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The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease. Article highlights Advances in targeted therapy Covalent inhibitors like sotorasib, adagrasib and divarasib represent significant advancements in targeted therapy aimed specifically at tumors harboring the KRASG12C mutation. Clinical efficacy Clinical trials have shown that KRAS G12C inhibitors improved objective response rates and progression-free survival compared with standard treatments. These trials have obtained promising results in personalized cancer therapy for non-small cell lung cancer (NSCLC) patients harboring the KRASG12C mutation. Importance of co-mutations Co-mutations in genes like KEAP1, SMARCA4 and CDKN2A can significantly impact patient outcomes and response to KRAS G12C inhibitors, with certain co-mutations associated with poor prognosis. Pharmacokinetics & safety Each KRAS G12C inhibitor comes with its own pharmacokinetics profile. Sotorasib and adagrasib are both well tolerated, though gastrointestinal adverse events are common and can be managed with supportive care. Predictive biomarkers Liquid biopsies show promise in detecting KRAS mutations, monitoring treatment response and predicting overall survival, making them a valuable tool in managing NSCLC. Resistance mechanisms Development of resistance to KRAS inhibitors can occur through various genetic alterations and activation of alternative pathways. Combination therapies may help overcome these resistance mechanisms. Future directions Ongoing and future clinical trials aim to further explore the efficacy of KRAS G12C inhibitors, their combinations with immunotherapies, and other novel compounds to improve treatment outcomes in NSCLC. [ABSTRACT FROM AUTHOR]

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB–IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)–IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease. [ABSTRACT FROM AUTHOR]

Introduction: Comprehensive molecular tumor profiling is widely used in the management of patients with cancer. Molecular tumor boards devise treatment strategies based on testing results. In this setting, the Transsectoral Molecular Tumor Board exchange platform Deutschland (TEAM-D) aims to drive peer-to-peer exchange to connect experts in the field. Methods: During the first virtual TEAM-D meeting, participants from 16 German universities and 5 nonacademic institutions discussed five cases with PIK3CA hotspot mutations. Furthermore, an illustrative case vignette was presented. Results: Overall, German caregivers show restraint in administering off-label PIK3CA inhibitor and favor clinical trials in this setting. Conclusion: In the setting of precision oncology, TEAM-D enables virtual case discussion across the different sectors of the German healthcare system. Based on the example of PIK3CA hotspot mutations, TEAM-D demonstrated the value of integrating knowledge from different healthcare professionals. [ABSTRACT FROM AUTHOR]

Abstract Hepatocellular carcinoma (HCC) is a primary liver malignancy with high mortality rates and poor prognosis. Recent advances in high-throughput sequencing and bioinformatic technologies have greatly enhanced the understanding of the genetic and epigenetic changes in liver cancer. Among these changes, RNA methylation, the most prevalent internal RNA modification, has emerged as a significant contributor of the development and progression of HCC. Growing evidence has reported significantly abnormal levels of RNA methylation and dysregulation of RNA-methylation-related enzymes in HCC tissues and cell lines. These alterations in RNA methylation play a crucial role in the regulation of various genes and signaling pathways involved in HCC, thereby promoting tumor progression. Understanding the pathogenesis of RNA methylation in HCC would help in developing prognostic biomarkers and targeted therapies for HCC. Targeting RNA-methylation-related molecules has shown promising potential in the management of HCC, in terms of developing novel prognostic biomarkers and therapies for HCC. Exploring the clinical application of targeted RNA methylation may provide new insights and approaches for the management of HCC. Further research in this field is warranted to fully understand the functional roles and underlying mechanisms of RNA methylation in HCC. In this review, we described the multifaceted functional roles and potential mechanisms of RNA methylation in HCC. Moreover, the prospects of clinical application of targeted RNA methylation for HCC management are discussed, which may provide the basis for subsequent in-depth research on RNA methylation in HCC.

Hepatocellular carcinoma (HCC) is a primary liver malignancy with high mortality rates and poor prognosis. Recent advances in high-throughput sequencing and bioinformatic technologies have greatly enhanced the understanding of the genetic and epigenetic changes in liver cancer. Among these changes, RNA methylation, the most prevalent internal RNA modification, has emerged as a significant contributor of the development and progression of HCC. Growing evidence has reported significantly abnormal levels of RNA methylation and dysregulation of RNA-methylation-related enzymes in HCC tissues and cell lines. These alterations in RNA methylation play a crucial role in the regulation of various genes and signaling pathways involved in HCC, thereby promoting tumor progression. Understanding the pathogenesis of RNA methylation in HCC would help in developing prognostic biomarkers and targeted therapies for HCC. Targeting RNA-methylation-related molecules has shown promising potential in the management of HCC, in terms of developing novel prognostic biomarkers and therapies for HCC. Exploring the clinical application of targeted RNA methylation may provide new insights and approaches for the management of HCC. Further research in this field is warranted to fully understand the functional roles and underlying mechanisms of RNA methylation in HCC. In this review, we described the multifaceted functional roles and potential mechanisms of RNA methylation in HCC. Moreover, the prospects of clinical application of targeted RNA methylation for HCC management are discussed, which may provide the basis for subsequent in-depth research on RNA methylation in HCC. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain (DNP) is one of the common and severe late-stage complications of diabetes mellitus, which could greatly influence the patients' quality of life. Patients with DNP often experience spontaneous pain and evoked pain such as mechanical allodynia and thermal hyperalgesia, meaning that their physical and psychological health are severely impaired. Unfortunately, the mechanisms of DNP remain highly elusive, so substantial breakthrough in effective DNP targeted treatments is still clinically challenging. This article will hence summarise the main mechanisms currently known to underlie DNP pathogenesis, along with describing some of the current and potential treatment methods against diabetic neuropathic pain. [ABSTRACT FROM AUTHOR]

Malgré les traitements disponibles, le lupus érythémateux systémique (LES) actif et corticodépendant constitue un défi thérapeutique majeur. Cette revue systématique avait pour objectif de proposer une mise à jour des thérapies ciblées en développement clinique dans le LES, avec une attention particulière accordée aux traitements les plus prometteurs. Nous avons mené une revue systématique des thérapies ciblées en développement clinique dans le LES à partir du registre des essais cliniques clinicaltrials.gov (date de la recherche : 28 août 2022). Les thérapies ciblées (médicaments conçus pour bloquer des molécules, récepteurs ou voies de signalisation spécifiques impliqués dans le développement du LES) ont été extraites. Pour chaque médicament évalué, seule l'étude ayant atteint la phase de développement clinique la plus avancée a été prise en compte. Sur un total de 203 essais cliniques consacrés au LES, nous avons identifié 92 thérapies ciblées différentes (58 DMARD biologiques [bDMARD] et 34 DMARD synthétiques ciblés [tsDMARD]). Les médicaments analysés ont atteint la phase I (n = 20), Ia/IIb (n = 6), II (n = 51), II/III (n = 1), III (n = 13) et IV (n = 1). Les essais correspondants étaient en cours de recrutement (n = 31), actifs mais au recrutement clos (n = 8), au recrutement à venir (n = 4), en recrutement par invitation (n = 2), complétés (n = 31), arrêtés prématurément (n = 12) et abandonnés dans 1 cas (statut inconnu dans 3 cas). Les principales stratégies thérapeutiques en développement dans le LES ciblent les cytokines/chimiokines pro-inflammatoires ou leurs récepteurs (n = 19), les voies de signalisation intracellulaire (n = 18), les lymphocytes B (n = 14) ou plasmocytes (n = 7), les molécules de co-stimulation des cellules T/B (n = 10), les protéines du complément (n = 5), les lymphocytes T (n = 2), les cellules dentritiques plasmacytoïdes (n = 2) ainsi que de nombreuses autres cibles de l'immunité (n = 15). La grande diversité des médicaments en développement dans le LES devrait permettre d'améliorer les stratégies Treat-to-Target avec pour objectif de modifier la maladie. L'identification de biomarqueurs compagnons sera nécessaire afin de mieux caractériser l'hétérogénéité du LES et d'optimiser le choix du traitement le plus adapté à chaque patient. Despite available therapies, persistently active and corticosteroid-dependent Systemic Lupus Erythematosus (SLE) represent a significant therapeutic challenge. The purpose of this systematic review was to provide an updated view of targeted therapies currently in clinical development in SLE, with a special focus on the most promising ones. We performed a systematic review of targeted therapies in clinical development in SLE in clinicaltrials.gov (search date: 28th of August 2022). Targeted therapies (defined as drugs specifically designed to block certain molecules, receptors, or pathways involved in the development of SLE) were extracted. For each investigational drug, we considered only the study at the most advanced stage of clinical development. The systematic review yielded a total of 92 targeted therapies (58 biological DMARDs [bDMARDs] and 34 targeted synthetic [ts]DMARDs) assessed in a total of 203 clinical trials. The candidate drugs reached phase I (n = 20), Ia/IIb (n = 6), phase II (n = 51), phase II/III (n = 1), phase III (n = 13) and phase IV (n = 1). These trials were reported as recruiting (n = 31), active but not recruiting (n = 8), not yet recruiting (n = 4), enrolling by invitation (n = 2), completed (n = 31), prematurely terminated (n = 12) and withdrawn in 1 (status unknown in 3). The main investigational drugs for SLE target inflammatory cytokines, chemokines or their receptors (n = 19), intracellular signaling pathways (n = 18), B cells (n = 14) or plasma cells (n = 7), T/B cells costimulation molecules (n = 10), complement molecules (n = 5), T lymphocytes (n = 2), plasmacytoid dendritic cells (n = 2), as well as various other immune targets (n = 15). The pipeline of investigational drugs in SLE is highly diversified and will hopefully enable more optimal Treat-To-Target with the goal of disease modification. Companion biomarkers will be needed to better characterized SLE heterogeneity and optimize treatment selection at the individual-patient level. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript focuses on improving the treatment of non-small cell lung cancer, with actionable gene alterations. The aim is to understand how the treatment with Tyrosine Kinase Inhibitors (TKIs) can be used and improved. Newer generations of TKIs have better results in controlling the disease and extending patient survival. These drugs also work better in the brain, which is crucial for patients with brain metastases. However, there are challenges. The use of newer TKIs may limit the role of older ones, and resistance to the drugs can emerge. The considerations from this manuscript suggest that understanding the biology of the tumor and the properties of the drugs could help develop new treatment strategies and ultimately benefit patients with this type of lung cancer. Tyrosine kinase inhibitors (TKIs) revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring most driver gene alterations. Starting from the first generation, research rapidly moved to the development of newer, more selective generations of TKIs, obtaining improved results in terms of disease control and survival. However, the use of novel generations of TKIs is not without limitations. We reviewed the main results obtained, as well as the ongoing clinical trials with TKIs in oncogene-addicted NSCLC, together with the biology underlying their potential strengths and limitations. Across driver gene alterations, novel generations of TKIs allowed delayed resistance, prolonged survival, and improved brain penetration compared to previous generations, although with different toxicity profiles, that generally moved their use from further lines to the front-line treatment. However, the anticipated positioning of novel generation TKIs leads to abolishing the possibility of TKI treatment sequencing and any role of previous generations. In addition, under the selective pressure of such more potent drugs, resistant clones emerge harboring more complex and hard-to-target resistance mechanisms. Deeper knowledge of tumor biology and drug properties will help identify new strategies, including combinatorial treatments, to continue improving results in patients with oncogene-addicted NSCLC. [ABSTRACT FROM AUTHOR]

Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.

Loss of function in epigenetic acting genes together with driver alterations in the PIK3CA pathway have been shown significantly associated with poor outcome in cervical squamous cell cancer. More recently, a CoxBoost analysis identified 16 gene alterations and 30 high level activated proteins to be of high interest, due to their association with either good or bad outcome, in the context of treatment received by chemoradiation. The objectives here were to review and confirm the significance of these molecular alterations as suggested by literature reports and to pinpoint alternate treatments options for poor-responders to chemoradiation. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain (DNP) is one of the common and severe late-stage complications of diabetes mellitus, which could greatly influence the patients’ quality of life. Patients with DNP often experience spontaneous pain and evoked pain such as mechanical allodynia and thermal hyperalgesia, meaning that their physical and psychological health are severely impaired. Unfortunately, the mechanisms of DNP remain highly elusive, so substantial breakthrough in effective DNP targeted treatments is still clinically challenging. This article will hence summarise the main mechanisms currently known to underlie DNP pathogenesis, along with describing some of the current and potential treatment methods against diabetic neuropathic pain.

BackgroundMetformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity.MethodsHere, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes.ResultsParent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients.ConclusionThese results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.

Despite recent advances in targeted drugs and immunotherapy, cancer remains "the emperor of all maladies" due to almost inevitable emergence of resistance. Drug resistance is thought to be driven by genetic alterations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are determined by two mutually inhibitory - main and alternative - pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solutions of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies from simulated data: static treatments with continuous and constant dosages, periodic treatments with regular intermittent active phases and drug holidays, and treatments derived from optimal control theory (OCT). Periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent plastic drug resistance. They can also be used to evaluate the efficacy of suboptimal treatments that may account for side effects of the treatment and the cost of its application.

This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM. • MPM is still a deadly disease with poor prognosis and small therapeutic options. • Identifying potential actionable alterations may be an opportunity in MPM. • Molecular heterogeneity in MPM challenges precision oncology. • Ongoing trials should seek optimal mutation-targeting strategies. [ABSTRACT FROM AUTHOR]

BackgroundIndividuals with fragile X syndrome (FXS) have both behavioral and medical comorbidities and the latter include obesity in approximately 30% and the Prader-Willi Phenotype (PWP) characterized by severe hyperphagia and morbid obesity in less than 10%. Metformin is a drug used in individuals with type 2 diabetes, obesity or impaired glucose tolerance and it has a strong safety profile in children and adults. Recently published studies in the Drosophila model and the knock out mouse model of FXS treated with metformin demonstrate the rescue of multiple phenotypes of FXS.Materials and methodsWe present 7 cases of individuals with FXS who have been treated with metformin clinically. One case with type 2 diabetes, 3 cases with the PWP, 2 adults with obesity and/or behavioral problems and, a young child with FXS. These individuals were clinically treated with metformin and monitored for behavioral changes with the Aberrant Behavior Checklist and metabolic changes with a fasting glucose and HgbA1c.ResultsWe found consistent improvements in irritability, social responsiveness, hyperactivity, and social avoidance, in addition to comments from the family regarding improvements in language and conversational skills. No significant side-effects were noted and most patients with obesity lost weight.ConclusionWe recommend a controlled trial of metformin in those with FXS. Metformin appears to be an effective treatment of obesity including those with the PWP in FXS. Our study suggests that metformin may also be a targeted treatment for improving behavior and language in children and adults with FXS.

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting is margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is a chronic autoimmune disease for which multiple immunomodulatory therapies are available. Nevertheless, MG has a significant impact on patient quality of life. In recent years, experts' main efforts have focused on optimizing treatment strategies, since disease burden is considerably affected by their safety and tolerability profiles, especially in patients with refractory phenotypes. This article aims to offer neurologists caring for MG patients an overview of the most innovative targeted drugs specifically designed for this disease and summarizes the recent literature and more recent evidence on agents targeting B cells and plasmablasts, complement inhibitors, and neonatal fragment crystallizable receptor (FcRn) antagonists. Positive clinical trial results have been reported, and other studies are ongoing. Finally, we briefly discuss how the introduction of these novel targeted immunological therapies in a changing management paradigm would affect not only clinical outcomes, disease burden, safety, and tolerability, but also health spending in a condition that is increasingly managed based on a patient-centred model. [ABSTRACT FROM AUTHOR]

Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

Simple Summary: Peripheral T-cell lymphomas are a group of rare cancers of T cells or natural killer cells, most often with a poor prognosis. In recent years, significant progress has been made through the development of more specific therapies. This review aims to provide an up-to-date overview of current treatments in nodal PTCL. Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of rare neoplasms of mature T cells or natural killer (NK) cell. PTCLs usually have an aggressive course and a poor outcome. In recent years, significant progress has been made in the knowledge of the molecular lymphomagenesis of PTCLs, and through the development of new, more specific therapeutic molecules, one can hope in the coming years for more personalized medicine and improved patient prognosis. This review aims to provide an up-to-date overview of the current therapeutic approaches in nodal PTCLs. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the leading single-gene cause of autism spectrum disorders. It is due to a loss of the fragile X mental retardation protein, which leads to molecular, behavioral, and cognitive deficits in these patients. Improvements in our understanding of its pathophysiology have led to the development of numerous targeted treatments in FXS as highlighted by metabotropic glutamate receptor antagonists and gamma-Aminobutyric acid receptor modulators. This review will summarize relevant pre-clinical data and results from clinical trials in human subjects with FXS. It will also highlight upcoming studies and future directions for clinical trials as well.

Neisseria pathogens express a Macrophage Infectivity Potentiator Protein (MIP), which belongs to the FK506 binding protein (FKBP) family of proteins that exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity. Neisseria MIP proteins are potential candidates for inclusion into vaccines for gonorrhoea caused by N. gonorrhoeae infection, and meningitis/sepsis caused by M. meningitidis infection. Neisseria MIP proteins are also potential targets for directed drug treatments, although this remains relatively unexplored. In this mini-review, we provide an update into the vaccine potential of Neisseria MIP and the few published drug targeting studies, and explore further the diversity of this protein amongst both pathogenic and commensal Neisseria spp. [ABSTRACT FROM AUTHOR]

Early diagnosis and personalised disease management remain serious challenges in the field of haematological malignancies, especially for acute conditions. Additionally, reliable and timely detection of minimal residual disease is the key to improving patients’ clinical management, including guiding therapy choice, monitoring treatment response, and detecting relapse. Genomic biomarkers provide valuable information in this regard. For example, chromosomal translocations and mutations in genes involved in haematopoietic proliferation and differentiation are considered the strongest predictors of treatment response and overall survival in acute myeloid leukaemia. Furthermore, NPM1 gene mutations and internal tandem duplications in FMS-like tyrosine kinase-3 (FLT3) are used to monitor minimal residual disease in acute myeloid leukaemia. Despite the growing availability of relevant molecular biomarkers, long turnaround times for genomic testing greatly impact the management of aggressive haematological disorders. Delayed access to laboratory test results both negatively influences patients’ psychological state and postpones therapy administration and adjustments. Depending on the technology used, next-generation sequencing allows high-throughput genome analyses within hours to days, at a relatively low cost. Simultaneously, it enables testing of large numbers and various types of biomarkers by targeted gene panels. At the present time, with the latest technological improvements, next-generation sequencing provides the means for advancing genomic-based diagnostics in haematological malignancies, by simplifying complex laboratory workflow and should be introduced more widely in routine clinical settings.

Abstract Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components—the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.

Neisseria pathogens express a Macrophage Infectivity Potentiator Protein (MIP), which belongs to the FK506 binding protein (FKBP) family of proteins that exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity. Neisseria MIP proteins are potential candidates for inclusion into vaccines for gonorrhoea caused by N. gonorrhoeae infection, and meningitis/sepsis caused by M. meningitidis infection. Neisseria MIP proteins are also potential targets for directed drug treatments, although this remains relatively unexplored. In this mini-review, we provide an update into the vaccine potential of Neisseria MIP and the few published drug targeting studies, and explore further the diversity of this protein amongst both pathogenic and commensal Neisseria spp.

Background and Objective: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options., Methods: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions., Key Findings and Limitations: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials., Conclusions and Clinical Implications: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Fragile X spectrum disorder (FXSD) includes: fragile X syndrome (FXS), fragile X-associated tremor ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI), as well as other medical, psychiatric and neurobehavioral problems associated with the premutation and gray zone alleles. FXS is the most common monogenetic cause of autism (ASD) and intellectual disability (ID). The understanding of the neurobiology of FXS has led to many targeted treatment trials in FXS. The first wave of phase II clinical trials in FXS were designed to target the mGluR5 pathway; however the results did not show significant efficacy and the trials were terminated. The advances in the understanding of the GABA system in FXS have shifted the focus of treatment trials to GABA agonists, and a new wave of promising clinical trials is under way. Ganaxolone and allopregnanolone (GABA agonists) have been studied in individuals with FXSD and are currently in phase II trials. Both allopregnanolone and ganaxolone may be efficacious in treatment of FXS and FXTAS, respectively. Allopregnanolone, ganaxolone, riluzole, gaboxadol, tiagabine, and vigabatrin are potential GABAergic treatments. The lessons learned from the initial trials have not only shifted the targeted system, but also have refined the design of clinical trials. The results of these new trials will likely impact further clinical trials for FXS and other genetic disorders associated with ASD.

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS.

B-cell acute lymphoblastic leukemia (B-ALL) represents the malignant counterpart of bone marrow (BM) differentiating B cells and occurs most frequently in children. While new combinations of chemotherapeutic agents have dramatically improved the prognosis for young patients, disease outcome remains poor after relapse or in adult patients. This is likely due to heterogeneity of B-ALL response to treatment which relies not only on intrinsic properties of leukemic cells, but also on extrinsic protective cues transmitted by the tumor cell microenvironment. Alternatively, leukemic cells have the capacity to shape their microenvironment towards their needs. Most knowledge on the role of protective niches has emerged from the identification of mesenchymal and endothelial cells controlling hematopoietic stem cell self-renewal or B cell differentiation. In this review, we discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment.

B-cell acute lymphoblastic leukemia (B-ALL) represents the malignant counterpart of bone marrow (BM) differentiating B cells and occurs most frequently in children. While new combinations of chemotherapeutic agents have dramatically improved the prognosis for young patients, disease outcome remains poor after relapse or in adult patients. This is likely due to heterogeneity of B-ALL response to treatment which relies not only on intrinsic properties of leukemic cells, but also on extrinsic protective cues transmitted by the tumor cell microenvironment. Alternatively, leukemic cells have the capacity to shape their microenvironment towards their needs. Most knowledge on the role of protective niches has emerged from the identification of mesenchymal and endothelial cells controlling hematopoietic stem cell self-renewal or B cell differentiation. In this review, we discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5' un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components-the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established. [ABSTRACT FROM AUTHOR]

Abstract Our understanding of fragile X syndrome (FXS) pathophysiology continues to improve and numerous potential drug targets have been identified. Yet, current prescribing practices are only symptom-based in order to manage difficult behaviors, as no drug to date is approved for the treatment of FXS. Drugs impacting a diversity of targets in the brain have been studied in recent FXS-specific clinical trials. While many drugs have focused on regulation of enhanced glutamatergic or deficient GABAergic neurotransmission, compounds studied have not been limited to these mechanisms. As a single-gene disorder, it was thought that FXS would have consistent drug targets that could be modulated with pharmacotherapy and lead to significant improvement. Unfortunately, despite promising results in FXS animal models, translational drug treatment development in FXS has largely failed. Future success in this field will depend on learning from past challenges to improve clinical trial design, choose appropriate outcome measures and age range choices, and find readily modulated drug targets. Even with many negative placebo-controlled study results, the field continues to move forward exploring both the new mechanistic drug approaches combined with ways to improve trial execution. This review summarizes the known phenotype and pathophysiology of FXS and past clinical trial rationale and results, and discusses current challenges facing the field and lessons from which to learn for future treatment development efforts.

Abstract Background Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity. Methods Here, we present nine children with FXS between 2 and 7 years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes. Results Parent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients. Conclusion These results support the need for a controlled trial of metformin in children with FXS under 7 years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.

• Tumour growth model with reversible (non-genetic) mechanism of resistance is developed. • Melanoma response to the treatment of a single (BRAF) inhibitor is chosen for a basal model system. • Optimal control theory is applied to construct treatment regimen minimizing a tumour size at given time horizon. • Other treatment regimens such as with constant drug dosage, periodic with intermittent drug holidays are optimized and compared with the optimal treatment. Despite recent advances in targeted drugs and immunotherapy, cancer remains "the emperor of all maladies" due to almost inevitable emergence of resistance. Drug resistance is thought to be driven by genetic alterations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this study, we propose a modelling framework to simulate population dynamics of heterogeneous tumour cells with reversible drug resistance. Drug sensitivity of a tumour cell is determined by its internal states, which are demarcated by coordinated activities of multiple interconnected oncogenic pathways. Transitions between cellular states depend on the effects of targeted drugs and regulatory relations between the pathways. Under this framework, we build a simple model to capture drug resistance characteristics of BRAF-mutant melanoma, where two cell states are determined by two mutually inhibitory – main and alternative – pathways. We assume that cells with an activated main pathway are proliferative yet sensitive to the BRAF inhibitor, and cells with an activated alternative pathway are quiescent but resistant to the drug. We describe a dynamical process of tumour growth under various drug regimens using the explicit solutions of mean-field equations. Based on these solutions, we compare efficacy of three treatment strategies from simulated data: static treatments with continuous and constant dosages, periodic treatments with regular intermittent active phases and drug holidays, and treatments derived from optimal control theory (OCT). Periodic treatments outperform static treatments with a considerable margin, while treatments based on OCT outperform the best periodic treatment. Our results provide insights regarding optimal cancer treatment modalities for heterogeneous tumours, and may guide the development of optimal therapeutic strategies to circumvent plastic drug resistance. They can also be used to evaluate the efficacy of suboptimal treatments that may account for side effects of the treatment and the cost of its application. Image, graphical abstract [ABSTRACT FROM AUTHOR]

Aim: Reporting toxicities of targeted therapies (TTs) and immunotherapy in oncology requires special attention. Materials & methods: We identified TTs and immunotherapies approved by the US FDA for solid malignancies in the adult population. Publications were reviewed according to a 24-point score based on the Consolidated Standards of Reporting Trials guidance. Results: We identified 81 trials (>45,000 patients). The experimental drug was studied as single agent in 51% of the cases; setting of disease was mainly (95%) advanced/metastatic. Lowest scores in adverse event (AE) description regarded: reporting recurrent/late toxicities and duration of the AEs (>90%), time of occurrence and indication of all-grade AEs (>75%). Conclusion: Suboptimal reporting of AEs in trials leading to approval of TTs and immunotherapy was shown. Improving AE descriptions should be a priority in ongoing trials. [ABSTRACT FROM AUTHOR]

Recent advances in cancer cell metabolism provide unprecedented opportunities for a new understanding of heart metabolism and may offer new approaches for the treatment of heart failure. Key questions driving the cancer field to understand how tumor cells reprogram metabolism and to benefit tumorigenesis are also applicable to the heart. Recent experimental and conceptual advances in cancer cell metabolism provide the cardiovascular field with the unique opportunity to target metabolism. This review compares cancer cell metabolism and cardiac metabolism with an emphasis on strategies of cellular adaptation, and how to exploit metabolic changes for therapeutic benefit.

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This project aimed to explore the attitudes of prenatal genetic counselors toward discussion of novel approved and experimental CF treatments in the prenatal setting, and to assess how knowledge of genotype-specific, targeted treatments may influence their current practices. Targeted treatments have the potential to impact the health-related quality of life of individuals affected with CF and therefore, knowledge of the availability of such treatments may influence the decision-making process of parents who receive a fetal diagnosis of CF. Using the 2012 FDA approval and introduction of ivacaftor into CF clinical practice as a case study, a survey was designed to explore the opinions and practices of prenatal genetic counselors with regard to counseling for a prenatal diagnosis of CF, and how those practices might be impacted by the availability of a new genotype-specific treatment. Approximately 800 genetic counselors were sent questionnaires in January of 2013. Respondents were provided information about this treatment and were asked to rate its perceived benefits, along with the likelihood that they would discuss potential benefits and limitations with parents receiving a prenatal diagnosis of CF. One-hundred sixty-nine prenatal genetic counselors (21.1 %) responded to the survey. Results indicated that 80 % of respondents 'never heard of the drug', or they were 'not exactly sure' what it was. After reading the materials provided, counselors felt the new treatment would have 'some' or a 'significant' impact on an affected individual's life. Their opinions varied on what information about this treatment they would choose to discuss with their patients; even if the treatment is currently FDA approved and clinically available for affected individuals with the genotype of the fetus. However, they would 'definitely' refer these patients to a specialist to discuss targeted treatments further. Most prenatal genetic counselors indicated there are certain scenarios in the prenatal setting which warrant a discussion of targeted treatments for CF, at least on some level. Counselor's views on sharing information about new treatment options are shaped by their familiarity with the treatment and their perception of its benefits and limitations, their comfort discussing these subjects, and their interpretation of the genetic counselor's role. Most genetic counselors had never heard of ivacaftor or Kalydeco™ prior to taking the survey. Therefore, counselors need to be better educated about the availability of CFTR mutation-based treatments before they will be able to incorporate discussion of new treatment options into their counseling. [ABSTRACT FROM AUTHOR]

Recent technological advances in DNA sequencing have enabled a remarkably detailed understanding of the molecular changes that define gynecologic and other cancers. Several groups have carried out large-scale genomic analyses of ovarian, uterine, and most recently, cervical cancer. These analyses have led to new insights into the molecular changes characterizing these cancers, which provide insight into clinical outcomes. These molecular characterizations have similarly led to new genomic-based classification schemas, which may better stratify clinical outcomes, help prognosticate and guide treatments. Discovery of characteristic mutations may also provide potential new targets for molecularly targeted chemotherapies, as has been already described with poly-ADP ribose polymerase inhibitors and ovarian cancer. The purpose of this article is to provide an overview of the defining molecular abnormalities and markers in gynecologic cancer, to discuss the clinical implications, and to provide a comprehensive view of the current state of genomic knowledge in gynecologic cancer. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.

Breast cancer (BC) is the most common malignancy and second only to lung cancer in terms of mortality in women. Despite the incredible progress made in this field, metastatic breast cancer has a poor prognosis. In an era of personalized medicine, there is an urgent need for better knowledge of the biology leading to the disease, which can lead to the design of increasingly accurate drugs against patients’ specific molecular aberrations. Among one of the actionable targets is the fibroblast growth factor receptor (FGFR) pathway, triggered by specific ligands. The Fibroblast Growth Factor Receptors/Fibroblast Growth Factors (FGFRs/FGFs) axis offers interesting molecular targets to be pursued in clinical development. This mini-review will focus on the current knowledge of FGFR mutations, which lead to tumor formation and summarizes the state-of-the-art therapeutic strategies for targeted treatments against the FGFRs/FGFs axis in the context of BC.

• Despite available therapies, persistently active and corticosteroid-dependent SLE represent a significant therapeutic challenge. • We performed a systematic review of targeted therapies in clinical development in SLE as of August 2022. • The systematic review yielded a total 92 targeted therapies, including 58 biological DMARDs and 34 targeted synthetic DMARDs assessed in a total of 203 clinical trials. • The pipeline of investigational drugs in SLE is highly diversified. Companion biomarkers are needed to guide treatment selection at the individual-patient level. Despite available therapies, persistently active and corticosteroid-dependent Systemic Lupus Erythematosus (SLE) represent a significant therapeutic challenge. The purpose of this systematic review was to provide an updated view of targeted therapies currently in clinical development in SLE, with a special focus on the most promising ones. We performed a systematic review of targeted therapies in clinical development in SLE in clinicaltrials.gov (search date: 28th of August 2022). Targeted therapies (defined as drugs specifically designed to block certain molecules, receptors, or pathways involved in the development of SLE) were extracted. For each investigational drug, we considered only the study at the most advanced stage of clinical development. The systematic review yielded a total of 92 targeted therapies (58 biological DMARDs [bDMARDs] and 34 targeted synthetic [ts]DMARDs) assessed in a total of 203 clinical trials. The candidate drugs reached phase I (n = 20), Ia/IIb (n = 6), phase II (n = 51), phase II/III (n = 1), phase III (n = 13) and phase IV (n = 1). These trials were reported as recruiting (n = 31), active but not recruiting (n = 8), not yet recruiting (n = 4), enrolling by invitation (n = 2), completed (n = 31), prematurely terminated (n = 12) and withdrawn in 1 (status unknown in 3). The main investigational drugs for SLE target inflammatory cytokines, chemokines or their receptors (n = 19), intracellular signaling pathways (n = 18), B cells (n = 14) or plasma cells (n = 7), T/B cells co-stimulation molecules (n = 10), complement molecules (n = 5), T lymphocytes (n = 2), plasmacytoid dendritic cells (n = 2), as well as various other immune targets (n = 15). The pipeline of investigational drugs in SLE is highly diversified and will hopefully enable more optimal Treat-To-Target with the goal of disease modification. Companion biomarkers will be needed to better characterized SLE heterogeneity and optimize treatment selection at the individual-patient level. [ABSTRACT FROM AUTHOR]

The mainstay of treatment for adult patients with gliomas, glioneuronal and neuronal tumors consists of combinations of surgery, radiotherapy, and chemotherapy. For many systemic cancers, targeted treatments are a part of the standard of care, however, the predictive significance of most of these targets in central nervous system (CNS) tumors remains less well-studied. Despite that, there is increasing use of advanced molecular diagnostics that identify potential targets, and tumor-agnostic regulatory approvals on targets also present in CNS tumors have been granted. This raises the question of when and for which targets it is meaningful to test in adult patients with CNS tumors. This evidence-based guideline reviews the evidence available for targeted treatment for alterations in the RAS/MAPK pathway (BRAF, NF1), in growth factor receptors (EGFR, ALK, fibroblast growth factor receptor (FGFR), neurotrophic tyrosine receptor kinase (NTRK), platelet-derived growth factor receptor alpha, and ROS1), in cell cycle signaling (CDK4/6, MDM2/4, and TSC1/2) and altered genomic stability (mismatch repair, POLE, high tumor mutational burden (TMB), homologous recombination deficiency) in adult patients with gliomas, glioneuronal and neuronal tumors. At present, targeted treatment for BRAF p.V600E alterations is to be considered part of the standard of care for patients with recurrent gliomas, pending regulatory approval. For approved tumor agnostic treatments for NTRK fusions and high TMB, the evidence for efficacy in adult patients with CNS tumors is very limited, and treatment should preferably be given within prospective clinical registries and trials. For targeted treatment of CNS tumors with FGFR fusions or mutations, clinical trials are ongoing to confirm modest activity so far observed in basket trials. For all other reviewed targets, evidence of benefit in CNS tumors is currently lacking, and testing/treatment should be in the context of available clinical trials., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)