Novel systemic therapies for small cell lung cancer

Abstract

A diagnosis of small cell lung cancer (SCLC) today confers essentially the same terrible prognosis that it did 25 years ago, when common use of cisplatin-based chemotherapy began for this disease. In contrast to past decades of research on many other solid tumors, studies of combination chemotherapy using later generation cytotoxics and targeted kinase inhibitors have not had a significant impact on standard care for SCLC. The past few years have seen suggestions of incrementally improved outcomes using standard cytotoxics, including cisplatin-based combination studies of irinotecan and amrubicin by Japanese research consortia. Confirmatory phase III studies of these agents are ongoing in the United States. Antiangiogenic strategies are also of primary interest and are in late-phase testing. Several novel therapeutics, including high-potency small molecule inhibitors of Bcl-2 and the Hedgehog signaling pathway, and a recently discovered replication-competent picornavirus, have shown remarkable activity against SCLC in preclinical models and are currently in simultaneous phase I clinical development. Novel therapeutic approaches based on advances in understanding of the biology of SCLC have the potential to radically change the outlook for patients with this disease.

Figure 1

Apoptotic induction by cytotoxics and the role of Bcl-2 in therapeutic resistance. Many cytotoxic agents induce DNA damage or disrupt critical oncogenic signaling pathways. These alterations, through activation of p53, suppression of Akt, and other pathways, lead to activation of small proapoptotic Bcl-2 family members (grey circles), termed BH3-only factors, either by transcriptional induction (Puma, Noxa, and others) or posttranscriptional modification (Bid, Bim, Bad, and others). Activated BH3-only factors (grey stars) translocate to the mitochondrial outer membrane, where they bind with high affinity to Bcl-2 and related antiapoptotic family members (white circles with B). This displaces Bcl-2 from interaction with the critical proapoptotic family members Bak and Bax (black circles), which can then homodimerize, leading to disruption of mitochondrial membrane integrity and release of key activators of the downstream apoptotic cascade, including cytochrome c (Cyt c), SMAC/Diablo, and apoptosis-inducing factor (AIF). Tumors with excess expression of Bcl-2 have increased capacity to absorb activated BH3-only factors while still preventing Bax/Bak activation. Targeted inhibition of Bcl-2 leads to increased sensitivity to cytotoxic therapy and can directly promote death of tumors dependent on high levels of Bcl-2 for survival.

Figure 2

Differential capacities of standard cytotoxics and stem cell-directed therapeutics. Small cell lung cancer (SCLC) is highly chemosensitive, but responses to standard cytotoxics are almost never durable. This suggests SCLC contains a subset of cells with tumorigenic potential (black) that may be selectively chemoresistant. New combinations of standard cytotoxics targeting the same chemosensitive bulk population may show minor improvements in response rate but are unlikely to have durable anticancer activity. In contrast, novel therapeutics, such as hedgehog pathway inhibitors, that may primarily target tumor stem cell populations may show minimal objective response rates, but may have longer-term durable effects, especially if combined with standard cytotoxics.