Citations

Abstract Purpose: Previous studies have suggested that higher circulating 25-hydroxyvitamin D [25(OH)D] levels are associated with decreased colorectal cancer risk and improved survival. However, the influence of vitamin D status on disease progression and patient survival remains largely unknown for patients with advanced or metastatic colorectal cancer. Experimental Design: We prospectively collected blood samples in 1,041 patients with previously untreated advanced or metastatic colorectal cancer participating in a randomized phase III clinical trial of first-line chemotherapy plus biologic therapy. We examined the association of baseline plasma 25(OH)D levels with overall survival (OS) and progression-free survival (PFS). Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs), adjusted for prognostic factors and confounders. Results: At study entry, 63% of patients were vitamin D deficient (<20 ng/mL) and 31% were vitamin D insufficient (20–<30 ng/mL). Higher 25(OH)D levels were associated with an improvement in OS and PFS (Ptrend = 0.0009 and 0.03, respectively). Compared with patients in the bottom quintile of 25(OH)D (≤10.8 ng/mL), those in the top quintile (≥24.1 ng/mL) had a multivariable-adjusted HR of 0.66 (95% CI, 0.53–0.83) for OS and 0.81 (95% CI, 0.66–1.00) for PFS. The improved survival associated with higher 25(OH)D levels was consistent across patient subgroups of prognostic patient and tumor characteristics. Conclusions: In this large cohort of patients with advanced or metastatic colorectal cancer, higher plasma 25(OH)D levels were associated with improved OS and PFS. Clinical trials assessing the benefit of vitamin D supplementation in patients with colorectal cancer are warranted.

Background:Mutations localized in the tyrosine kinase domain activation loop of FLT3 (FLT3‐TKD), induce constitutive tyrosine phosphorylation, and activation of the receptor tyrosine kinase similarly to FLT3 internal tandem duplication (ITD) mutations. However, the prognostic role of FLT3‐TKD in AML is not well established. In the phase 3 RATIFY trial [CALGB 10603/Alliance; NCT00651261; Stone et al. N Engl J Med. 2017] midostaurin, in combination with standard chemotherapy, improved survival outcomes across all three FLT3 stratification subgroups (ITD high allelic ratio (AR) [≥ 0.7], ITD low AR [< 0.7] and TKD) vs placebo.Aims:Here, a post hoc analysis was used to establish the efficacy of midostaurin in patients (pts) in the RATIFY trial stratified by FLT3‐TKD AR and NPM1 mutational status.Methods:In RATIFY, newly diagnosed pts with AML 18–60 years (y) old were randomly assigned to receive midostaurin or placebo together with standard induction and consolidation therapy followed by twelve 28‐day cycles of maintenance therapy with midostaurin or placebo. FLT3‐TKD mutation was detected by PCR and capillary electrophoresis at nine reference laboratories. The FLT3‐TKD AR was calculated as the ratio between the areas under the curve of mutant to wild‐type allele. Pts were categorized as NPM1 mutated (mut) or NPM1 wild‐type (WT) using PCR. Efficacy outcomes included complete remission (CR), overall survival (OS), event‐free survival (EFS) and disease‐free survival (DFS). EFS and DFS analyses were performed considering CR within a 60‐day window. P values presented were not adjusted for multiplicity.Results:Of 163 FLT3‐TKD pts, 134 with available NPM1 data had consented for exploratory analysis and were included in this study. Overall, 58.9% of pts had NPM1‐mut, 47.8% were male and the median age was 49 y (range: 19.3–59.9 y). The median white blood cell (WBC) count was higher in pts with NPM1‐mut than in pts with NPM1‐WT (34.1 vs 15.5 × 109 /L). The median FLT3‐TKD AR was 0.4 (range: 0–2.7). Overall CR rate (regardless of NPM1 genotype) was 64% for midostaurin and 56% for placebo in FLT3‐TKD pts. Pts with FLT3‐TKD AR ≥ 0.4 treated with midostaurin showed a trend towards improved OS and reduced cumulative incidence of relapse (CIR) (Figure). In FLT3‐TKD AR ≥ 0.4 pts, the presence of a NPM1 mutation had a significant prognostic effect for all endpoints consistently with hazard ratios (HRs) around 0.50 or lower. Regardless of treatment OS, EFS, and DFS estimates at 3 y were 73% vs 52%, 48% vs 25%, and 74% vs 47%, respectively, for the 45 pts with FLT3‐TKD/NPM1‐mut vs the 25 pts with FLT3‐TKD/NPM1‐WT. It should be noted that the number of pts in each subgroup was small. Multivariate analyses in these FLT3‐TKD pts revealed that NPM1 genotype was an independent prognostic factor for OS and EFS (2‐sided P < 0.05), whereas study drug, age, sex, TKD AR, WBC at baseline and stem cell transplantation (SCT) (no/yes) did not reach this level of significance in the Cox model.Summary/Conclusion:This post hoc analysis of the subset of FLT3‐TKD pts in the RATIFY trial showed the high prognostic value of NPM1 mutational status. Midostaurin showed an overall benefit in the FLT3‐TKD pts for OS, EFS, CR and DFS, with the impact of treatment on outcome for NPM1‐mut pts being greatest in those with higher FLT3‐TKD allelic burden. U10CA180821, U10CA180882, U24CA196171, U10CA180861; Novartis; htt∗∗∗ps://acknowledgments.alliancefound.orgimage

Immunotherapy holds promise for patients with multiple myeloma (MM), but little is known about how MM-induced immunosuppression influences response to therapy. Here, we investigated the impact of disease progression on immunotherapy efficacy in the Vk*MYC mouse model. Treatment with agonistic anti-CD137 (4-1BB) mAbs efficiently protected mice when administered early but failed to contain MM growth when delayed more than 3 weeks after Vk*MYC tumor cell challenge. The quality of the CD8 + T cell response to CD137 stimulation was not altered by the presence of MM, but CD8 + T cell numbers were profoundly reduced at the time of treatment. Our data suggest that an insufficient ratio of CD8 + T cells to MM cells (CD8/MM ratio) accounts for the loss of anti-CD137 mAb efficacy. We established serum M-protein levels prior to therapy as a predictive factor of response. Moreover, we developed an in silico model to capture the dynamic interactions between CD8 + T cells and MM cells. Finally, we explored two methods to improve the CD8/MM ratio: anti-CD137 mAb immunotherapy combined with Treg depletion or administered after chemotherapy treatment with cyclophosphamide or melphalan efficiently reduced MM burden and prolonged survival. Together, our data indicate that consolidation treatment with anti-CD137 mAbs might prevent MM relapse.

Abstract Purpose: Choriocarcinoma is most commonly gestational (androgenetic or biparental) but can be of germ cell origin or can develop as a component of a somatic neoplasm (genetically related to the patient). The latter type are aggressive neoplasms for which the underlying genetic alterations are not well characterized. Experimental Design: To investigate the relationship between the different components of somatic neoplasms with choriocarcinomatous elements, the genetic differences between gestational and nongestational tumors, and identify potential targetable alterations, we analyzed 23 samples from 11 tumors, including five gynecologic-type somatic neoplasms with choriocarcinomatous differentiation (two to three different components each) and six pure choriocarcinomas, for somatic mutations, single-nucleotide polymorphisms, and PD-L1 expression. Results: In mixed tumors, gynecologic-type carcinoma components demonstrated lineage-characteristic and lineage-specific alterations, with choriocarcinomatous components sharing some of these as well as demonstrating novel alterations, supporting a clonal relationship with divergent differentiation of the choriocarcinoma from the somatic carcinoma. TP53 mutation only occurred in nongestational tumors. Diffuse PD-L1 expression was characteristic of choriocarcinoma in both pure and mixed tumors but not seen in the gynecologic-type carcinoma components. Conclusions: Given that the somatic carcinomatous and choriocarcinomatous components of mixed tumors have distinct genetic alterations and biomarker expression, separate analysis of these components is required to guide targeted therapy. High PD-L1 expression suggests a role for checkpoint inhibitor–based immunotherapy in tumors with a choriocarcinoma component. The underlying mechanisms by which cancer stem cells reprogram and initiate trophoblastic retrodifferentiation in some somatic tumors warrant further investigation.

Apolipoprotein E (apoE) is linked to the risk for Alzheimer’s disease (AD) and thus has been suggested to be an important therapeutic target. In our drug screening effort, we identified Ondansetron (OS), an FDA-approved 5-HT3 antagonist, as an apoE-modulating drug. OS at low micromolar concentrations significantly increased apoE secretion from immortalized astrocytes and primary astrocytes derived from apoE3 and apoE4-targeted replacement mice without generating cellular toxicity. Other 5-HT3 antagonists also had similar effects as OS, though their effects were milder and required higher concentrations. Antagonists for other 5-HT receptors did not increase apoE secretion. OS also increased mRNA and protein levels of the ATB-binding cassette protein A1 (ABCA1), which is involved in lipidation and secretion of apoE. Accordingly, OS increased high molecular weight apoE. Moreover, the liver X receptor (LXR) and ABCA1 antagonists blocked the OS-induced increase of apoE secretion, indicating that the LXR-ABCA1 pathway is involved in the OS-mediated facilitation of apoE secretion from astrocytes. The effects of OS on apoE and ABCA1 were also observed in human astrocytes derived from induced pluripotent stem cells (iPSC) carrying the APOE ε3/ε3 and APOE ε4/ε4 genotypes. Oral administration of OS at clinically-relevant doses affected apoE levels in the liver, though the effects in the brain were not observed. Collectively, though further studies are needed to probe its effects in vivo, OS could be a potential therapeutic drug for AD by modulating poE metabolism through the LXR-ABCA1 pathway.

Abstract The oncolytic reovirus (RV) has demonstrated clinical efficacy and minimal toxicity in a variety of cancers, including multiple myeloma (MM). MM is a malignancy of plasma cells that is considered treatable but incurable because of the 90% relapse rate that is primarily from drug resistance. The systemic nature of MM and the antitumor immunosuppression by its tumor microenvironment presents an ongoing therapeutic challenge. In the present study, we demonstrate that RV synergizes with the standard-of-care MM drug bortezomib (BTZ) and, importantly, enhances its therapeutic potential in therapy-resistant human MM cell lines in vitro. Using the syngeneic Vk*MYC BTZ-resistant immunocompetent transplantable MM murine model, we also demonstrate that mice harboring BTZ-insensitive MM tumors respond to the RV/BTZ combination treatment in terms of decreased tumor burden and improved overall survival (P &lt; .00001). We demonstrate that BTZ augments RV replication in tumor-associated endothelial cells and myeloma cells, leading to enhanced viral delivery and thereby stimulating cytokine release, immune activity, apoptosis, and reduction of the MM-associated immune suppression. We conclude that combined RV/BTZ is an attractive therapeutic strategy with no safety signals for the treatment of MM.