Molecular Target For Cancer Therapy Research Articles

Abstract PO4-10-12: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023

Abstract Title: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 Background: The number of FDA-approved genome-targeted cancer drugs for metastatic breast cancer has increased, providing the potential for personalized therapy. To help physicians, patients, and policymakers differentiate meaningful from trivial innovation in this field, we assessed the validity of the targets and value of the outcomes used in the pivotal trials supporting approval. Methods: We analyzed trials supporting genome-targeted breast cancer drugs FDA-approved between 2006-2023, defined as those using a genomic test in which the drug targeted a given genomic alteration. From FDA drug labels and trial reports, we extracted characteristics of pivotal trials. For Accelerated Approvals—a special FDA program allowing approval based on unvalidated surrogate measures—if the drug later received traditional approval based on a confirmatory trial, only the latter was analyzed. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for approved indications was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets qualifying for ESCAT category level I-A or I-B associated with ESMO-MCBS grade 4 or 5 were rated as high-benefit genomic-targeted breast cancer treatments. Results: Fifteen genome-targeted drugs covered 17 indications and targeted 8 driver alterations. Among the 17 pivotal trials supporting these indications, most were randomized (11, 65%), phase 3 (11, 65%) and open-label (14, 82%). The most common primary endpoint leading to approval (10, 59%) was progression-free survival. Eleven trials (65%) had a I-A ESCAT targetability, 5 (29%) had a I-C targetability score and 1 (6%) was categorized as II-A. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were classified as tier I-A due to randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. RET fusions, NTRK fusions, and microsatellite instability were classified as tier I-C, while high-tumor mutational burden was categorized as tier II-A. Eighteen percent of trials (3/17) demonstrated ESMO-MCBS grades 4-5. Overall, 3 of 17 (18%) indications had high-benefit genomic-based cancer treatments. Conclusions: Among molecular-targeted cancer therapies approved for metastatic breast cancer, fewer than a fifth demonstrated substantial patient benefits at approval. Benefit frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Consolacion Molto Valiente, Jerry Avorn, Aaron Kesselheim. Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-12.

Abstract PO5-10-08: Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer

Abstract Background: Genomic testing has expanded the possibilities of precision cancer medicine, particularly for advanced, treatment-resistant breast cancer cases. However, the clinical significance of most genetic alterations remains uncertain, potentially overestimating tailored therapies. The National Comprehensive Cancer Network (NCCN) guidelines are evidence-based cancer-specific recommendations used in clinical practice and that are often determinative for insurance coverage. In this study, we assessed the validity of the targets and the clinical benefit of genome-targeted cancer drugs recommended in the NCCN guidelines for metastatic breast cancer. Methods: We identified genome-targeted oncology therapies supporting advanced breast cancer recommendations in the most recent NCCN breast cancer guideline (version 4.2023). Genome-targeted drugs were defined as involving use of a genomic test in which the drug targeted a genomic alteration. We analyzed data from trials supporting advanced genome-targeted breast cancer drugs recommendations. When multiple (or overlapping) articles for the same study were identified, the most recent publication was included. We extracted key details of each trial, including trial design, blinding, phase of clinical trial and primary efficacy end points. We cross-referenced the FDA-approved indications as of 30 June 2023 with the NCCN recommendations for each drug. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for genome-targeted oncology therapies was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We considered a substantial clinical benefit as a grade of 4 or 5. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-targeted breast cancer treatments. Results: We identified 47 recommendations supporting 17 genome-targeted drugs, which targeted 11 driver alterations. Out of these recommendations, 29 (62%) aligned with the FDA indications. We associated 47 trials with these recommendations, most randomized (24, 51%), phase 3 (23, 49%) and open-label (42, 89%). The most common primary endpoint (22, 47%) was overall response rate, followed by progression-free survival/time to progression (21, 45%). Twenty-four trials (51%) had a I-A ESCAT targetability, 7 (15%) had a I-B targetability, 6 (13%) had a I-C targetability score and 10 (21%) were categorized as II-B. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were mainly classified as tier I-A based on randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. By contrast, RET fusions, NTRK fusions, high-tumor mutational burden and microsatellite instability were ranked as tier I-C and somatic BRCA mutations, germline PALB2 mutations and HER-2 mutations as II-B. Six trials (14%, 6/42) supporting drug approval demonstrated substantial ESMO-MCBS clinical benefit. Overall, 6 recommendations (14%) had high-benefit genomic-based cancer treatments. Conclusions: Fewer than one-fifth of molecular-targeted cancer therapies recommended in NCCN guidelines for metastatic breast cancer demonstrated substantial patient benefits. Value frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Jerry Avorn, Aaron Kesselheim. Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-08.

CD44: A New Prognostic Marker in Colorectal Cancer?

Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial-mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications.

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies

The number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost. To assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration-approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials. In this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed. The strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments. A total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments. The results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.

Abstract 5929: HuR-targeted therapy promotes the adaptive immune response in medulloblastoma through the cGAS-Sting pathway

Abstract HuR is an RNA binding protein overexpressed in multiple human cancers and is involved in tumorigenesis, invasion, and metastasis. Genetic and pharmacologic inhibition of HuR demonstrated antitumor activity establishing HuR as a molecular target for cancer therapy. However, little is known about HuR’s role in medulloblastoma (MB). In the present study, we investigated the effect of CMLD2, a small molecule inhibitor of HuR, on MB cell growth and on the adaptive immune response by assessing the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway. The cytoplasmic double-stranded DNA (dsDNA) sensing cGAS-STING signaling pathway plays pivotal role in host defense against cancers. Activation of the cGAS-STING signaling cascade induces the expression of pro-inflammatory cytokines and type I interferons promoting anti-tumor immunity. Human MB Daoy cells were treated with DMSO (control) or CMLD2 (20uM and 30uM). At 48 and 72 h after treatment, cells were collected and cell viability was determined using Trypan blue assay. A time and dose-dependent cytotoxicity was observed with 22.5% and 32.5% reduction in cell number with 20uM treatment (p<0.01) and 38.3% and 50.2% reduction with 30uM treatment (p<0.001) at 48 h and 72 h respectively compared to DMSO-treated control. Western blot analysis showed CMLD2 treatment inhibited HuR and markedly increased the expression of cGAS-STING pathway proteins (p-STING Ser366, p-TBK1 Ser172, p-IRF3Ser396 and pNF-KBSer536) at the two drug concentrations tested albeit greater increase in cGAS-STING protein expression was observed with 20uM treatment. Analysis for chemokines (CXCL10 and CCL5) and cytokine (IL-6) associated with the cGAS-STING pathway in cell culture supernatant collected from 20uM CMLD2 treatment showed significant increase in CXCL10 (1.96 ± 0.12 and 2.12 ± 0.06 fold increase at 48 h and 72 h; p<0.01) and CCL5 (1.21 ± 0.09 and 1.86 ± 0.05 fold increase at 48 h and 72 h; p=ns at 48 h; p<0.01 at 72 h) over DMSO-treated control. IL-6 expression significantly increased at 72h (1.98± 0.24 fold, p<0.001) but not at 48h after 20uM CMLD2 treatment compared to DMSO treated control. Our study results demonstrate CMLD2 mediated HuR targeting induces MB cell cytotoxicity and concurrently activates the cGAS-STING pathway. Testing of CMLD2 treatment in additional MB cell models and studying the impact of the cGAS-STING activation on immune cells (T cells, NK cells and macrophages) will aid in developing novel HuR-targeted treatment strategies in MB. Funding: The study was supported in part by a grant received from the National Cancer Institute of the National Institutes of Health (R01 CA 282735-01) and funds from the Jim and Christy Everest Endowed Chair in Cancer Developmental Therapeutics. Citation Format: Meghna Mehta, Rajeswari Raguraman, Anupama Munshi, Rajagopal Ramesh. HuR-targeted therapy promotes the adaptive immune response in medulloblastoma through the cGAS-Sting pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5929.

Financial toxicity and patient experience associated with financial burden of molecular-targeted and immune therapies for cancer: an observational study under public health insurance

BackgroundFinancial burden of cancer treatment can negatively affect patients and their families. This study aimed to evaluate the financial toxicity of patients treated with molecular-targeted and immune therapies and explore the relationship between financial toxicity and patient experiences associated with the financial burden of cancer treatment.MethodsThis anonymous, self-administered questionnaire survey conducted across nine hospitals in Japan included patients aged 20–60 years who were receiving molecular-targeted agents or immune checkpoint inhibitors for any type of cancer for ≥ 2 months. Financial toxicity was evaluated using the COmprehensive Score for Financial Toxicity (COST). Patient experience was examined using 11 items based on previous studies. Independent factors related to financial toxicity were explored using multiple regression analyses.ResultsThe mean COST score was 17.0 ± 8.4, and 68 (49.3%) participants reported COST scores at or below the cutoff point. The factors contributing to financial toxicity were “hesitation regarding continuing treatment based on finances” (sβ = − 0.410, p < 0.001), “cutting through my deposits and savings” (sβ = − 0.253, p = 0.003), and “reducing spending on basics like food or clothing” (sβ = − 0.205, p = 0.046) along with comorbidities (sβ = − 0.156, p = 0.032).ConclusionPatients receiving molecular-targeted and immune therapies are at risk of experiencing profound financial toxicity and a reduced quality of life. The independently related factors that we identified have the potential to serve as indicators of profound financial toxicity and the need for specialized intervention.

Oridonin inhibits bladder cancer survival and immune escape by covalently targeting HK1

BackgroundHexokinase I (HK1) is highly expressed in a variety of malignancies, regulates glycolytic pathway in cancer cells, and thus considered to be one of the promising molecular targets for cancer therapy. Nonetheless, the development of a specific inhibitor against HK1 remains elusive. PurposeThis study aims to elucidate the mechanism by which oridonin inhibits the proliferation and immune evasion of bladder cancer cells, specifically through the suppression of HK1. MethodsTo examine the mechanisms by which oridonin directly binds to cysteines of HK1 and inhibits bladder cancer growth, this study utilized a variety of methods. These included the Human Proteome Microarray, Streptavidin-agarose affinity assay, Biolayer Interferometry (BLI) ainding analysis, Mass Spectrometry, Cellular Thermal Shift Assay, Extracellular Acidification Rate measurement, and Xenotransplant mouse models. ResultsAs indicated by our current findings, oridonin forms a covalent bond with Cys-813, located adjacently to glucose-binding domain of HK1. This suppresses the enzymatic activity of HK1, leading to an effective reduction of glycolysis, which triggers cell death via apoptosis in cells derived from human bladder cancer. Significantly, oridonin also inhibits lactate-induced PD-L1 expression in bladder cancer. Furthermore, pairing oridonin with a PD-L1 inhibitor amplifies the cytotoxicity of CD8+ T cells against bladder cancer. ConclusionThis research strongly suggests that oridonin serves as a covalent inhibitor of HK1. Moreover, it indicates that functional cysteine residue of HK1 could operate as viable targets for selective inhibition. Consequently, oridonin exhibits substantial potential for the evolution of anti-cancer agents targeting the potential therapeutic target HK1 via metabolism immunomodulation.

PIM3 Kinase: A Promising Novel Target in Solid Cancers

PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials.

Emerging Role of Galectins as Molecular Targets for Cancer Therapy: A Review

In recent decades cancer incidences and mortality rates have increased. Although there is significant progress in identifying the root causes and emerging therapies, there are many molecular, cellular mechanism’s unrevealed and current treatments have yet to deliver on their promises. Common characteristics of cancer that are controlled by various mechanisms, including those involving glycosylation-dependent proliferative signalling, the ability of tumor cells and their microenvironment to sustain proliferative signalling, enhancing the replicative immortality, evading the effects of growth suppressors, resisting apoptosis, sustaining invasion and metastasis, stimulation of angiogenesis and triggering immune response are few to name. An evolutionarily conserved family of glycan-binding proteins known as galectins has a significant impact in controlling these cascades. Galectins belong to animal lectin family that function by interacting with matrix glyco-proteins on extracellular surface and also with nuclear proteins modulating the cell signalling cascades intracellularly. In this review, we analyse how galectins influence the cellular pathways that control tumor activity, providing relevant examples and highlighting their therapeutic perspective in the fight against cancer.

SAR131675 exhibits anticancer activity on human ovarian cancer cells through inhibition of VEGFR-3/ERK1/2/AKT signaling pathway

Vascular endothelial growth factor receptor-3 (VEGFR-3) is known to participate in tumorigenesis and lymphangiogenesis, and as such, has the potential to serve as a molecular target for cancer therapy. SAR131675 is a highly selective VEGFR-3 antagonist that has an inhibitive effect on lymphatic cell growth. However, the anticancer effects and underlying mechanisms of SAR131675 in ovarian cancer remain poorly understood. In this study, we investigated the pathological role of VEGFR-3, and the effects of SAR131675 on proliferation, cell cycle, migration, and apoptosis in ovarian cancer cells. Our results showed that the mRNA and protein of VEGFR-3 were expressed in OVCAR3 and SKOV3 ovarian cancer cells, and this receptor was activated following stimulation with 50 ng/ml VEGF-C Cys156Ser (VEGF-CS), a selective ligand for VEGFR-3. Enhancing VEGFR-3 phosphorylation by treatment of ovarian cancer cells with VEGF-CS resulted in increased levels of phosphorylated extracellular signal-regulated kinases 1/2 (ERK1/2) and AKT. Moreover, our data demonstrated that SAR131675 inhibited VEGF-CS-mediated proliferation, colony formation, and migration of cancer cells in a dose-dependent manner. In addition, inhibition of VEGFR-3 activation with SAR131675 significantly increased cell cycle arrest and promoted apoptosis in both OVCAR3 and SKOV3 cells. Mechanistically, SAR131675 effectively suppressed the VEGF-CS-induced phosphorylation of VEGFR-3 and its downstream effectors including activated ERK1/2 and AKT in ovarian cancer cells. Our results reveal an anticancer activity of SAR131675 on the growth and migration of ovarian cancer cells, which may be through inhibiting VEGFR-3/ERK1/2/AKT pathway. SAR131675 may serve as an effective targeted drug for ovarian cancer.

Functions and mechanisms of lactylation in carcinogenesis and immunosuppression.

As critical executors regulating many cellular operations, proteins determine whether living activities can be performed in an orderly and efficient manner. Precursor proteins are inert and must be modified posttranslationally to enable a wide range of protein types and functions. Protein posttranslational modifications (PTMs) are well recognized as being directly associated with carcinogenesis and immune modulation and have emerged as important targets for cancer detection and treatment. Lactylation (Kla), a novel PTM associated with cellular metabolism found in a wide range of cells, interacts with both histone and nonhistone proteins. Unlike other epigenetic changes, Kla has been linked to poor tumor prognosis in all current studies. Histone Kla can affect gene expression in tumors and immunological cells, thereby promoting malignancy and immunosuppression. Nonhistone proteins can also regulate tumor progression and treatment resistance through Kla. In this review, we aimed to summarize the role of Kla in the onset and progression of cancers, metabolic reprogramming, immunosuppression, and intestinal flora regulation to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.

Venetoclax is a potent hepsin inhibitor that reduces the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells.

Introduction: Hepsin is a type II transmembrane serine protease and its expression has been linked to greater tumorigenicity and worse prognosis in different tumors. Recently, our group demonstrated that high hepsin levels from primary tumor were associated with a higher risk of metastasis and thrombosis in localized colorectal cancer patients. This study aims to explore the molecular role of hepsin in colorectal cancer. Methods: Hepsin levels in plasma from resected and metastatic colorectal cancer patients were analyzed by ELISA. The effect of hepsin levels on cell migration, invasion, and proliferation, as well as on the activation of crucial cancer signaling pathways, was performed in vitro using colorectal cancer cells. A thrombin generation assay determined the procoagulant function of hepsin from these cells. A virtual screening of a database containing more than 2000 FDA-approved compounds was performed to screen hepsin inhibitors, and selected compounds were tested in vitro for their ability to suppress hepsin effects in colorectal cancer cells. Xenotransplantation assays were done in zebrafish larvae to study the impact of venetoclax on invasion promoted by hepsin. Results: Our results showed higher plasma hepsin levels in metastatic patients, among which, hepsin was higher in those suffering thrombosis. Hepsin overexpression increased colorectal cancer cell invasion, Erk1/2 and STAT3 phosphorylation, and thrombin generation in plasma. In addition, we identified venetoclax as a potent hepsin inhibitor that reduced the metastatic and prothrombotic phenotypes of hepsin-expressing colorectal cancer cells. Interestingly, pretreatment with Venetoclax of cells overexpressing hepsin reduced their invasiveness in vivo. Discussion: Our results demonstrate that hepsin overexpression correlates with a more aggressive and prothrombotic tumor phenotype. Likewise, they demonstrate the antitumor role of venetoclax as a hepsin inhibitor, laying the groundwork for molecular-targeted therapy for colorectal cancer.

Engineered Synthetic STxB for Enhanced Cytosolic Delivery.

Many molecular targets for cancer therapy are located in the cytosol. Therapeutic macromolecules are generally not able to spontaneously translocate across membranes to reach these cytosolic targets. Therefore a strong need exists for tools that enhance cytosolic delivery. Shiga toxin B-subunit (STxB) is used to deliver therapeutic principles to disease-relevant cells that express its receptor, the glycolipid Gb3. Based on its naturally existing membrane translocation capacity, STxB delivers antigens to the cytosol of Gb3-positive dendritic cells, leading to the induction of CD8+ T cells. Here, we have explored the possibility of further increasing the membrane translocation of STxB to enable other therapeutic applications. For this, our capacity to synthesize STxB chemically was exploited to introduce unnatural amino acids at different positions of the protein. These were then functionalized with hydrophobic entities to locally destabilize endosomal membranes. Intracellular trafficking of these functionalized STxB was measured by confocal microscopy and their cytosolic arrival with a recently developed highly robust, sensitive, and quantitative translocation assay. From different types of hydrophobic moieties that were linked to STxB, the most efficient configuration was determined. STxB translocation was increased by a factor of 2.5, paving the path for new biomedical opportunities.

Therapeutic potential of TRPM8 channels in cancer treatment.

Cancer is a multifactorial process associated with changes in signaling pathways leading to cell cycle variations and gene expression. The transient receptor potential melastatin 8 (TRPM8) channel is a non-selective cation channel expressed in neuronal and non-neuronal tissues, where it is involved in several processes, including thermosensation, differentiation, and migration. Cancer is a multifactorial process associated with changes in signaling pathways leading to variations in cell cycle and gene expression. Interestingly, it has been shown that TRPM8 channels also participate in physiological processes related to cancer, such as proliferation, survival, and invasion. For instance, TRPM8 channels have an important role in the diagnosis, prognosis, and treatment of prostate cancer. In addition, it has been reported that TRPM8 channels are involved in the progress of pancreatic, breast, bladder, colon, gastric, and skin cancers, glioblastoma, and neuroblastoma. In this review, we summarize the current knowledge on the role of TRPM8 channels in cancer progression. We also discuss the therapeutic potential of TRPM8 in carcinogenesis, which has been proposed as a molecular target for cancer therapy.

Effect of shRNA‑mediated knockdown EBF1 gene expression on the proliferation of lung cancer cell line A549 invitro and invivo.

The incidence of lung cancer is increasing year by year. The study of the proliferation and metastasis of lung adenocarcinoma cells is of positive significance to improve the prognosis of patients with lung adenocarcinoma, but there is still a lack of more effective treatment for the proliferation and metastasis of lung adenocarcinoma cells. The present study found that a lymphocyte lineage specific transcription factor early B‑cell factor 1 (EBF1), was frequently expressed in human lung cancer tissues. EBF1 short hairpin RNA and knocked down EBF1 expression in lung adenocarcinoma cell line A549 could inhibit the proliferation of lung adenocarcinoma cells invitro and inhibit the growth of tumors invivo. The effects of EBF1 expression on the proliferation of lung cancer cells were examined by cell proliferation assay, cell cycle assay and invivo animal experiments in mice, to explore the possible molecular mechanism of EBF1 involvement in lung cancer cell proliferation. Its mechanism may be related to its influence by blocking cell cycle in G1 phase, which involves the decrease of cyclin dependent kinase 6 expression and the upregulation of P21/P27 expression. The present study will supplement the hypothesis that the heterotopic expression of hematogenous transcription factors in lung cancer affects tumor proliferation and discover new molecular targets for cancer therapy.

Management of the adverse effects of targeted therapy for cancer

Background: Advances in genomics and molecular biology over the past 20 years have resulted in numerous approved molecular targeted cancer therapies. The two main approaches for targeted cancer therapy are monoclonal antibodies and small molecules. Targeted therapy is expected to exert few side effects, but a new class of toxicities has been reported. Thus, the classical chemotherapy-induced toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been replaced in patients receiving targeted therapies by dermatologic, cardiovascular, gastrointestinal, endocrine, ocular, and pulmonary toxicities, and infusion reactions.Current Concepts: Targeted therapy toxicities vary, but common side effects include skin rash, diarrhea, and stomatitis. Most of these side effects are mild and can be prevented and treated. Rare and dangerous side effects, including pneumonitis, cardiotoxicities, and infusion reactions, can also be induced by targeted therapies. In most cases, toxicities are low grade (grade ≤2) and can be treated effectively, but in some cases, they can be fatal without appropriate intervention. Symptoms can be nonspecific, rendering identification of early symptoms challenging. Physicians should thus be aware of these side effects and manage toxicities appropriately.Discussion and Conclusion: The side effects of targeted therapy exert a critical impact on survival and quality of life. Most patients receiving targeted therapy need help to prevent and relieve toxicities. Management of the toxicities of targeted therapy involves patient monitoring, adjusting therapeutic dose or frequency, and providing supportive care. Serious side effects require early detection and prompt intervention, including discontinuation of targeted therapy and the use of corticosteroids.

Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies

Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics. Highlights Molecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex. SP, RO, AZ, CL, and ER were the most promising and commercially available candidates. Molecular dynamics simulations for 200 ns for the most promising five complexes. MM-GBSA calculations for the frontier five complexes. SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line. Potent TOP-2 inhibitory potentials were recorded for ER and RO.

Albumin-based drug carrier targeting urokinase receptor for cancer therapy

Urokinase plasminogen activator receptor (uPAR) is a key participant in extracellular proteolysis, tissue remodeling and cell motility. uPAR overexpresses in most solid tumors and several hematologic malignancies, but has low levels on normal tissues, thus is advocated as a molecular target for cancer therapy. One of the obstacles for the evaluation of uPAR targeting agents in preclinical study is the species specificity, where targeting agents for human uPAR usually not bind to murine uPAR. Here, we develop a targeting agent that binds to both murine and human uPAR. This targeting agent is genetically fused to human serum albumin, a commonly used drug carrier, and the final construct is named as uPAR targeting carrier (uPARTC). uPARTC binds specifically to uPAR-overexpressing 293T/huPAR and 293T/muPAR as demonstrated by flow cytometry. A cytotoxic compound, celastrol, is embedded into uPARTC non-covalently. The resulting macromolecular complex show effective proliferation inhibition on both murine and human uPAR overexpressing cells, and exhibit potent antitumor efficacy on hepatoma H22-bearing mice. This work demonstrates that uPARTC is a promising tumor targeting drug carrier, which address the species-specificity challenge of uPAR targeting agents and can be used to load other cytotoxic compounds.

G-quadruplex binding affinity variation on molecular encapsulation of ligands by porphyrin-tethered cyclodextrin

Non-canonical nuclei acid forms exist in the genome and are widely involved in the control of biological processes. Guanine-rich nucleic acid sequences can form non-canonical DNA forms known as G-quadruplexes. They have become molecular targets in cancer therapy. The structural differences of DNA-binding molecules lead to the alteration of binding affinities for G-quadruplexes. In this article, we present the synthesis and characterization of a series of benzimidazole derivatives. In addition, inclusion complexes of the compounds are made with a porphyrin-β-CD derivative. 2D ROESY spectra provide evidence of the structure of the inclusion complexes. The binding interaction of the benzimidazoles and the inclusion complexes with double-stranded and three G-quadruplex DNAs are studied employing spectroscopic techniques. An order 10⁶–107 M−1 is observed as binding strengths in particular cases. The G-quadruplex selectivity is discussed based on the binding constants. The bromo- substituted compound shows a greater affinity for G-quadruplexes over the duplex DNA, showing a high G-quadruplex selectivity. It indicates the structural dependence of the ligand on the strength of binding to quadruplex DNAs. Further, circular dichroism is utilized to extend insight into the interaction of the strong-binding compound with the duplex and G-quadruplex DNAs.

Effect of sensory neuron-derived growth factors on acquired resistance to molecular-targeted therapies for epidermal growth factor receptor-mutated non-small cell lung cancer

Effect of sensory neuron-derived growth factors on acquired resistance to molecular-targeted therapies for epidermal growth factor receptor-mutated non-small cell lung cancer