title: Development of molecularly targeted agents and immunotherapies in small cell lung cancer.
abstract: Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC.
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom; Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
authors.forename: Adam
authors.initials: A
authors.lastname: Sharp
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Jaishree
authors.initials: J
authors.lastname: Bhosle
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom; Clinical Pathology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Fatma
authors.initials: F
authors.lastname: Abdelraouf
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom; Imperial College, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: O'Brien
authors.affiliation: Lung Cancer Unit, Department of Medicine, Royal Marsden Hospital, London, United Kingdom; Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom. Electronic address: timothy.yap@icr.ac.uk.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000276:immunology; D004249:DNA Damage / Q000187:drug effects / Q000276:immunology; D004260:DNA Repair / Q000187:drug effects / Q000276:immunology; D055808:Drug Discovery; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000628:therapy*; D058990:Molecular Targeted Therapy / Q000379:methods*; D057285:Precision Medicine / Q000379:methods; D055752:Small Cell Lung Carcinoma / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents
keywords: Angiogenesis; Antibody-drug conjugate; Apoptosis; Cell signalling; DNA repair; Immunotherapies; Molecular analysis; Precision medicine; Small cell lung cancer; Targeted therapies