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

Abstract

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.

Keywords: ASCL1; Gene mutations; Neuroendocrine; SCLC; Therapy.

Figure 1:. Some of the many areas of current therapeutic interest in small cell lung cancer.

Cell surface targets include a number of receptor tyrosine kinases implicated in proliferative signaling, invasion, and angiogenesis; factors regulating neuroendocrine differentiation that are being explored as targets for antibody drug conjugates; immunologic regulators; and targets for tumor-specific vaccine strategies. Intracellular pathways of particular interest include metabolic and apoptotic regulators, cell cycle and DNA damage checkpoint controls, developmental signaling pathways, transcriptional regulators including the MYC family of transcriptional factors, and epigenetic modifiers of histones that affect chromosomal accessibility and gene expression. FAK, focal adhesion kinase; RET, ret proto-oncogene; FGFR1, fibroblast growth factor receptor 1; VEGFR, vascular endothelial growth factor receptor; DLL3, delta-like 3 (Drosophila); CD56, neural cell adhesion molecule 1; Fuc-GM1, fucosyl-monosialotetrahexosylganglioside; PD-L1, programmed death ligand-1; CTLA4, cytotoxic T-lymphocyte associated protein 4; MHC 1, Major Histocompatibility Complex 1; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; mTOR, mammalian target of rapamycin; BCL2, B-cell lymphoma 2; MCL1, MCL1 apoptosis regulator, BCL2 family member ; ASCL1, achaete-scute family bHLH transcription factor 1; NEUROD1, neuronal differntiation 1; WNT, wingless-type MMTV integration site family member; AURKA/B, Aurora kinase A/B; PLK1, Polo-like Kinase 1; WEE1, WEE1 G2 checkpoint kinase; CHK1, checkpoint kinase 1; PARP1, poly-ADP ribose polymerase 1; CDK7, Cyclin Dependent Kinase 7; MYCL, MYCL proto-oncogene, BHLH transcription factor; MYCN, MYCN proto-oncogene, BHLH transcription factor; MYC, MYC proto-oncogene, BHLH transcription factor; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; LSD1, lysine (K)-specific demethylase 1A; MLL2, myeloid/lymphoid or mixed-lineage leukemia 2; HDAC, Histone Deacetylase; BET, bromodomain and extra-terminal domain; IMPDH1/2, inosine monophosphate dehydrogenase 1/2

Figure 2:. Small cell carcinoma.

A) This tumor is composed of small cells with scant cytoplasm, finely granular chromatin and frequent mitoses. Nucleoli are absent. B) Ki-67 shows strong nuclear staining in 100% of the tumor cells. Combined small cell carcinoma and adenocarcinoma. C) Low power image of tumor composed of two components: small cell carcinoma (upper left) and adenocarcinoma with acinar pattern (lower right). D) High power image of the SCLC component from C.

Figure 3.. Diagram of the relative abundance, MYC status, and NE character of the four molecular subtypes of SCLC, each identified by their key transcriptional regulator.

These subtypes may exhibit distinct targetable vulnerabilities, which are represented in the table beneath the pie chart. Proportions of each subtype are as follows: ASCL1 (0.70 95% CI [0.60, 0.79]), NEUROD1 (0.11 95% CI [0.06, 0.20]), YAP1 (0.02 95% CI [0.01, 0.09]), POU2F3 (0.16 95% CI [0.10, 0.26]). ASCL1, achaete-scute homologue 1; AURKA/B, Aurora kinase A/B; BCL2, B-cell lymphoma 2; CREBBP, CREB binding protein; CHK1, checkpoint kinase 1; DLL3, delta-like ligand 3; IMPDH, inosine-5’ monophosphate dehydrogenase; IGF-R1, insulin-like growth factor 1 receptor; IO, immuno-oncology; LSD1, lysine-specific histone demethylase 1; NE, neuroendocrine; NEUROD1, neurogenic differentiation factor 1; POU2F3, POU class 2 homeobox 3; YAP1, yes-associated protein 1.