Immune Checkpoint Inhibitors in Neuroendocrine Tumors: A Single Institution Experience With Review of Literature

This unique case series and review of literature suggests that immune checkpoint inhibitors may have clinical activity in neuroendocrine tumors. Objective: Summarize advances of immuno-oncology in neuroendocrine tumors with the help of a case series. Design: Case series and review of literature. Intervention or Exposure: The patients were treated with immune checkpoint inhibitors (pembrolizumab or nivolumab). Main Outcome(s) and Measures(s): Life expectancy, quality of life, disease progression. Results: Maximum durable response of 16 months in one of the patients so far. All patients showed improvement in quality of life before disease progression. Two out of four are still on therapy. None of the patients experienced immune checkpoint inhibitor associated side-effects. All patients had failed standard of care therapy prior to the initiation of immune checkpoint inhibitors and were on the verge of hospice. Conclusions: Immune checkpoint inhibitors have revolutionized cancer management and the last 5 years have seen a rapid expansion in the indications for this class of drug. Neuroendocrine tumors, unfortunately, have been slow to catch on to the immuno-oncology, partly due to difficulties in establishing relevant preclinical neuroendocrine tumors models for immune-oncology studies. In this manuscript, we review the current status of immunotherapy in neuroendocrine tumors

Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma

Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis

Statistically significant and replicated SNP associations at 3q25 and 4p16.

<p>Statistically significant and replicated SNP associations at 3q25 and 4p16.</p

rs6441201 risk allele at 3q25 correlates with increased <i>MLF1</i> expression and <i>MLF1</i> silencing results in decreased cell growth in neuroblastoma cells.

<p><b>(a)</b><i>MLF1</i> mRNA expression is significantly higher in neuroblastoma cell lines harboring one or more copies of the rs6441201 risk allele (A) compared to neuroblastoma cell lines homozygous for the protective allele (GG). <b>(b)</b> Silencing of RSRC1 or MLF1 expression using pooled siRNAs resulted in 50–90% reduced mRNA levels by real-time quantitative PCR in neuroblastoma cell lines. <b>(c)</b> Confirmation by Western blot of knockdown at the protein level for RSRC1 and MLF1 after siRNA mediated silencing in neuroblastoma cell lines. <b>(d-g)</b> siRNA mediated silencing of MLF1 results in significant growth inhibition of neuroblastoma cells compared to non-targeting control siRNA; no effect was observed upon silencing of RSRC1. Cell growth measured by real-time cell sensing system (RT-ces).</p

Discovery of neuroblastoma susceptibility loci at chromosome 3q25 and 4p16.

<p>Regional association plots of genotyped and imputed SNPs novel susceptibility loci. Plots were generated using LocusZoom. Y-axes represent the significance of association (-log10 transformed P values) and the recombination rate. SNPs are color-coded based on pair-wise linkage disequilibrium (r²) with indicated SNPs <b>(a)</b> 3q25 locus: rs6441201 shown in purple (3.01 x 10⁻⁷; Odds Ratio: 1.21, 95% C.I.: 1.12–1.30). <b>(b)</b> 4p16 locus: rs3796727 shown in purple (p = 5.25 x 10⁻⁹; Odds Ratio: 1.26, 95% C.I.: 1.16–1.36).</p