Asthma and COPD are significant lung diseases for which anti-inflammatories, including inhaled corticosteroids and leukotriene- targeted drugs, represent a key element of current therapy. Oligonucleotides comprise a diverse family of emerging drug candidates for the treatment of these diseases.

There is a commonality in the chemistry of oligonucleotide drug molecules but, importantly, individual candidates are distinct in their molecular targets and also possess different mechanisms of action. Oligonucleotides may be divided in two groups based on their main mechanism of action: (i) RNA-targeting; and (ii) protein-targeting.

Antisense oligonucleotides and siRNAs, both of which belong to the RNA-targeting group, and the immunostimulatory sequence-based drugs, which are members of the protein-targeting group, are progressing through clinical trials. In principle, the development of these agents is facilitated by a series of significant advantages, such as those associated with delivery to the lung via inhalation, and targeting to the site of action, resulting in reduced levels of systemic exposure. Although no oligonucleotide-based drug has been approved for the treatment of asthma or COPD, this class of compounds holds significant promise in the treatment of these two diseases.

Several oligonucleotide drug candidates have been evaluated in the clinic with no significant adverse safety findings, while clinical proof of concept based on short-term inhalation protocols in challenge models in humans has also been established.

We investigated the presence of autoantibodies as immuno-biomarkers to a panel of tumour-associated antigens in a group of individuals with small cell lung cancer (SCLC), a disease group which has a poor overall cancer prognosis and therefore may benefit most from early diagnosis.

EXPERIMENTAL DESIGN: Sera from 243 patients with confirmed SCLC and normal controls matched for age, sex and smoking history, were analysed for the presence of these early immuno-biomarkers (ie autoantibodies to p53, CAGE, NY-ESO-1, GBU4-5, Annexin I, SOX2 and Hu-D) by enzyme-linked immunosorbent assay.

RESULTS: Autoantibodies were seen to at least 1 of 6 antigens in 55% of all the SCLC patients' sera tested, with a specificity of 90% compared to controls. Using a higher assay cut-off to achieve a specificity of 99%, autoantibodies were still detectable in 42% of SCLC patients (receiver operator characteristic area under the curve, 0.76). There was no significant difference in sensitivity when analysed by stage of the cancer, or by patient age or gender. The frequency of autoantibodies to individual antigens varied, ranging from 4% for GBU4-5 to 35% for SOX2. Levels of Annexin I autoantibodies were not elevated in patients with SCLC. Antibodies were also detected in four separate patients, whose sera were taken up to three months before tumor diagnosis.

CONCLUSIONS: The presence of an autoantibody to one or more cancer-associated antigens may provide an important addition to the armamentarium available to the clinician to aid early cancer detection in high-risk individuals.

A phase II trial of irinotecan and cisplatin (IP) as induction chemotherapy followed by conventional thoracic irradiation concurrent with low-dose weekly cisplatin for limited-disease small-cell lung cancer (LDS-SCLC).

Between February 2005 and December 2008, 34 chemotherapy-naïve patients with LD-SCLC were enrolled. Treatment consisted of two 21-day cycles of cisplatin 40 mg/m(2) and irinotecan 80 mg/m(2) intravenously (IV) on days 1 and 8 followed by conventional thoracic irradiation at a dose of 54 Gy concurrent with cisplatin at dose of 20 mg/m(2) weekly then prophylactic cranial irradiation at dose of 30 Gy in 10 fractions for those achieved complete or partial response. Only 33 patients received the treatment protocol, and they were assessed for response and toxicity. After induction chemotherapy, overall response rate was (72.73%). After median follow-up of 27 months, the median survival was 25 months (95% CI, 21.249-28.751) with 1 and 2-year overall survival rates of 83 and 55%, respectively. Median progression-free survival (PFS) was 15 months (95% CI, 10.311-19.689) with a 1- and 2-year PFS of 59 and 38%, respectively. The most common toxicities during induction chemotherapy were neutropenia (81%), thrombocytopenia (69%), and diarrhea (63%) while esophagitis (84%) and pneumonitis (30%) were the most common toxicities during concurrent chemo-radiation. Relapse rate was 61% with distant metastasis in 42% and local recurrence in 26%.

This protocol of induction irinotecon-based regimen followed by delayed concurrent thoracic irradiation with low-dose weekly cisplatin is effective with acceptable toxicities. Based on the favorable outcome in this trial, this regimen should be evaluated in a large phase III trial.

Radiotherapy is a critical component of multi-modality treatment of LS-SCLC and has an emerging role in ES-SCLC. Many of the recent advances in the management of SCLC have come by refining the role of radiotherapy in this disease. A significant amount of research is currently focused on the targeting of specific signaling cascades implicated in SCLC pathogenesis (eg Hedgehog, c-MET, insulin-like growth factor receptor 1 [IGFR-1R], mammalian target of rapamycin [mTOR], vascular endothelial growth factor [VEGF], and p53 and Bcl-2 pathways) and on other novel approaches to therapy including treatment with a novel oncolytic virus with tropism for neuroendocrine cells and CD56-targeted drug delivery.

Clinical investigations of many of these therapies are ongoing, and the results may become available over the next several years.