The dynamics of drug resistance: A mathematical perspective

Resistance to chemotherapy is a key impediment to successful cancer treatment that has been intensively studied for the last three decades. Several central mechanisms have been identified as contributing to the resistance. In the case of multidrug resistance (MDR), the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Mathematical models of drug resistance have dealt with many of the known aspects of this field, such as pharmacologic sanctuary and location/diffusion resistance, intrinsic resistance, induced resistance and acquired resistance. In addition, there are mathematical models that take into account the kinetic/phase resistance, and models that investigate intracellular mechanisms based on specific biological functions (such as ABC transporters, apoptosis and repair mechanisms). This review covers aspects of MDR that have been mathematically studied, and explains how, from a methodological perspective, mathematics can be used to study drug resistance. We discuss quantitative approaches of mathematical analysis, and demonstrate how mathematics can be used in combination with other experimental and clinical tools. We emphasize the potential benefits of integrating analytical and mathematical methods into future clinical and experimental studies of drug resistance.     

Recent trends in cancer drug resistance reversal strategies using nanoparticles

Introduction: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc.

Areas covered: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors.

Expert opinion: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.     

Intrinsic and acquired drug resistance in malignant tumors. The main reason for therapeutic failure

Drug resistance is the major reason for failure in cancer chemotherapy. Resistance may be either pre-existent (intrinsic resistance), or induced by drugs (acquired resistance), So far, no strategy has been found to overcome resistance, which is based on highly complex and individually variable biological mechanisms. In present clinical practice, drug resistance can only be recognized during treatment, after long lag times. Thus diagnostic tests are re quired, indicating resistance at an earlier stage, in order to avoid unnecessary medication, frequently associated with toxic side-effects. A number of new anti-cancer drugs are now available. In contrast to the unspecifically acting cytostatic chemotherapy, these compounds have targeted actions. However, as recent studies have shown, resistances and severe side-effects can also be found with targeted drugs. With the increasing number of new treatment regimens, the early diagnosis of resistance will optimize therapy, and indeed will be indispensable for individual cancer therapy. The resistance assays available for use in clinical practice should be integrated into cancer therapy. Research into this neglected area needs to be intensified.     

Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer

Introduction: EGFR has been implicated in various malignancies such as NSCLC, breast, head and neck, and pancreatic cancer. Numerous drugs have been developed in order to target the tyrosine domain of EGFR as an approach in cancer treatment.

Areas covered: This article focuses on the different generations of EGFR tyrosine kinase inhibitors (TKIs). This spans from the emergence of the first-generation EGFR-TKIs to overcoming drug resistance using second-generation EGFR-TKIs and to reducing adverse effect (AE) using mutant-selective third-generation EGFR-TKIs.

Expert opinion: Current TKI treatment is frequently accompanied by drug resistance and/or serious AEs. There has been the promise of advancements in second-generation EGFR-TKIs that could overcome drug resistance, acting as second- or third-line salvage treatment, but this promise has yet to be met. That being said, both issues are currently being addressed with mutant-selective EGFR-TKIs with the expectation of bringing more EGFR-targeted therapy into the next phase of cancer therapy in the future.     

Preclinical development of cancer stem cell drugs

Background: Despite recent progress in cancer treatment, the current cancer chemotherapy can mainly produce remission but often fails to cure cancer due to the existence of cancer stem cells. The emerging cancer stem cell hypothesis offers new insight into the failure of current cancer drugs and suggests new approaches for improved understanding of cancer biology and cancer drug development. Objective: In this review, we discuss the concept of cancer stem cells, origin of cancer stem cells and different approaches for isolating or enriching cancer stem cells. We also review the resistance of cancer stem cells to standard chemotherapy and radiation therapy and potential mechanisms for the resistance. Finally, based on the current knowledge on cancer stem cells, we discuss potential approaches for developing new drugs that target cancer stem cells and propose new methods for evaluation of cancer stem cell drugs. Conclusion: Improved cancer treatment is likely to be achieved by a combination of drugs that kill both replicating cancer cells and more quiescent cancer stem cells.     

Structural biology in the battle against BCR-Abl

Background: The clinical success of the tyrosine kinase inhibitor imatinib (Gleevec; STI-571) in the treatment of several leukemias has emphasized the proof-of-concept that molecularly targeted drug design is a viable approach to cancer therapy. However, the emergence of imatinib-resistant phenotypes has spurred a vast amount of research towards finding newer and more potent kinase inhibitors that can overcome drug resistance. Unexpectedly, the newest inhibitors are often less specific than imatinib, inhibiting not only BCR-Abl (the target of imatinib), but also the Src family of tyrosine kinases, which have recently been shown to be downstream effectors of BCR-Abl. Objective: This review summarizes some of the new BCR-Abl inhibitors that have followed from the teaming of combinatorial library searches and structure-based drug design, giving attention to the structural aspects of drug recognition. Conclusion: The use of lower-specificity inhibitors seemingly undermines the rationale behind targeted therapy, yet it appears to be a critical aspect of overcoming drug resistance. Combination therapy with a cocktail of drugs, including an inhibitor of the T315I resistance mutation, will be the next maneuver in the battle against BCR-Abl in the treatment of chronic myelogenous leukemia.     

Gene therapy in pediatric oncology

Summary An increased understanding of the molecular mechanisms of cancer and the ability to introduce exogenous genes into mammalian cells has led to the development of oncologic treatment strategies based upon gene transfer. Preclinical animal models have suggested a variety of approaches which are now being tested in pediatric trials. Studies using marker genes to trace cell origin have already generated important information regarding autologous bone marrow transplantation for pediatric cancers. A variety of therapeutic genes are also being clinically tested. Trials are underway to determine if introduction of immunostimulatory genes into cancer cells can be used to enhance host antitumor immunity. Treatment of primary brain tumors with insertion of drug sensitization genes is a promising new therapy that is also being clinically evaluated. Other strategies such as insertion of drug resistance genes into hematopoietic cells, anti-oncogene therapy, and tumor suppressor gene replacement are being tested in adults and may find use in pediatric cancer treatment. Although gene transfer offers promising new approaches for the therapy of pediatric cancer, many technical problems remain which limit efficacy and widespread use. Further basic research in the molecular biology of cancer and in vector development will be required to realize the full potential of gene therapy strategies. Address for offprints: Brian P. Sorrentino, Division of Experimental Hematology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA     

Drug resistance in the mouse cancer clinic

Drug resistance is one of the most pressing problems in treating cancer patients today. Local and regional disease can usually be adequately treated, but patients eventually die from distant metastases that have become resistant to all available chemotherapy. Although work on cultured tumor cell lines has yielded a lot of information on potential drug resistance mechanisms, it has proven difficult to translate these results to clinical drug resistance in patients. The controversy regarding the contribution of ABC transporters to drug resistance in patients is one example. The study of genetically engineered mouse models (GEMMs), which closely resemble cancer in human patients, can help to bridge this gap. In models for BRCA1- or BRCA2-associated breast cancer, we observed a substantial synergy between the defect in homology-directed DNA repair and sensitivity to DNA-targeting drugs. Nevertheless, tumors are not easily eradicated and eventually drug resistance develops. In this review we will discuss the use of the new generation mouse models to address major clinical problems, such as mechanisms of drug resistance, predicting chemotherapy response or characterizing the nature of residual tumor cells that escape eradication. Moreover, we will address the contribution of ABC transporters to drug resistance in our model.     

Towards a targeted multi-drug delivery approach to improve therapeutic efficacy in breast cancer

Importance of the field: Significant improvements in breast cancer treatments have resulted in a significant decrease in mortality. However, current breast cancer therapies, for example, chemotherapy, often result in high toxicity and nonspecific side effects. Other treatments, such as hormonal and antiangiogenic therapies, often have low treatment efficacy if used alone. In addition, acquired drug resistance decreases further the treatment efficacy of these therapies. Intra-tumor heterogeneity of the tumor tissue may be a major reason for the low treatment efficacy and the development of chemoresistance. Therefore, targeted multi-drug therapy is a valuable option for addressing the multiple mechanisms that may be responsible for reduced efficacy of current therapies.

Areas covered in this review: In this article, different classes of drugs for treating breast cancer, the possible reasons for the drug resistance in breast cancer, as well as different targeted drug delivery systems are summarized. The current targeting strategies used in cancer treatment are discussed.

What the reader will gain: This article considers the current state of breast cancer therapy and the possible future directions in targeted multi-drug delivery for treating breast cancer.

Take home message: A better understanding of tumor biology and physiological responses to nanoparticles, as well as advanced nanoparticle design, are needed to improve the therapeutic outcomes for treating breast cancer using nanoparticle-based targeted drug delivery systems. Moreover, selective delivery of multi-drugs to tumor tissue using targeted drug delivery systems may reduce systemic toxicity further, overcome drug resistances, and improve therapeutic efficacy in treating breast cancer.     

Targeting microtubules for cancer chemotherapy

Chemical compounds that interfere with microtubules such as the vinca alkaloids and taxanes are important chemotherapeutic agents for the treatment of cancer. As our knowledge of microtubule-targeting drugs increases, we realize that the mechanism underlying the anti-cancer activity of these agents may mainly lie in their inhibitory effects on spindle microtubule dynamics, rather than in their effects on microtubule polymer mass. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell cycle progression at mitosis and eventually leading to apoptotic cell death. The effectiveness of microtubule-targeting drugs for cancer therapy has been impaired by various side effects, notably neurological and hematological toxicities. Drug resistance is another notorious factor that thwarts the effectiveness of these agents, as with many other cancer chemotherapeutics. Several new microtubule-targeting agents have shown potent activity against the proliferation of various cancer cells, including cells that display resistance to the existing microtubule-targeting drugs. Continued investigation of the mechanisms of action of microtubule-targeting drugs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance may provide more effective therapeutic options for cancer patients.     

Understanding resistance to combination chemotherapy

The current clinical application of combination chemotherapy is guided by a historically successful set of practices that were developed by basic and clinical researchers 50–60 years ago. Thus, in order to understand how emerging approaches to drug development might aid the creation of new therapeutic combinations, it is critical to understand the defining principles underlying classic combination therapy and the original experimental rationales behind them. One such principle is that the use of combination therapies with independent mechanisms of action can minimize the evolution of drug resistance. Another is that in order to kill sufficient cancer cells to cure a patient, multiple drugs must be delivered at their maximum tolerated dose – a condition that allows for enhanced cancer cell killing with manageable toxicity. In light of these models, we aim to explore recent genomic evidence underlying the mechanisms of resistance to the combination regimens constructed on these principles. Interestingly, we find that emerging genomic evidence contradicts some of the rationales of early practitioners in developing commonly used drug regimens. However, we also find that the addition of recent targeted therapies has yet to change the current principles underlying the construction of anti-cancer combinatorial regimens, nor have they made substantial inroads into the treatment of most cancers. We suggest that emerging systems/network biology approaches have an immense opportunity to impact the rational development of successful drug regimens. Specifically, by examining drug combinations in multivariate ways, next generation combination therapies can be constructed with a clear understanding of how mechanisms of resistance to multi-drug regimens differ from single agent resistance.     

Recent advances in drug delivery strategies for treatment of ovarian cancer

Introduction: Ovarian cancer is associated with the highest mortality rate of all gynecological malignancies, due in part to inadequate treatment strategies and the asymptomatic nature of the disease. Current standard of care includes surgery and systemic chemotherapy. However, this approach can result in toxicities and eventual disease relapse, due to the emergence of multidrug resistance. Drug delivery systems (DDS) have shown promise in overcoming many of the limitations facing conventional treatment regimens.

Areas covered: This review provides an overview of recent advances in DDS strategies for the treatment ovarian cancers. Nano-sized systems, including nanoparticles, micelles, liposomes and drug conjugates; microspheres; implants and injectable depots are discussed. The advantages, limitations and clinical potential of these strategies are also outlined.

Expert opinion: Nano-sized DDS enable passive targeting to tumors due to their size, and further improvements in tumor localization can be made using targeting moieties. Microspheres, implants and injectable depots have been investigated for peritoneal localized and sustained therapy. Overall, the benefits of using DDS for ovarian cancer therapy include higher drug levels at the diseased site, circumvention of drug resistance mechanisms, minimization of non-specific toxicities, improvements in solubility of poorly soluble drugs and elimination of toxicities associated with conventionally used pharmaceutical excipients.     

New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARgamma agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy

In search of new strategies for the treatment of cancer, the interaction between tumor and stroma attracts more and more attention. Disruption of stroma functions, e.g. angiogenesis, has evolved into a promising target for cancer therapies. Since stromal cells are genetically stable, stroma-targeted therapies seem to be less susceptible to the development of drug resistance. Several well-established drugs, which had initially been developed for other indications, also exhibit antitumor activity. Among those, PPARgamma agonists, COX-2 inhibitors, and mTOR antagonists are the most remarkable examples. Current research data and clinical experience suggest that these drugs target stroma functions in cancer, in particular angiogenesis, but immunological mechanisms and direct antitumor effects seem to participate as well. In addition to these drugs, frequent administration of low-dose chemotherapeutics, referred to as metronomic chemotherapy, reveals profound anti-angiogenic effects. In the meantime, a multitude of preclinical and clinical studies have been undertaken, which demonstrate the efficacy of these drugs in cancer therapy. Combinatorial use of these agents has been suggested to be superior in terms of antitumor efficacy and prevention of drug resistance. The toxicity of these therapies is surprisingly low compared with conventional high-dose chemotherapy regimens. Patients with advanced disease, often heavily pretreated and presenting multiple drug resistance, could particularly profit from such tumor-stroma-targeted therapies. However, larger randomized clinical trials are required for further evaluation and optimization of this concept.     

DNA synthesis inhibitors for the treatment of gastrointestinal cancer

Introduction: Intensive laboratory, preclinical and clinical studies have identified and validated molecular targets in cancers, leading to a shift toward the development of novel, rationally designed and specific therapeutic agents. However, gastrointestinal cancers continue to have a poor prognosis, largely due to drug resistance.

Areas covered: Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.

Expert opinion: Conventional agents, including DNA synthesis inhibitors such as fluoropyrimidines and platinum analogs, remain the most effective therapeutics and are the standards against which new drugs are compared. Novel DNA synthesis inhibitors for the treatment of gastrointestinal malignancies include a combination of the antimetabolite TAS-102, which consists of trifluorothymidine with a thymidine phosphorylase inhibitor, and a novel micellar formulation of cisplatin NC-6004 that uses a nanotechnology-based drug delivery system. The challenges of translational cancer research using DNA synthesis inhibitors include the identification of drugs that are specific to tumor cells to reduce toxicity and increase antitumor efficacy, biomarkers to predict pharmacological responses to chemotherapeutic drugs, identification of ways to overcome drug resistance and development of novel combination therapies with DNA synthesis inhibitors and other cancer therapies, such as targeted molecular therapeutics. Here, we discuss the current understanding of DNA synthesis inhibitors and their mechanisms of action for the treatment of gastrointestinal malignancies.     

Mathematical modeling for novel cancer drug discovery and development

Introduction: Mathematical modeling enables: the in silico classification of cancers, the prediction of disease outcomes, optimization of therapy, identification of promising drug targets and prediction of resistance to anticancer drugs. In silico pre-screened drug targets can be validated by a small number of carefully selected experiments.

Areas covered: This review discusses the basics of mathematical modeling in cancer drug discovery and development. The topics include in silico discovery of novel molecular drug targets, optimization of immunotherapies, personalized medicine and guiding preclinical and clinical trials. Breast cancer has been used to demonstrate the applications of mathematical modeling in cancer diagnostics, the identification of high-risk population, cancer screening strategies, prediction of tumor growth and guiding cancer treatment.

Expert opinion: Mathematical models are the key components of the toolkit used in the fight against cancer. The combinatorial complexity of new drugs discovery is enormous, making systematic drug discovery, by experimentation, alone difficult if not impossible. The biggest challenges include seamless integration of growing data, information and knowledge, and making them available for a multiplicity of analyses. Mathematical models are essential for bringing cancer drug discovery into the era of Omics, Big Data and personalized medicine.     

Nanoparticle-assisted combination therapies for effective cancer treatment

Combination chemotherapy and nanoparticle drug delivery are two areas that have shown significant promise in cancer treatment. Combined therapy of two or more drugs promotes synergism among the different drugs against cancer cells and suppresses drug resistance through distinct mechanisms of action. Nanoparticle drug delivery, on the other hand, enhances therapeutic effectiveness and reduces side effects of the drug payloads by improving their pharmacokinetics. These two active research fields have been recently merged to further improve the efficacy of cancer therapeutics. This review article summarizes the recent efforts in developing nanoparticle platforms to concurrently deliver multiple types of drugs for combination chemotherapy. We also highlight the challenges and design specifications that need to be considered in optimizing nanoparticle-based combination chemotherapy.     

Recent trends in cancer drug resistance reversal strategies using nanoparticles

INTRODUCTION: Resistance to chemotherapy is a major obstacle in the successful amelioration of tumors in many cancer patients. Resistance is either intrinsic or acquired, involving mechanisms such as genetic aberrations, decreased influx and increased efflux of drugs. Strategies for the reversal of resistance involve the alteration of enzymes responsible for drug resistance, the modulation of proteins regulating apoptosis mechanisms and improving the uptake of drugs using nanotechnology. Novel strides in the reversal of drug resistance are emerging, involving the use of nanotechnology, targeting stem cells, etc. AREAS COVERED: This paper reviews the most recent cancer drug reversal strategies involving nanotechnology for targeting cancer cells and cancer stem cells (CSCs), for enhanced uptake of micro- and macromolecular inhibitors. EXPERT OPINION: Nanotechnology used in conjunction with existing therapies, such as gene therapy and P-glycoprotein inhibition, has been shown to improve the reversal of drug resistance; the mechanisms involved in this include specific targeting of drugs and nucleotide therapeutics, enhanced cellular uptake of drugs and improved bioavailability of drugs with poor physicochemical characteristics. Important strategies in the reversal of drug resistance include: a multifunctional nanoparticulate system housing a targeting moiety; therapeutics to kill resistant cancer cells and CSCs; cytotoxic drugs and a tumor microenvironment stimuli-responsive element, to release the encapsulated therapeutics.     

顺铂联合用药治疗乳腺癌的研究进展

乳腺癌发病率持续上升，严重影响女性健康。其治疗手段从手术治疗到化、放疗，再到内分泌治疗与免疫治疗，不断更新，但化疗仍是晚期乳腺癌或发生乳腺外转移的主要临床治疗手段。顺铂是治疗乳腺癌的一线化疗药物，但其不良反应和耐药性限制了其临床应用。目前众多研究报道顺铂联合其他药物可减轻顺铂不良反应、克服其耐药性，从而提高抗乳腺癌效果。本文拟对顺铂与天然活性成分、化疗药、抗体以及核酸类药联合治疗乳腺癌的最新研究进展进行综述，以期为乳腺癌联合治疗方案的选择提供参考。     

Challenges with in vitro and in vivo experimental models of urinary bladder cancer for novel drug discovery

ABSTRACT

Introduction: Urinary bladder cancer (UBC) is the second most frequent malignancy of the urinary system and the ninth most common cancer worldwide, affecting individuals over the age of 65. Several investigations have embarked on advancing knowledge of the mechanisms underlying urothelial carcinogenesis, understanding the mechanisms of antineoplastic drugs resistance and discovering new antineoplastic drugs. In vitro and in vivo models are crucial for providing additional insights into the mechanisms of urothelial carcinogenesis. With these models, various molecular pathways involved in urothelial carcinogenesis have been discovered, allowing therapeutic manipulation.

Areas covered: This paper provides critical information on existing in vitro and in vivo models to screen the efficacy and toxicity of innovative UBC therapies and point out the challenges for new and improved models.

Expert opinion: In our opinion, results obtained with in vitro and in vivo models should be interpreted together, as a set of delicate biological tools that can be used at different stages in the drug discovery process, to address specific questions. With the development of new technologies, new assays and biomarkers are going to play an important role in the study of UBC. The molecular diagnostics and genomic revolution will not only help to develop new drug therapies, but also to achieve tailored therapies.     

Old and New Molecular Mechanisms Associated with Platelet Resistance to Antithrombotics

Current available data show that about 5 to 40% of coronary patients treated with conventional doses of antithrombotic drugs do not display adequate antiplatelet response. Nowadays, aspirin remains the main antiplatelet therapy. However, a significant number of patients show platelet resistance to aspirin therapy, and recurrent thrombotic events occur. Combined antithrombotic therapies with thienopyridines, such as clopidogrel have been used to resolve this problem. However, clopidogrel treatment has been also associated with wide response variability, and non-responsiveness to clopidogrel also occurs in some patients. Therefore, the main question arising about the antithrombotic therapy is why particular patients do not benefit from the therapy and how they might be identified to improve their treatment. Different hypotheses have been suggested, including genetic factors, platelet heterogeneity, non-compliance and others. However, it is probably that many molecular mechanisms involved in platelet resistance to antithrombotic therapies still remains unknown. New technologies, such as proteomics and genetic, are beginning to show new unknown biological biomarkers and molecular mechanisms which may be associated with platelet antithrombotic drug resistance.