Small Cell Lung Cancer: Can recent advances in biology and molecular biology be translated into improved outcomes? (original) (raw)

Targets in small cell lung cancer

Biochemical Pharmacology, 2014

Recurrent small cell lung cancer is a recalcitrant malgnancy. The application of genomic technologies has begun to elucidate the large number of genetic abnormalities in SCLC. Several cell surface receptors are known to be overexpressed by SCLC in clinic specimens and cell in culture including GPCRs such as the bradykinin receptor, the chemokine receptor CXCR4, the vasopression receeptor and the three bomebsin receptors. The glucose transporter GLUT1, the tetraspanin family member PETA/CD151 and the immunoglobulin superfamily member ALCAM/CD166 are also overexpressed by SCLC. NCAM/CD56 is overexpressed by nearly all SCLC and is currently the target for an antibody drug conjugate in Phase II trial. Although SCLC is not considered a RTK driven disease, IGF1R and FGFRs are often overexpressed by SCLC. SCLC abberantly expresses several developmental transcription factors including ASCL1, SOX2, 4, and 11, OCT4, NANOG, PAX5; however, overexpression of MYC may be a driver in SCLC. Like other cancers, SCLC expresses survival factors and uses aerobic glycolysis as a major source of ATP. The drawback of many ponteial targets overexpressed by SCLC is expression of the same proteins by normal tissues. We are slowly learning more about the molecular abnormalities that occur in SCLC; however, therapeutic impact from new findings remains a goal to work toward. Published by Elsevier Inc.

New Approaches to SCLC Therapy: From the Laboratory to the Clinic

Journal of Thoracic Oncology

The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state. Included within this discussion, is a snapshot of the current biomarker and clinical trial landscapes for SCLC. Finally, we identify key knowledge gaps that should be addressed to advance the field in pursuit of reduced SCLC mortality. This review largely summarizes work presented at the Third Biennial International Association for the Study of Lung Cancer SCLC Meeting.

Advanced small cell lung cancer (SCLC): new challenges and new expectations

Annals of translational medicine, 2018

Small cell lung cancer (SCLC) remains one of the most lethal malignancies and a major health riddle. The therapeutic options are limited. The combination of etoposide or irinotecan with platinum chemotherapy is the standard of care at any stage. The last decade systemic efforts have been done to reveal specific therapeutic targets for small cell lung carcinomas. In this review, we focus on the new therapeutic strategies of SCLC, including immune-related treatment that may change the prognosis of the disease. The main genetic mutations observed in SCLC are TP53 and RB1 mutations; however, it is well known that these molecules are not yet targetable. In recent years, research has revealed other frequent genetic alterations and activated signaling pathways that might be an effective treatment target. Loss of PTEN, activating PI3K mutations, inhibition of NOTCH pathway and aurora kinase activation are among them. Moreover, FDGFR1 amplification, activation of the Hedgehog pathway and rep...

Comprehensive genomic profiles of small cell lung cancer

Nature, 2015

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, arises in heavy smokers, and the tumour cells express neuroendocrine markers. Although chemotherapy is initially effective in the treatment of SCLC, recurrence arises rapidly in the vast majority of cases, usually killing the patient within only a few months 1. SCLC is rarely Reprints and permissions information is available at www.nature.com/reprints.

Pathways in small cell lung cancer and its therapeutic perspectives

Frontiers in Bioscience-Landmark

Introduction 3. Challenges in SCLC treatment 4. Developmental signalling pathways in SCLC initiation and progression 4.1 Hedgehog signalling pathway 4.2 NOTCH signalling pathway 4.3 Fibroblast Growth Factors signalling pathway 4.4 Other developmental signalling pathways in SCLC 5. Role of immunotherapy on signalling pathways 6. Conclusion and future prospects 7. Author contributions 8. Ethics approval and consent to participate 9. Acknowledgment 10. Funding 11. Conflict of interest 12. References

Small Cell Lung Cancer: Current and Future Strategies

Oncomedicine, 2016

Small cell lung cancer (SCLC) represents approximately 15% of all lung cancer diagnoses and over the last 20 years, in the Western world, the proportion of patients with SCLC has decreased to 13% due to world campaign for smoking cessation. Due to high growth fraction of the disease, to early dissemination with widespread metastases and also to early development of drug resistance, the treatment of SCLC remains discouraging. The median survival time without treatment is 2-4 months and with treatment the 5-year survival rate remains low at <7% overall and the most of the patients relapse within one year after first-line treatment. Chemotherapy with a platinum regimen and etoposide is the gold of standard of treatment for limited (LD) and extensive disease (ED), by adding radical thoracic radiotherapy for patients with good performance status, with LD. The new TNM classification should be used also for SCLC. For the patients who have any response is indicated the prophylactic cranial irradiation (PCI) due to high risk of brain metastases. The benefit from second-line therapy is limited and maintenance therapy did not appear to improve overall survival (OS) or progression free survival (PFS) for patients with SCLC. Many targeted agents have been investigated in LD and ED, almost all of them in unselected populations, but also with pessimistic results. Due to unchanged therapeutic options for almost four decades, is required desperately to understand better the molecular basis of SCLC and to proceed in to clinical trials for new drugs and targeted agents.