Small Cell Lung Cancer: Therapies and Targets

Abstract

Small cell lung cancer (SCLC) remains a very fatal disease due to limited therapeutic options. Systemic chemotherapy is the bedrock of treatment for both the limited and extensive stages of the disease. However, the established management paradigm of platinum-based chemotherapy has reached an efficacy plateau. A modest survival improvement, approximately 5%, was witnessed with the addition of cranial or thoracic radiation to systemic chemotherapy. Other strategies to improve outcome of platinum-based chemotherapy in the last 2 decades have met with minimal success. The substitution of irinotecan for etoposide in the frontline treatment of SCLC achieved significant efficacy benefit in Japanese patients but similar benefit could not be reproduced in other patient populations. Salvage treatment for recurrent or progressive SCLC is particularly challenging where topotecan remains the only agent with regulatory approval to date. Ongoing evaluation of biologic agents targeting angiogenesis, sonic hedgehog pathway, DNA repair pathway and immune checkpoint modulators hold some promise for improved outcome in this fatal disease. It is hoped that the coming decade will witness the application of new molecular biology and genomic research techniques to improve our understanding of SCLC biology and identification of molecular subsets that can be targeted appropriately using established and emerging biological agents similar to the accomplishments of the last decade with non small cell lung cancer.

KAT6B Is a Tumor Suppressor Histone H3 Lysine 23 Acetyltransferase Undergoing Genomic Loss in Small Cell Lung Cancer

“…However, these hopes were shattered by the recognition of low 5-year survival rates, in most instances only approximately 5% (1,2,42). More recent trials with targeted therapies in SCLC have failed with no new drugs progressing treatments beyond those of cisplatin and etoposide (1,2,42). One of the main reasons for this disappointing scenario is our limited knowledge of the molecular driver events in SCLC.…”

“…Importantly, we have poor second-line therapies especially when the cancer comes back quickly after first-line therapy is completed. In this regard, no new biologically targeted therapeutics have shown activity in this tumor type (2). Comprehensive genomic analyses have revealed genetically altered therapeutic targets in non-small cell lung carcinoma (3), but little is known about the genetic events involved in SCLC beyond the long-recognized high rate of TP53 and RB1 mutations (1).…”

Genomic Landscape Survey Identifies SRSF1 as a Key Oncodriver in Small Cell Lung Cancer

“…SRSF1 occurs in the same protein complex with topoisomerase 1 (Top1) [33]. Topotecan is a Top1 inhibitor and the only agent with regulatory approval for the treatment of relapsed SCLC [34]. In normal cells, Top1 cooperates with SRSF1 to prevent the formation of DNA-RNA hybrids (R-loops), unscheduled replication fork arrest, and genomic instability.…”

Small cell lung cancer: Recruitment of macrophages by circulating tumor cells

“…1,2 Despite excellent initial responses to platinum-based chemotherapy, SCLC recurs within approximately one year as chemoresistant tumor, not amenable to effective further treatment. 3 Furthermore, this malignancy exhibits comparatively high numbers of CTCs, an underlying cause of early tumor spread.…”