microbial products in mitigating cancer progression. The review also summarizes the impact of drug repurposing in cancer therapy and discusses the novel avenues for future therapeutic drug development against cancer.