Making NSCLC Crystal Clear:How Kinase Structures Revolutionized Lung Cancer Treatment

The parallel advances of different scientific fields provide a contemporary scenario where collaboration is not a differential, but actually a requirement. In this context, crystallography has had a major contribution on the medical sciences, providing a “face” for targets of diseases that previously were known solely by name or sequence. Worldwide, cancer still leads the number of annual deaths, with 9.6 million associated deaths, with a major contribution from lung cancer and its 1.7 million deaths. Since the relationship between cancer and kinases was unraveled, these proteins have been extensively explored and became associated with drugs that later attained blockbuster status. Crystallographic structures of kinases related to lung cancer and their developed and marketed drugs provided insight on their conformation in the absence or presence of small molecules. Notwithstanding, these structures were also of service once the initially highly successful drugs started to lose their effectiveness in the emergence of mutations. This review focuses on a subclassification of lung cancer, non-small cell lung cancer (NSCLC), and major oncogenic driver mutations in kinases, and how crystallographic structures can be used, not only to provide awareness of the function and inhibition of these mutations, but also how these structures can be used in further computational studies aiming at addressing these novel mutations in the field of personalized medicine

New directions in antimalarial target validation

Introduction: Malaria is one of the most prevalent human infections worldwide with over 40% of the world's population living in malaria-endemic areas. In the absence of an effective vaccine, emergence of drug-resistant strains requires urgent drug development. Current methods applied to drug target validation, a crucial step in drug discovery, possess limitations in malaria. These constraints require the development of techniques capable of simplifying the validation of Plasmodial targets. Areas covered: The authors review the current state of the art in techniques used to validate drug targets in malaria, including our contribution - the protein interference assay (PIA) - as an additional tool in rapid in vivo target validation. Expert opinion: Each technique in this review has advantages and disadvantages, implying that future validation efforts should not focus on a single approach, but integrate multiple approaches. PIA is a significant addition to the current toolset of antimalarial validation. Validation of aspartate metabolism as a druggable pathway provided proof of concept of how oligomeric interfaces can be exploited to control specific activity in vivo. PIA has the potential to be applied not only to other enzymes/pathways of the malaria parasite but could, in principle, be extrapolated to other infectious diseases

Relevance and Effectiveness of Molecular Tumor Board Recommendations for Patients With Non-Small-Cell Lung Cancer With Rare or Complex Mutational Profiles

PURPOSEMolecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non-small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG).METHODSThe UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed.RESULTSThe MTB recommended targeted therapy for 59 of 110 NSCLC cases with complex molecular profiles: 24 within a clinical trial, 15 in accordance with guidelines (on label) and 20 off label. All but 16 recommendations involved patients with an EGFR or ALK mutation. Treatment outcome was analyzed for patients with available follow-up (10 on label and 16 off label). Adherence to the MTB recommendation (21 of 26; 81%) resulted in an objective response rate of 67% (14 of 21), with a median progression-free survival of 6.3 months (interquartile range, 3.2-10.6 months) and an overall survival of 10.4 months (interquartile range, 6.3-14.6 months).CONCLUSIONTargeted therapy recommendations resulting from the UMCG-MTB workflow for complex molecular profiles were highly adhered to and resulted in a positive clinical response in the majority of patients with metastatic NSCLC

Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance

Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with autosomal dominant inheritance. Genetic testing for SCA leads to diagnosis, prognosis and risk assessment for patients and their family members. While advances in sequencing and computing technologies have provided researchers with a rapid expansion in the genetic test content that can be used to unravel the genetic causes that underlie diseases, the large number of variants with unknown significance (VUSes) detected represent challenges. To minimize the proportion of VUSes, follow-up studies are needed to aid in their reclassification as either (likely) pathogenic or (likely) benign variants. In this study, we addressed the challenge of prioritizing VUSes for follow-up using (a combination of) variant segregation studies, 3D protein modeling, in vitro splicing assays and functional assays. Of the 39 VUSes prioritized for further analysis, 13 were eligible for follow up. We were able to reclassify 4 of these VUSes to LP, increasing the molecular diagnostic yield by 1.1%. Reclassification of VUSes remains difficult due to limited possibilities for performing variant segregation studies in the classification process and the limited availability of routine functional tests

Making NSCLC Crystal Clear: How Kinase Structures Revolutionized Lung Cancer Treatment

The parallel advances of different scientific fields provide a contemporary scenario where collaboration is not a differential, but actually a requirement. In this context, crystallography has had a major contribution on the medical sciences, providing a "face" for targets of diseases that previously were known solely by name or sequence. Worldwide, cancer still leads the number of annual deaths, with 9.6 million associated deaths, with a major contribution from lung cancer and its 1.7 million deaths. Since the relationship between cancer and kinases was unraveled, these proteins have been extensively explored and became associated with drugs that later attained blockbuster status. Crystallographic structures of kinases related to lung cancer and their developed and marketed drugs provided insight on their conformation in the absence or presence of small molecules. Notwithstanding, these structures were also of service once the initially highly successful drugs started to lose their effectiveness in the emergence of mutations. This review focuses on a subclassification of lung cancer, non-small cell lung cancer (NSCLC), and major oncogenic driver mutations in kinases, and how crystallographic structures can be used, not only to provide awareness of the function and inhibition of these mutations, but also how these structures can be used in further computational studies aiming at addressing these novel mutations in the field of personalized medicine