Expensive molecular therapies for rare genetic disorders: carrier detection or newborn screening should be the strategy. A personal opinion.

Haluk Topaloglu,Yeditepe University School of MedicineDepartment of Pediatricsİstanbul, Turkey

Molecular Classification and Therapeutic Targets in Ependymoma

Ependymoma is a biologically diverse tumor wherein molecular classification has superseded traditional histological grading based on its superior ability to characterize behavior, prognosis, and possible targeted therapies. The current, updated molecular classification of ependymoma consists of ten distinct subgroups spread evenly among the spinal, infratentorial, and supratentorial compartments, each with its own distinct clinical and molecular characteristics. In this review, the history, histopathology, standard of care, prognosis, oncogenic drivers, and hypothesized molecular targets for all subgroups of ependymoma are explored. This review emphasizes that despite the varied behavior of the ependymoma subgroups, it remains clear that research must be performed to further elucidate molecular targets for these tumors. Although not all ependymoma subgroups are oncologically aggressive, development of targeted therapies is essential, particularly for cases where surgical resection is not an option without causing significant morbidity. The development of molecular therapies must rely on building upon our current understanding of ependymoma oncogenesis, as well as cultivating transfer of knowledge based on malignancies with similar genomic alterations.

Focused Ultrasound Mediated Opening of the Blood-Brain Barrier for Neurodegenerative Diseases

The blood brain barrier (BBB) is an obstacle for the delivery of potential molecular therapies for neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). Although there has been a proliferation of potential disease modifying therapies for these progressive conditions, strategies to deliver these large agents remain limited. High intensity MRI guided focused ultrasound has already been FDA approved to lesion brain targets to treat movement disorders, while lower intensity pulsed ultrasound coupled with microbubbles commonly used as contrast agents can create transient safe opening of the BBB. Pre-clinical studies have successfully delivered growth factors, antibodies, genes, viral vectors, and nanoparticles in rodent models of AD and PD. Recent small clinical trials support the safety and feasibility of this strategy in these vulnerable patients. Further study is needed to establish safety as MRI guided BBB opening is used to enhance the delivery of newly developed molecular therapies.

EPID-27. GEOGRAPHIC BURDEN OF CNS TUMORS AND DENSITY OF NEURO-ONCOLOGISTS IN THE UNITED STATES

CNS cancer care relies heavily on exam and imaging interpretation skills distinctive to a neurology-trained oncologist, and access to this subspecialty is increasingly more essential as targeted molecular therapies evolve. We sought to explore the supply of neuro-oncologists in terms of geographic CNS tumor incidence. Using the UCNS online directory, we generated a heat map representing the location (set to 75-mile radius) and density of active neuro-oncologists. We overlaid this data upon yearly incidence of CNS tumors per neuro-oncologist for each state using most recent CBTRUS data. We highlight the significant distance Americans outside of urban areas must travel for care and that isolation from academic centers and exclusion from clinical trials are substantial barriers to cancer care for a significant proportion of the population. Telemedicine may in part improve patient access to care and clinical trial participation, but significant state-to-state legal variability for providing telehealth services across state lines remains a national challenge. Short-term strategies for equitably meeting this subspecialty need may require policy changes that optimize employment of telemedicine, and long-term must ensure a robust fellowship pipeline with thoughtful incentivization and allocation of resources.

Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma

Head and neck cancer affects nearly 750,000 patients, with more than 300,000 deaths annually. Advances in first line surgical treatment have improved survival rates marginally particularly in developed countries, however survival rates for aggressive locally advanced head and neck cancer are still poor. Recurrent and metastatic disease remains a significant problem for patients and the health system. As our knowledge of the genomic landscape of the head and neck cancers continues to expand, there are promising developments occurring in molecular therapies available for advanced or recalcitrant disease. The concept of precision medicine is underpinned by our ability to accurately sequence tumour samples to best understand individual patient genomic variations and to tailor targeted therapy for them based on such molecular profiling. Not only is their purported response to therapy a factor of their genomic variation, but so is their inclusion in biomarker-driven personalised medicine therapeutic trials. With the ever-expanding number of molecular druggable targets explored through advances in next generation sequencing, the number of clinical trials assessing these targets has significantly increased over recent years. Although some trials are focussed on first-line therapeutic approaches, a greater majority are focussed on locally advanced, recurrent or metastatic disease. Similarly, although single agent monotherapy has been found effective in some cases, it is the combination of drugs targeting different signalling pathways that seem to be more beneficial to patients. This paper outlines current and emerging molecular therapies for head and neck cancer, and updates readers on outcomes of the most pertinent clinical trials in this area while also summarising ongoing efforts to bring more molecular therapies into clinical practice.

Precision Medicine Trials in Retinal Degenerations

The beginning of the twenty-first century was marked by the innovative use of pharmacochemical interventions, which have since expanded to include gene-based molecular therapies. For years, treatment has focused on tackling the pathophysiology of monogenic orphan diseases, and one of the first applications of these novel genome editing technologies was the treatment of rare inherited retinal dystrophies. In this review, we present recent, ongoing, and future gene therapy–based treatment trials for choroideremia, X-linked retinitis pigmentosa, Stargardt disease, and age-related macular degeneration. As these trials pave the way toward halting the progression of such devastating diseases, we will begin to see the exciting development of newer, cutting-edge strategies including base editing and prime editing, ushering in a new era of precision medicine.

Analyzing and Identifying the Molecular Targets and Regulators Controlling Cardiac Hypertrophy Progression

Cardiac hypertrophy is the major pathway by which neurohormonal and mechanical stimuli act upon cardiomyocytes which gives the response to these stimuli. It leads to heart failure and ventricular dilation which is the main root of mortality in the western world. Many molecular targets are controlling cardiac hypertrophy development which may influence the growth factors signaling, cytokine release and gene expression. Through clinical trials on different models, recent research shows that cardiac hypertrophy might be inhibited or reversed. These findings have developed a vast drive to recognize specific and novel regulators of cardiac hypertrophy. Many molecular targets and signaling modulators have been studied in this review that induce the hypertrophic response which may involve MAPK pathway, oxidative stress, calcineurin, Cardiac angiogenesis, serum protein concentration, microRNA, and periodontitis. For the treatment of cardiac hypertrophy, the scientific knowledge of these signaling pathways and factors may be translated into potential nutritional and molecular therapies for the betterment of this diseases. The current and previous knowledge of molecular markers can be compiled in this review for the treatment of the molecular pathogenesis of cardiac hypertrophy.

New Scope of Targeted Therapies in Lung Carcinoma

: Lung cancer (LC) is the leading cause of cancer deaths worldwide. Recent research has also shown LC as a genomic disease, causing somatic mutations in patients. Tests related to mutational analysis and genome profiles have lately expanded significantly in the genetics/genomics field of LC. This review summarizes the current knowledge about different signalling pathways of LC based on the clinical impact of molecular targets. It describes the main molecular pathways and changes involved in the development, progression, and cellular breakdown of LC and the molecular changes. This review focuses on approved and targeted experimental therapies such as immunotherapy and clinical trials that examine the different targeted approaches to treating LC. We aimto clarify the differences in the extent of various genetic mutations in several areas for LC patients. Targeted molecular therapies for LC can be continued with advanced racial differences in genetic changes, which have a significant impact on the choice of drug treatment and our understanding of the profile of drug susceptibility/resistance. The most relevant genes described in this review are EGFR, KRAS, MET, BRAF, PIK3CA, STK11, ERBB3, PTEN, and RB1. Combined research efforts in this field are required to understand the genetic difference in LC outcomes in the future.