Citations

Abstract Children who are exposed to secondhand smoke (SHS) are faced with an increased risk of nicotine dependence later in life. We have previously shown that children exposed to SHS have an increased risk of lung cancer as adults. Furthermore, genetic variation plays a role in the susceptibility of individuals to lung cancer. The gene DRD1 mediates dopamine signaling following nicotine exposure, thus we reasoned that DRD1 may be related to lung cancer via modulation of the nicotine reward pathway. Our previous studies identified 4 SNPs (rs4809294, rs2292975, rs4861327, rs686) that were predicted to modulate a microRNA binding site and we assessed the association of these SNPs with lung cancer risk. Our current study investigated whether these SNPs were associated with nicotine dependence and whether this had a subsequent effect on lung cancer risk. We used the National Cancer Institute-Maryland lung cancer case-control study. Cases and controls were recruited from the greater Baltimore metropolitan area. We used ordinal logistic regression to examine the association between SNPs and nicotine dependence. Logistic regression adjusted for age, gender and smoking was used to assess the association between SNPs and lung cancer risk. No significant associations were found between genotypes in the 4 SNPs and nicotine dependence levels (n=1,450). Individuals with the heterozygous allele (AG) exposed to SHS during childhood had increased odds of lung cancer compared to those with the homozygous wild type allele (AA) for rs686 (OR=1.52, CI= 1.12, 2.07). Individuals with the homozygous variant allele (GG) exposed to childhood SHS had increased odds of lung cancer compared to individuals with the homozygous wild type allele (AA) (OR=2.11, CI= 1.45, 3.10). Individuals with the heterozygous allele (GA) and the highest levels of nicotine dependence who were also exposed to childhood SHS, had higher odds of lung cancer than those with the homozygous recessive allele (AA) (OR=3.50, CI=1.37, 8.96). Consistent with earlier findings, heterozygotes (AG) had increased odds of lung cancer but this was not statistically significant (OR=1.90, CI= 0.82, 4.40). To further explore this association, we examined the effect of race on this relationship. Caucasians with the heterozygous allele (AG), the highest levels of nicotine dependence and childhood SHS, had increased odds of lung cancer compared to those with the homozygous recessive allele (AA) for rs686 (OR=1.47, CI=1.06, 2.05). Caucasians with the homozygous allele (GG) who were exposed to childhood SHS, had higher odds of lung cancer compared to individuals with the homozygous recessive allele (AA) for rs686 (OR=1.84, CI=1.15, 2.98). No association was found among African Americans. Although none of the SNPs examined were found to be associated with nicotine dependence, it appears that variations in rs686 may modify an individual's susceptibility to lung cancer due to SHS exposure. Citation Format: Victoria A. Zigmont, Brid M. Ryan, Jin Jen, Ana I. Robles, Cain McClary, Kara Calhoun, Elise D. Bowman, Kirsi Vähäkangas, K. Leigh Greathouse, Wang Yi, Angela S. Wenzlaff, Bo Deng, Ping Yang, Ann G. Schwartz, Curtis C. Harris, Susan Olivo Marston. Childhood exposure to secondhand smoke, nicotine dependence, and DRD1 are associated with lung cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2156. doi:10.1158/1538-7445.AM2014-2156

Abstract Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder. SMM is distinguished from monoclonal gammopathy of undetermined significance by a much higher risk of progression to multiple myeloma (MM). There have been major advances in the diagnosis, prognosis, and management of SMM in the last few years. These include a revised disease definition, identification of several new prognostic factors, a classification based on underlying cytogenetic changes, and new treatment options. Importantly, a subset of patients previously considered SMM is now reclassified as MM on the basis of biomarkers identifying patients with an ≥80% risk of progression within 2 years. SMM has assumed greater significance on the basis of recent trials showing that early therapy can be potentially beneficial to patients. As a result, there is a need to accurately diagnose and risk-stratify patients with SMM, including routine incorporation of modern imaging and laboratory techniques. In this review, we outline current concepts in diagnosis and risk stratification of SMM, and provide specific recommendations on the management of SMM.

Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in epithelial ovarian cancers, especially relapsed platinum-sensitive high-grade serous disease. Consistent with preclinical studies, ovarian cancers and a number of other solid tumor types occurring in patients with deleterious germline mutations in BRCA1 or BRCA2 seem to be particularly sensitive. However, it is also becoming clear that germline BRCA1/2 mutations are neither necessary nor sufficient for patients to derive benefit from PARP inhibitors. We provide an update on PARP inhibitor clinical development, describe recent advances in our understanding of PARP inhibitor mechanism of action, and discuss current issues in the development of these agents.

Key Points Elderly patients with myeloma are heterogeneous and assessment strategies are needed to define the frailty profile. The proposed frailty score aims to better assess patients and provide them with more suitable therapies.

AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.

AbstractMatching molecularly targeted therapies with cancer subtype‐specific gene mutations is revolutionizing oncology care. However, for rare cancers this approach is problematic due to the often poor understanding of the disease's natural history and phenotypic heterogeneity, making treatment of these cancers a particularly unmet medical need in clinical oncology. Advanced Sézary syndrome (SS), an aggressive, exceedingly rare variant of cutaneous T‐cell lymphoma (CTCL) is a prototypical example of a rare cancer. Through whole genome and RNA sequencing (RNA‐seq) of a SS patient's tumor we discovered a highly expressed gene fusion between CTLA4 (cytotoxic T lymphocyte antigen 4) and CD28 (cluster of differentiation 28), predicting a novel stimulatory molecule on the surface of tumor T cells. Treatment with the CTLA4 inhibitor ipilimumab resulted in a rapid clinical response. Our findings suggest a novel driver mechanism for SS, and cancer in general, and exemplify an emerging model of cancer treatment using exploratory genomic analysis to identify a personally targeted treatment option when conventional therapies are exhausted.

Abstract Purpose: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. Experimental design: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25–1,000 mg/m2 through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. Results: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m2 combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. Conclusions: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies. Clin Cancer Res; 21(6); 1305–12. ©2014 AACR.