Search

While synthetic lethality (SL) holds promise in developing effective cancer therapies, SL candidates found via experimental screens often have limited translational value. Here we present a data-driven approach, ISLE (identification of clinically relevant synthetic lethality), that mines TCGA cohort to identify the most likely clinically relevant SL interactions (cSLi) from a given candidate set of lab-screened SLi. We first validate ISLE via a benchmark of large-scale drug response screens and by predicting drug efficacy in mouse xenograft models. We then experimentally test a select set of predicted cSLi via new screening experiments, validating their predicted context-specific sensitivity in hypoxic vs normoxic conditions and demonstrating cSLi's utility in predicting synergistic drug combinations. We show that cSLi can successfully predict patients' drug treatment response and provide patient stratification signatures. ISLE thus complements existing actionable mutation-based methods for precision cancer therapy, offering an opportunity to expand its scope to the whole genome.

The concept of synthetic lethality has great potential for anticancer therapy as a new strategy to specifically kill cancer cells while sparing normal cells. To further understand the potential molecular interactions and gene characteristics involved in synthetic lethality, we performed a comprehensive analysis of predicted cancer-specific genetic interactions. Many genes were identified as cancer-associated genes that contributed to multiple biological processes and pathways, and the gene features were not random, indicating their potential roles in human carcinogenesis. Some relevant genes detected in multiple cancers were prone to be enriched in specific biological progresses and pathways, especially processes associated with DNA damage, chromosome-related functions and cancer pathways. These findings strongly implicated potential roles for these genes in cancer pathophysiology and functional relationships, as well as applications for future anticancer drug discovery. Further experimental validation indicated that the synthetic lethal interaction of APC and GFER may provide a potential anticancer strategy for patients with APC-mutant colon cancer. These results will contribute to further exploration of synthetic lethal interactions and broader application of the concept of synthetic lethality in anticancer therapeutics., (© 2022 Federation of European Biochemical Societies.)

Results of treatment for osteosarcoma of the extremity have been poor with metastases usually causing death within 2 years following diagnosis. Because of the great risk of development of metastases, 20 patients have received adjuvant chemotherapy with Adriamycin, cyclophosphamide and high-dose methotrexate-leucovorin rescue for up to 12 months following amputation for osteosarcoma. Sixteen of these patients are surviving; 11 are free of evident tumor from 6 to 34 months following amputation. Five patients were found to have pulmonary metastases while receiving chemotherapy and three patients developed metastases following completion of chemotherapy. One patient died following her third treatment with high-dose methotrexate-leucorovin rescue. Other toxicity included nausea, vomiting, mucosal ulcerations, infections, hematologic abnormalities, changes in kidney and liver functions tests, and minor coagulation abnormalities. The natural history of osteosarcoma may have been modified by the use of these agents for periods exceeding the median time to predicted detection of pulmonary metastases. Microscopic metastases of some patients were eradicated by this adjuvant chemotherapy. For patients who developed metastases, these metastases were delayed in their time of detection and in their number at the time of detection.

Paclitaxel, a natural anticancer drug, is widely recognized and extensively utilized in the treatment of breast cancer (BC). However, it may lead to certain side effects or drug resistance. Fortunately, combination therapy with another anti-tumor agent has been explored as an option to improve the efficacy of paclitaxel in the treatment of BC. Herein, we first evaluated the synergistic effects of paclitaxel and flubendazole through combination index (CI) calculations. Secondly, flubendazole was demonstrated to synergize paclitaxel-mediated BC cell killing in vitro and in vivo. Moreover, we discovered that flubendazole could reverse the drug resistance of paclitaxel-resistant BC cells. Mechanistically, flubendazole was demonstrated to enhance the inhibitory effect of paclitaxel via HIF1α/PI3K/AKT signaling pathways. Collectively, our findings demonstrate the effectiveness of flubendazole in combination with paclitaxel for treating BC, providing an insight into exploiting more novel combination therapies for BC in the future. [ABSTRACT FROM AUTHOR]

Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma. [ABSTRACT FROM AUTHOR]

Drug repositioning, the approach of discovering different uses for existing drugs, has gained enormous popularity in recent years in the anticancer drug discovery field due to the increasing demand for anticancer drugs. Additionally, the repurposing of veterinary antiparasitic drugs for the treatment of cancer is gaining traction, as supported by existing literature. A prominent example is the proposal to implement the use of veterinary antiparasitics such as benzimidazole carbamates and halogenated salicylanilides as novel anticancer drugs. These agents have revealed pronounced anti-tumor activities and gained special attention for "double repositioning", as they are repurposed for different species and diseases simultaneously, acting via different mechanisms depending on their target. As anticancer agents, these compounds employ several mechanisms, including the inhibition of oncogenic signal transduction pathways of mitochondrial respiration and the inhibition of cellular stress responses. In this review, we summarize and provide valuable information about the experimental, preclinical, and clinical trials of veterinary antiparasitic drugs available for the treatment of various cancers in humans. This review suggests the possibility of new treatment options that could improve the quality of life and outcomes for cancer patients in comparison to the currently used treatments. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) is the second most common cancer in men. Common treatments include active surveillance, surgery, or radiation. Androgen deprivation therapy and chemotherapy are usually reserved for advanced disease or biochemical recurrence, such as castration-resistant prostate cancer (CRPC), but they are not considered curative because PCa cells eventually develop drug resistance. The latter is achieved through various cellular mechanisms that ultimately circumvent the pharmaceutical's mode of action. The need for novel therapeutic approaches is necessary under these circumstances. An alternative way to treat PCa is by repurposing of existing drugs that were initially intended for other conditions. By extrapolating the effects of previously approved drugs to the intracellular processes of PCa, treatment options will expand. In addition, drug repurposing is cost-effective and efficient because it utilizes drugs that have already demonstrated safety and efficacy. This review catalogues the drugs that can be repurposed for PCa in preclinical studies as well as clinical trials. [ABSTRACT FROM AUTHOR]

Benzimidazoles, which interfere with the complex life cycle of worms, are essential in the treatment of helminthiasis. Four benzimidazole antihelmintics have been used in human therapy: albendazole, mebendazole, thiabendazole, triclabendazole. The history, representatives, synthesis, physicochemical properties, structure-activity relationships of anthelmintic benzimidazoles are presented in the review, as well as the pharmacological properties and mechanism of action of these agents. In the last decade, benzimidazole carbamate-structured anthelmintics have also been studied for their antitumor activity. [ABSTRACT FROM AUTHOR]

Background/Aim: High-dose methotrexate (HDMTX) is pivotal chemotherapy in the treatment of patients with osteosarcoma. Blood concentrations of MTX are associated with several side effects, but there are large individual differences in the elimination of MTX. The aim of this study was to explore risk factors for delayed elimination of MTX in children, adolescents and young adults with osteosarcoma. Patients and Methods: We conducted a retrospective study on Japanese patients with osteosarcoma who were treated with HD-MTX at Kanazawa University Hospital from April 2006 to March 2015. Risk factors for delayed elimination of methotrexate were identified by multiple logistic regression analysis. Results: A total of 92 cycles of HD-MTX therapy were analyzed. Female and lower creatinine clearance (CCr) were identified as independent risk factors for delayed elimination of MTX. Conclusion: Knowing the factors associated with delayed elimination of MTX could lead to safer and optimized chemotherapy for patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

The ataxia telangiectasia and Rad3-related (ATR) protein kinase is a key regulator of the cellular response to DNA damage. Due to increased amount of replication stress, cancer cells heavily rely on ATR to complete DNA replication and cell cycle progression. Thus, ATR inhibition is an emerging target in cancer therapy, with multiple ATR inhibitors currently undergoing clinical trials. Here, we describe dual genome-wide CRISPR knockout and CRISPR activation screens employed to comprehensively identify genes that regulate the cellular resistance to ATR inhibitors. Specifically, we investigated two different ATR inhibitors, namely VE822 and AZD6738, in both HeLa and MCF10A cells. We identified and validated multiple genes that alter the resistance to ATR inhibitors. Importantly, we show that the mechanisms of resistance employed by these genes are varied, and include restoring DNA replication fork progression, and prevention of ATR inhibitor-induced apoptosis. In particular, we describe a role for MED12-mediated inhibition of the TGFβ signaling pathway in regulating replication fork stability and cellular survival upon ATR inhibition. Our dual genome-wide screen findings pave the way for personalized medicine by identifying potential biomarkers for ATR inhibitor resistance. Author summary: Cancer cells rely on the ATR replication stress response pathway to ensure DNA replication and continued cellular proliferation. As such, inhibitors of the ATR kinase activity represent promising new anti-cancer drugs. However, the tumors' susceptibility to these drugs can be markedly impacted by their genomic profile. To address this, we employed dual CRISPR knockout and activation genome-wide genetic screens to catalog the genetic determinants of the cellular resistance to multiple ATR inhibitors. We identified several mechanisms which control this resistance, including regulation of apoptosis and stabilization of replication fork stability. Our work lays the foundation for personalized deployment of ATR inhibitors in cancer therapy. [ABSTRACT FROM AUTHOR]

Agents able to modify microtubule dynamics are important anticancer drugs. The absence of microtubules resulting from drug-induced depolymerization is easy to detect. However the detection of a stabilized microtubule network needs specific assays since there is not a significant visual difference between normal and stabilized microtubule networks. Here, we describe a quantitative cell-based assay, suitable for automation, which allows the detection of stabilized microtubules without the need of microscopic examination. The rationale of this assay is based on the drug-induced resistance of the microtubule network to the depolymerizing agent combretastatin A4 and the subsequent detection of the residual microtubules by immunoluminescence. Using this assay to screen a kinase inhibitor library allowed the selection of seven known kinase inhibitors: selonsertib, masatinib, intedanib, PF0477736, SNS-314 mesylate, MPI0479605, and ponatinib. The yet undescribed ability of these inhibitors to stabilize cellular microtubules was confirmed using additional markers of stable microtubules and time-lapse video-microscopy to track individual microtubules in living cells. None of the compounds interacted, however, directly with tubulin. By employing other inhibitors of the same kinases, which have structurally unrelated scaffolds, we determined if the microtubule stabilizing effect was due to the inhibition of the targeted kinase, or to an off-target effect. Many of these inhibitors are clinically approved or currently assayed in phase 2 or phase 3 clinical trials. Their microtubule-stabilizing effect may account for their therapeutic effect as well as for some of their adverse side effects. These results indicate also a possible repurposing of some of these drugs. [ABSTRACT FROM AUTHOR]

As in the systemic treatment of any disease, it is crucial for anti-cancer drugs to reach their target at a sufficient that is a therapeutically effective dose. However, unlike normal organs, solid tumors have a tendency to be undersupplied and hypoxic. This not only leads to insufficient supply of oxygen and nutrients but also to inefficient transport of drugs into tumors. As a consequence, administered doses have to be raised, resulting in increased side effects and often premature termination of treatment. A better understanding of the mechanisms that hamper transport of drugs into tumors could lead to the development of auxiliary strategies aimed at increasing tumor drug delivery and accumulation and thereby improving the efficacy of anti-cancer drugs at our disposal. The tumor microenvironment (TME), i.e., its vasculature, stroma, extracellular matrix and immune environment affect the transport of drugs to the tumor and their distribution within the tumor tissue in various ways. In this review we will highlight the current research regarding the cellular and molecular mechanisms that remain as an obstacle towards an effective cancer therapy, and also focus on the various strategies to alter the TME to increase tumor drug exposure and thereby treatment efficacy. [ABSTRACT FROM AUTHOR]

Abstract: Although dysregulation of histamine H4 receptor (H4R) has widely and frequently been documented in digestive carcinomas and correlates with the malignancy and proliferation of these tumors, the existence of H4R and its pathophysiological function in esophageal squamous cell carcinoma (ESCC) remains unknown. In our present study, we explored the expression and function of H4R in human ESCC samples and cell lines. H4R was overexpressed in poorly differentiated ESCC samples and cell lines and correlated with the median survival of ESCC patients. H4R activation not only significantly blocked cell proliferation, cell cycle, and invasion but also inhibited the growth of TE-2 xenografts and increased the survival of xenograft-bearing mice. According to the mechanistic experiments, both metabolism (acetyl-coenzyme A synthetase 2 (ACSS2))- and non-metabolism (mitogen-activated protein kinase (MAPK))-related pathways were involved in the effect of H4R activation on suppressing tumor proliferation and invasion. Based on these findings, H4R was overexpressed in esophageal cancer and exerted antitumor effects on ESCC proliferation and invasion, suggesting that H4R may be a novel potential target of therapies for ESCC.Key messages: The function of H4R in ESCC and the underlying mechanisms were investigated.H4R expression was correlated with ESCC cell differentiation and patients’ survival.Both metabolism (ACSS2) and non-metabolism (MAPK)-related pathways were involved.This study provided new insight into the relationship between H4R and ESCC.H4R may be a novel potential therapeutic target for ESCC. [ABSTRACT FROM AUTHOR]

The properties of benzimidazole and its derivatives have been studied over more than one hundred years. Benzimidazole derivatives are useful intermediates/subunits for the development of molecules of pharmaceutical or biological interest. Substituted benzimidazole derivatives have found applications in diverse therapeutic areas such as antiulcer, anticancer agents, and anthelmintic species to name just a few. This work systematically gives a comprehensive review in current developments of benzimidazole-based compounds in the whole range of medicinal chemistry as anticancer, antibacterial, antifungal, anti-inflammatory, analgesic agents, anti- HIV, antioxidant, anticonvulsant, antitubercular, antidiabetic, antileishmanial, antihistaminic, antimalarial agents, and other medicinal agents. This review will further be helpful for the researcher on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole drugs/compounds. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of the new antifolate CB 3717 were studied in 20 patients during its phase-I clinical evaluation. The drug was administered at doses of 100-550 mg/m2 in 1-h and 12-h infusions, resulting in peak plasma concentrations of CB 3717 of 40-200 microM. There was a linear relationship between the dose and both CB 3717 AUC and peak plasma levels. Following a 1-h infusion, drug levels in the plasma decayed biphasically (t1/2 alpha = 49 +/- 9 min, t1/2 beta = 739 +/- 209 min). 27% +/- 2% of the dose was excreted in urine in the 24-h period after treatment, suggesting that the major route of elimination was via the bile. Furthermore, the parent compound CB 3717 and its desglutamyl metabolite, CB 3751, were found in a faecal collection although the metabolite was not detected in plasma or urine samples. Plasma protein binding of CB 3717 was extensive (97.6% +/- 0.1%). Significant quantities of CB 3717 penetrated into ascitic fluid but not into cerebrospinal fluid. Residual drug was detected in postmortem kidney tissue from a patient who died of progressive disease 8 days after treatment with 330 mg/m2 CB 3717. Thus, dose-limiting renal toxicity (maximum tolerated dose 600 mg/m2) may be due to drug precipitation in the renal tubules. Elevation of liver enzymes, in particular transaminases, occurred frequently as a toxic manifestation of CB 3717 therapy. In 11 patients studied after their first treatment there was a positive correlation between the rise in serum alanine transaminase and peak drug levels (r = 0.69, P = 0.02). These pharmacokinetic studies have shown that, by analogy with experimental systems, cytotoxic plasma levels of CB 3717 are archieved in man. In addition, they have been valuable in interpreting toxicities observed during phase-I clinical studies. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC. [ABSTRACT FROM AUTHOR]