BACKGROUND: The impact of constantly developing molecular sciences on the various imaging modalities (particularly nuclear, magnetic resonance-based, optical techniques) has produced the beginning of a new complex science - the molecular imaging - that, through the exploitation of specific molecule-probes instead of nonspecific conventional contrast materials, is aimed at the characterization of the tumor-related molecular abnormalities, to adopt innovative targeted therapeutic measures, even at the genetic level. OBJECTIVES: Aim for this review is to focus on recent significant accomplishments of different molecular imaging modalities moreover outlining the challenges of current theranostic developments. EMERGING KNOWLEDGES: The spatial resolution of almost all imaging techniques is more and more increasing, so that some experimental in vivo imaging modalities can allow an extremely detailed three-dimensional resolution. From the constant developments of molecular biology it follows that, instead of relatively gross conventional diagnostic criteria on malignancies (anatomic location and size, surrounding tissue involvement, distant spread), more specific molecular imaging parameters might be adopted - such as tumor cell kinetics, genetic alterations, variety of involved growth factors - to reach, by innovative targeted drugs and biological agents, therapeutic effects at the molecular level. In animal models - particularly in cancer xenografts - the molecular imaging, through the resort to SIAFS (small animal imaging facilities), allows in vivo thorough investigations on the tumor development-related mechanisms, furthermore improving the research on pharmacokinetics and pharmacodynamics of newly developed drugs. CONCLUSIONS: Current applications of molecular imaging are due to its capability of both in vivo identifying tumor early molecular abnormalities and monitoring personalized therapies. Foreseeably the research advances will tremendously expand in the near future, particularly considering that simultaneous both imaging- and therapy implications of the theranostics can improve, to the highest degree, the potential of molecular imaging.
The new molecular targeted therapy has been developed over the past decades by using the molecular targeted molecular changes discovered in specific types of cancer. Unfortunately, most of these agents (epidermal growth factor receptors, multi-targeted small molecule tyrosine kinase inhibitors, monoclonal antibodies) have severe cutaneous adverse reactions, that not only interfere with the patient's quality of life, but also are dose-limiting and may require treatment interruptions. These cutaneous complications and their management must be very well known by any oncologist and dermatologist who treat oncologic patients. ABBREVIATIONS: EGFR = epidermal growth factor receptors, EGFRI = epidermal growth factor receptors inhibitors.
Meningiomas are the most common primary intracranial tumors of adults. For meningiomas that progress or recur despite surgical resection and radiotherapy, additional treatment options are limited due to a lack of proven efficacy. Meningiomas show recurring molecular aberrations, which may serve as predictive markers for systemic pharmacotherapies with targeted drugs or immunotherapy, radiotherapy, or radioligand therapy. Here, we review the evidence for a predictive role of a wide range of molecular alterations and markers including NF2, AKT1, SMO, SMARCE1, PIK3CA, CDKN2A/B, CDK4/6, TERT, TRAF7, BAP1, KLF4,ARID1/2, SUFU, PD-L1, SSTR2A, PR/ER, mTOR, VEGF(R), PDGFR, as well as homologous recombination deficiency, genomic copy number variations, DNA methylation classes, and combined gene expression profiles. In our assessment based on the established ESMO ESCAT (European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets) evidence-level criteria, no molecular target reached ESCAT I ("ready for clinical use") classification, and only mTOR pathway activation and NF2 alterations reached ESCAT II ("investigational") classification, respectively. Our evaluations may guide targeted therapy selection in clinical practice and clinical trial efforts and highlight areas for which additional research is warranted.
Targeted therapy and precision oncology aim to improve efficacy and minimize side effects by targeting specific molecules involved in cancer growth and spread. With the advancements in genomics, proteomics, and transcriptomics with the accessible modalities such as next-generation sequencing, circulating tumor cells, and tumor Deoxyribonucleic Acid (DNA), more number of patients are being offered the targeted therapy in form of monoclonal antibodies and various intracellular targets, specific for their tumor. The harnessing of host immunity against the cancer cells by utilizing immune-oncology agents and chimeric antigen receptor T-cell therapy has further revolutionized the management of various cancers. These agents, however, have the challenge of managing the adverse effects that are peculiar to the class of drugs and very different from the conventional chemotherapy. This review article discusses the molecular basis, diagnostics, and use of targeted therapy in oncology.
Among the areas defined by the National Cancer Institute as "Extraordinary Opportunities for Research Investment" that are highly relevant to the technology-oriented disciplines within the broad field of radiology are cancer imaging, defining the signatures (ie, underlying molecular features) of cancer cells, and molecular targets of prevention and treatment. In molecular target credentialing, a specific molecular target is imaged, the molecular signature is defined, a treatment is given, and the effect of the intervention on the image findings and the signature is then evaluated. Such an approach is used to validate the proposed target as a legitimate one for cancer therapy or prevention and to provide the opportunity to ultimately individualize therapy on the basis of both the initial characteristics of the tumor and the tumor's response to an intervention. Therapeutic radiation is focused biology (ie, radiation produces molecular events in the irradiated tissue). Radiation can (a) kill cancer cells by itself, (b) be combined with cytotoxic or cytostatic drugs, and (c) serve to initiate radiation-inducible molecular targets that are amenable to treatment with drugs and/or biologic therapies. Focused biology can be anatomically confined with various types of external beams and with brachytherapy, and it can be used systemically with targeted radioisotopes. These new paradigms link diagnostic imaging, radiation therapy, and nuclear medicine in unique ways by way of basic biology. It is timely to develop new collaborative research, training, and education agendas by building on one another's expertise and adopting new fields of microtechnology, nanotechnology, and mathematical analysis and optimization.
ABSTRACT Aim To identify factors influencing adherence to oral molecular therapies in haematology‐oncology outpatients. Method Patients prescribed imatinib and thalidomide participated in the study. A quantitative questionnaire incorporating validated assessment tools and developed from issues raised in the literature was used to collect data about demographic characteristics, motivations and perceptions, impact of social environment, and aspects of medication regimens. These factors were assessed for association with adherence to molecular therapies, estimated using the Morisky score. Results 24 patients were recruited, all of whom reported high or moderate adherence to oral molecular therapies based on their Morisky score. Adherence was positively related with age (Rho = +0.510; p = 0.011) and overall patient satisfaction with hospital services and support from family and friends (Rho = +0.609; p = 0.003). There were a number of social environment factors which were found to have a significant inverse relationship with adherence to molecular therapies including: forgetting to take the medication, change in daily routine, feeling sick/ill, wanting to avoid adverse effects and having problems taking medication at certain times. The overall impact of a patient's social environment was found to contribute negatively to adherence (Rho = −0.542; p = 0.017). Conclusion Factors affecting adherence to molecular therapies can be assessed by pharmacists, allowing implementation of strategies to encourage adherent behaviour in difficult circumstances.
The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. The articles in this CCR Focus provide insights into molecular mechanisms of resistance to targeted therapy. Recent discoveries of the molecular pathways that mediate intrinsic resistance to targeted therapy have led to the identification of predictive biomarkers that allow for better patient selection for front line treatment. Equally important, the identification of mechanisms of acquired resistance following front line therapy has led to the discovery of novel agents that overcome these resistance mechanisms. Improving the efficacy of targeted therapies in the future will require expanding our understanding of resistance mechanisms, the development of new generations of rationally designed targeted agents, and translating this information to the clinic to select patients for appropriate therapy. (Clin Cancer Res 2009;15(24):7471-8).
The impressive advances in the knowledge of biomarkers and molecular targets has enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas of pharmacology have contributed to these therapeutic outcomes-mainly targeted therapy, immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological profiles of these therapeutic classes and intends, on the one hand, to provide a systematic definition and, on the other, to highlight some aspects related to pharmacovigilance, namely the monitoring of safety and the identification of potential toxicities and adverse drug reactions. Although clinicians often consider pharmacovigilance a non-priority area, it highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies, which represent the most innovative and promising horizon in oncology.
Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK- and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALK-rearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a molecular-defined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists.
Molecular imaging is revolutionizing the way we study the inner workings of the human body, diagnose diseases, approach drug design, and assess therapies. The field as a whole is making possible the visualization of complex biochemical processes involved in normal physiology and disease states, in real time, in living cells, tissues, and intact subjects. In this review, we focus specifically on molecular imaging of intact living subjects. We provide a basic primer for those who are new to molecular imaging, and a resource for those involved in the field. We begin by describing classical molecular imaging techniques together with their key strengths and limitations, after which we introduce some of the latest emerging imaging modalities. We provide an overview of the main classes of molecular imaging agents (i.e., small molecules, peptides, aptamers, engineered proteins, and nanoparticles) and cite examples of how molecular imaging is being applied in oncology, neuroscience, cardiology, gene therapy, cell tracking, and theranostics (therapy combined with diagnostics). A step-by-step guide to answering biological and/or clinical questions using the tools of molecular imaging is also provided. We conclude by discussing the grand challenges of the field, its future directions, and enormous potential for further impacting how we approach research and medicine.
More than 300,000 new cases worldwide are being diagnosed with oral squamous cell carcinoma annually. This aggressive epithelial malignancy is associated with a high mortality and severe morbidity among the long-term survivors. The ability to intervene prior to this advanced stage may improve treatment results. This requires the early identification of molecular events that represent early phases of malignant transition, which is possible through measurement of DNA ploidy in epithelial cells of oral leukoplakia. Recently, we showed that patients with aneuploid dysplastic oral lesions had a 96% rate of oral cancer (26 of the 27 patients received the diagnosis) with a 70% rate within three years, an 81% rate of subsequent cancer (22 of 27), a 74% rate of death from cancer (21 of 27) and virtually no help from complete resection-all hallmarks of biologically aggressive cancer. Standard treatment of oral leukoplakia-a precursor lesion of oral cancer-varies from watchful waiting to complete resection. We have recently demonstrated that complete resection of aneuploid oral leukoplakia does not prevent the occurrence of clinically aggressive and highly lethal oral cancer. Oral carcinogenesis is a complex multifocal process of multiclonal field carcinogenesis and intraepithelial clonal spread. The multifocal nature of early oral carcinogenesis may hinder local treatment modalities. Inhibitors of cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR), either alone or in combination, may be used for reversing or stopping the oral carcinogenesis at an early stage of disease. The failure of standard treatment to control aneuploid oral leukoplakia justifies clinical trials with new treatment modalities, such as systemic therapy with molecular targeting agents, which in patients with aggressive leukoplakia is tantamount to cancer therapy.
Technological advances in high-throughput next-generation sequencing (NGS) along with advances in computational processes have brought about the dawn of the genomic medicine era. NGS has enabled molecular characterization of malignancies, and facilitated the development and approval of gene- and immune-targeted therapies, both of which impact the mutanome. Clinical implementation of this technology, approval of novel targeted agents, and establishment of molecular tumor boards has enabled precision oncology to become a reality.
Oncology is a rapidly evolving field with a shift toward personalized cancer treatment. The use of therapies targeted to the molecular features of individual tumors and the tumor microenvironment has become much more common. In this review, anti-angiogenic and other molecular targeted therapies are discussed, with a focus on typical and atypical response patterns and imaging manifestations of drug toxicities.
During recent years, significant advances have been made in the field of molecular therapy in urologic oncology, mainly for advanced renal cell carcinoma. In this hitherto largely treatment-refractory disease, several agents have been developed targeting the von Hippel-Lindau metabolic pathway which is involved in carcinogenesis and progression of the majority of renal cell carcinomas. Although cure may not be expected, new drugs, such as the multikinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycine inhibitor temsirolimus, frequently stabilize the disease course and may improve survival. Fewer data are available supporting molecular therapies in prostate, bladder, and testicular cancers. Preliminary data suggest a potential role of high-dose calcitriol and thalidomide in hormone-refractory prostate cancer, whereas targeted therapies in bladder and testicular cancers are still more or less limited to single-case experiences. The great theoretical potential and the multitude of possible targets and drug combinations, however, support further research into this exciting field of medical treatment of urologic malignancies.
The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.
Next-generation sequencing (NGS) and liquid biopsy are new technologies that can allow overall tumor profiling in a single analysis and play an important role in the implementation of precision oncology. However, the lack of guidelines in this setting has limited the development of precision oncology in Italy. This article summarizes recommendations for the appropriate use of NGS in tumor gene profiling, as well as access to tests and target drugs, that were prepared by a group of key opinion leaders and relevant stakeholders. In particular, the need to create laboratory networks capable of carrying out NGS tests in Italy is highlighted. It also appears necessary to establish an adequate reimbursement system for NGS tests. However, the expert panel recommends that the use of NGS tests in clinical practice should be limited to specific tumor types, based on the number and complexity of biomarkers and the availability of treatments.
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
For decades, retinoids and their synthetic derivatives have been well established anticancer treatments due to their ability to regulate cell growth and induce cell differentiation and apoptosis. Many studies have reported the promising role of retinoids in attaining better outcomes for adult or pediatric patients suffering from several types of cancer, especially acute myeloid leukemia and neuroblastoma. However, even this promising differentiation therapy has some limitations: retinoid toxicity and intrinsic or acquired resistance have been observed in many patients. Therefore, the identification of molecular markers that predict the therapeutic response to retinoid treatment is undoubtedly important for retinoid use in clinical practice. The purpose of this review is to summarize the current knowledge on candidate markers, including both genetic alterations and protein markers, for retinoid resistance and sensitivity in human malignancies.
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