Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer

The Recalcitrant Cancer Research Congressional Act of 2012 (H.R.733) directs the National Cancer Institute (NCI) to utilize resources for research and treatment of recalcitrant cancers having five-year relative survival rates of less than 20% that have not seen substantial progress in diagnosis or treatment. The initial focus will be on pancreatic carcinoma and small cell cancer of the lung (SCLC). SCLC is strongly associated with tobacco exposure and is characterized by rapid growth, early metastasis, and a five-year survival rate of less than 7%. The basic therapeutic approach for SCLC has remained unchanged for three decades, and no effective targeted therapies exist to date ( 1 , 2 ). SCLC is a poster child for recalcitrant cancers as documented in subsequent NCI responses and workshop proceedings ( 3 , 4 ).

Front-line therapy for SCLC is usually etoposide-platinum-based doublet chemotherapy for extensive-stage disease (∼75% of cases) ( 1 ) and often combined with thoracic irradiation for limited-stage disease (∼25% of cases) and prophylactic intracranial irradiation. While initial objective tumor response rates to chemotherapy and radiation therapy are very high, they are usually of short duration and recurrent tumors are nearly always resistant to further therapies. We do not understand the mechanisms underlying either the initial sensitivity or the subsequent omnipresent resistance to standard chemotherapy. Intense efforts of many clinical trials over the past 30 years have failed to find highly active new therapies for front-line or second-line therapy. Thus, the therapy and survival of SCLC patients have not changed in many decades. In addition, sophisticated efforts in molecular analyses have failed to translate to the clinic in a manner similar to those that have revolutionized our approach to non–small cell lung cancer (NSCLC) ( 5 ). In response, the NCI and multiple investigators have fast-tracked the comprehensive development of new diagnostic, prevention, and therapeutic approaches for SCLC, with reasons for optimism outlined below, in the NCI special reports and elsewhere ( 6 ).

To develop new therapeutic strategies for SCLC and identify molecular biomarkers for response, NCI investigators, led by Dr. Beverly Teicher, approached this problem as reported in this issue of the Journal by Polley et al. ( 7 ) and in a companion study ( 8 ). Their extensive recent study tested responses of a large panel of 63 SCLC lines to 103 US Food and Drug Administration (FDA)–approved anticancer agents and a library of more than 400 investigational drugs and correlated their findings with global gene expression and microarray expression patterns. Etoposide and topotecan are two FDA-approved drugs for SCLC, and they were used as comparators for other agents (surprisingly, no platinum drug is on the list). Platin-etoposide drug combinations were not tested, even though they are frequently used clinically. This large study and the deposited data will be a highly valuable resource for future research. Surprisingly, they failed to identify a “magic bullet,” and their findings are thus sobering, reinforcing the difficulties involved and the need for radical approaches to finding new therapies. There was considerable heterogeneity (differences in drug response IC50 phenotypes) in the responses of SCLC lines to the comparators; however, the etoposide and topotecan responses were highly correlated to each other. The SCLC lines tended to display intrinsic multidrug sensitivity or resistance to most drugs, and those from treatment-naive patients were not more sensitive than those from previously treated patients.

These findings cannot be explained currently, but their understanding will be of crucial clinical importance. While approximately 40% of the investigational drugs were inactive, activity against some targets including BCL2, MTOR , and stem cells appeared promising ( 7 ). Likewise, Kaur et al. and other investigators found a subset of SCLCs very sensitive to bromodomain inhibitors but did not find differential sensitivity to drugs targeting stem cell pathways ( 8 , 9 ). These approaches were relevant because the PI3K/AKT/MTOR pathway is deregulated in many SCLC tumors ( 10 ), the anti-apoptotic molecule BCL2 is often upregulated ( 11 ), and SCLC tumors and cell lines contain a very high percentage of stem cells ( 12 , 13 ), indicating that these leads are worthy of further investigation. In searching for predictive biomarkers, they found mRNA patterns in general were not associated with drug responses, while miRNA expression patterns had some associations with drug sensitivity.

A major obstacle to translational SCLC research has been the paucity of tumor materials as surgical resections are rare, highlighting the need for fresh approaches to clinical trials to obtain such materials and for developing relevant preclinical models. Also, unlike NSCLC, repeat biopsies of recurrent SCLC tumors are uncommon, despite their potential value for exploring mechanisms of resistance. Of the major triad of preclinical models (SCLC lines, patient-derived xenografts [PDXs], and genetically engineered mouse models), Polley et al. chose SCLC lines, the most abundant and widely studied of the models ( 14 ). Each model has advantages and shortcomings. Cell lines are easily handled, are easily genetically manipulated, and can generate xenografts but lack a microenvironment and immune and vascular systems and may differ epigenomically from tumors and PDXs. PDXs may more closely resemble human tumors, but they are difficult to manipulate, relatively expensive, and time consuming to study; have a murine microenvironment; and lack an immune system. Many excellent genetically engineered mouse models for SCLC exist for neuroendocrine (NE) lung carcinomas and are useful for studying preneoplastic changes and pathogenesis ( 15 ), but their latent times are lengthy and lack of tobacco exposure results in many fewer tumor mutations than in their human counterparts, possibly affecting therapeutic responses ( 16 ). We need new approaches to improve existing models, and the recently demonstrated ability to establish circulating tumor cell–derived xenografts from the high circulating tumor cell burden of SCLC patients is an important step ( 17 ). We also need matched SCLC lines and PDXs from tumors before and after therapy to understand and overcome drug resistance. Another potential improvement is platforms that permit the simultaneous testing of multiple drugs or combinations within a single tumor or xenograft ( 18 , 19 ). Drug “repositioning,” the process of finding new uses of existing drugs, will also be of assistance ( 20 ).

SCLC is a high-grade NE cancer of the lung, along with the closely related large cell neuroendocrine carcinoma (LCNEC). These two tumor types constitute approximately 20% of lung cancers, and any successful therapy for SCLC may be effective against LCNEC. NE lung cancers mainly arise from the small numbers of normal NE cells present in the normal lung ( 21 ). However, in the early embryonic phase of fetal lung development there is only a single primordial stem cell, and thus all lung carcinomas are developmentally related. This helps explain the interconversion of SCLC and NSCLC tumors, including the histological alteration of EGFR -mutant NSCLC tumors to SCLC after tyrosine kinase inhibitor therapy ( 22 ). The SCLC NE program is driven by transcription factors ASCL1 or NEUROD1 ( 23 ) (and potentially others) that, while not mutated or amplified, function as “lineage oncogenes.” The resultant possible phenotypes ( ASCL1 +/ NEUROD1 -, ASCL1 -/ NEUROD 1+, ASCL 1+/ NEUROD 1+, and ASCL 1-/ NEUROD 1-) show considerable heterogeneity in morphology, growth characteristics, expression of NE properties and activation of downstream oncogenes and other pathways. Other transcription factors important in SCLC pathogenesis are amplification and overexpression of MYC family members ( 24 ) and over-expression of NFIB. Essentially, all SCLC tumors have inactivation of the genes TP53 and RB1 ( 21 ) and have undergone allelic loss of a large part of chromosome arm 3p, presumably the location of other key tumor suppressors, but lack other frequently recurring mutations. High tobacco exposure results in numerous SCLC “passenger” mutations. This heterogeneity may result in individual patient variations in response to novel therapeutic approaches. In addition, widespread genomic disruption of the accompanying nonmalignant respiratory epithelium in SCLC patients ( 25 ) may be the reason for the explosive onset of SCLC and the lack of recognized precursor lesions.

As summarized in the report from the recent Small Cell Lung Cancer Meeting in New York City, 2015, comprehensive genomic characterization of pulmonary NE carcinomas, coupled with sophisticated bioinformatics, has revealed a wealth of potential therapeutic targets ( 23 ). In addition to the pathways already mentioned, they include apoptotic agents, targeting the MYC family, FGFR, SOX2, RET , PK3CA, and other oncogenes, inhibiting PARP, EZH2, AURKA, Notch , bromodomain-containing genes, Sonic Hedgehog (SHH), FAK, cytokines, and anti-angiogenesis agents. As of 2015, at least 23 targeted agents for SCLC had undergone or were in clinical trial although to date most results were less than stellar ( 26 ).

Recently, immune checkpoint therapy, which targets regulatory pathways in T-cells to enhance antitumor immune responses, resulting in durable clinical responses and long-term remissions in many cancers including NSCLC ( 27 ), has generated considerable excitement. This requires an ability to understand human immune responses in the tumor microenvironment. We need to know how SCLCs escape these immune responses and how to reinstate antitumor immunity, and exciting new SCLC immunotherapy trials are underway ( 28 ).

After several decades of neglect, SCLC had become the “forgotten cancer”—one that was understudied, underfunded, and without effective therapeutic options. As part of its Congressional mandate, the NCI has recently issued requests for proposals for interactive studies of early detection, prevention, novel therapeutic approaches, and for a center to coordinate these efforts. Along with our deeper understanding of its molecular pathogenesis and a new era of scientific cooperation, including sharing of data and precious resources, these newer initiatives have resulted in a remarkable reawakening of interest and expectations, and hopefully SCLC will be removed from the list of recalcitrant cancers within our lifetime.

Note

The authors declare that they receive licensing fees for the cell lines that they have initiated. This work was supported by a grant from the NCI, P50CA070907.