Citations

Tumor-initiating cells (TIC) are dynamic cancer cell subsets that display enhanced tumor functions and resilience to treatment but the mechanism of TIC induction or maintenance in lung cancer is not fully understood. In this study, we show the calcium pathway transcription factor NFATc2 is a novel regulator of lung TIC phenotypes, including tumorspheres, cell motility, tumorigenesis, as well as in vitro and in vivo responses to chemotherapy and targeted therapy. In human lung cancers, high NFATc2 expression predicted poor tumor differentiation, adverse recurrence-free and cancer-specific overall survivals. Mechanistic investigations identified NFATc2 response elements in the 3’ enhancer region of SOX2, and NFATc2/SOX2 coupling upregulates ALDH1A1 by binding to its 5’ enhancer. Through this axis, oxidative stress induced by cancer drug treatment is attenuated, leading to increased resistance in a mutation-independent manner. Targeting this axis provides a novel approach for the long-term treatment of lung cancer through TIC elimination.

Abstract FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317–27. ©2017 AACR.

Abstract The primary objective of phase I oncology trials is to find the MTD. The 3+3 design is easy to implement but performs poorly in finding the MTD. A newer design, such as the modified toxicity probability interval (mTPI) design, provides better accuracy to identify the MTD but tends to overdose patients. We propose the keyboard design, an intuitive Bayesian design that conducts dose escalation and de-escalation based on whether the strongest key, defined as the dosing interval that most likely contains the current dose, is below or above the target dosing interval. The keyboard design can be implemented in a simple way, similar to the traditional 3+3 design, but provides more flexibility for choosing the target toxicity rate and cohort size. Our simulation studies demonstrate that compared with the 3+3 design, the keyboard design has favorable operating characteristics in terms of identifying the MTD. Compared with the mTPI design, the keyboard design is safer, with a substantially lower risk of treating patients at overly toxic doses, and has the better precision to identify the MTD, thereby providing a useful upgrade to the mTPI design. Software freely available at http://www.trialdesign.org facilitates the application of the keyboard design. Clin Cancer Res; 23(15); 3994–4003. ©2017 AACR. See related commentary by Paoletti et al., p. 3977

Objectives: To analyze the radiographic outcomes of intertrochanteric osteotomy for the treatment of femoral neck nonunion with “undercorrection” of the Pauwels angle and relative preservation of the proximal femoral anatomy. Design: Retrospective cohort study. Setting: Level-1 trauma center. Patients: Thirty-two patients with established femoral neck nonunions that had been treated with intertrochanteric osteotomy were retrospectively identified through Current Procedural Terminology codes. Seven patients were treated with 30 degree closing wedge osteotomy and 25 with a 20 degree or smaller osteotomy. Intervention: Valgus-producing intertrochanteric osteotomy with a blade plate. Main Outcome Measurements: Femoral neck and intertrochanteric osteotomy osseous union. Results: Thirty-one of 32 patients (97%) went on to osseous union of the femoral neck and all intertrochanteric osteotomies healed. There was no significant difference in the rate of union of the femoral neck between those patients treated with 30 versus 20 degree or less osteotomies. After osteotomy, the mean Pauwels angle decreased from 71 degrees (range 52–95 degrees) to 47 degrees (range 23–67 degrees) and the mean proximal femoral offset decreased by 11 mm (range 0–23 mm). Seven patients developed radiographic signs of avascular necrosis after osteotomy (22%). Three patients of these patients were converted to total hip arthroplasty (9%). Patients treated with a 30 degree osteotomy were more likely to develop avascular necrosis (67% vs. 12%, P-value = 0.014). Conclusions: Valgus-producing intertrochanteric osteotomy with a smaller degree of correction than has been traditionally described leads to an excellent rate of radiographic union while preserving more of the native proximal femoral anatomy. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

593 Background: Cancer stem cells or stemness-high cancer cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin, a first-in-class cancer stemness inhibitor in clinical development, suppresses cancer stemness by targeting Stat3-driven gene transcription. Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapeutics and targeted agents. Methods: This study was performed to assess signs of anti-tumor activity of napabucasin in combination with FOLFIRI +/- Bev in CRC pts. Napabucasin was administered at 240 mg BID. FOLFIRI (5-FU 400 mg/m2 bolus with 2400 mg/m2, irinotecan 180 mg/m2, and leucovorin 400 mg/m2 infusion) +/- Bev 5 mg/kg was administered biweekly until disease progression or other discontinuation criterion. pSTAT3 status of archival tumor tissue was assayed by immunohistochemistry using the H-score with pSTAT3highdefined as ≥ 5% pSTAT3+ cancer cells and tumor stroma staining at ≥ 2+ intensity. Results: 63 CRC pts with an average of >2 prior therapy lines were enrolled. No pharmacokinetic interactions or dose-limiting toxicity was observed. Most common adverse events (AEs) included grade 1/2 diarrhea, nausea, vomiting and fatigue. 25 pts had grade 3 AEs, including diarrhea (14), fatigue (4), dehydration (2), electrolyte imbalance (4), nausea (1) and weight loss (1) resolved with dose reduction and supportive care. Among 63 pts enrolled who received RECIST evaluation, disease control (CR+PR+SD) was observed in 49 pts (86%) with an overall response (CR+PR) of 28% with 1 pt achieving CR. Clinical trial information: NCT02024607. Conclusions: This phase Ib/II study suggests napabucasin may sensitize chemorefractory CRC to FOLFIRI +/- Bev. Encouraging signs of synergistic activity between napabucasin and FOLFIRI was observed in CRC pts regardless of pSTAT3 status.[Table: see text]

On‐board magnetic resonance (MR) image guidance during radiation therapy offers the potential for more accurate treatment delivery. To utilize the real‐time image information, a crucial prerequisite is the ability to successfully segment and track regions of interest (ROI). The purpose of this work is to evaluate the performance of different segmentation algorithms using motion images (4 frames per second) acquired using a MR image‐guided radiotherapy (MR‐IGRT) system. Manual contours of the kidney, bladder, duodenum, and a liver tumor by an experienced radiation oncologist were used as the ground truth for performance evaluation. Besides the manual segmentation, images were automatically segmented using thresholding, fuzzy k‐means (FKM), k‐harmonic means (KHM), and reaction‐diffusion level set evolution (RD‐LSE) algorithms, as well as the tissue tracking algorithm provided by the ViewRay treatment planning and delivery system (VR‐TPDS). The performance of the five algorithms was evaluated quantitatively by comparing with the manual segmentation using the Dice coefficient and target registration error (TRE) measured as the distance between the centroid of the manual ROI and the centroid of the automatically segmented ROI. All methods were able to successfully segment the bladder and the kidney, but only FKM, KHM, and VR‐TPDS were able to segment the liver tumor and the duodenum. The performance of the thresholding, FKM, KHM, and RD‐LSE algorithms degraded as the local image contrast decreased, whereas the performance of the VP‐TPDS method was nearly independent of local image contrast due to the reference registration algorithm. For segmenting high‐contrast images (i.e., kidney), the thresholding method provided the best speed ( ) with a satisfying accuracy ( ). When the image contrast was low, the VR‐TPDS method had the best automatic contour. Results suggest an image quality determination procedure before segmentation and a combination of different methods for optimal segmentation with the on‐board MR‐IGRT system. PACS number(s): 87.57.nm, 87.57.N‐, 87.61.Tg

260 Background: The purpose of this study was to evaluate cell free nucleic acid based biomarkers for prognosis in mCRPC stage. Methods: Uniformly collected blood from mCRPC patients was processed for plasma which was used for exosomal RNA extraction. RNA sequencing was applied to examine microRNA (miRNA) profiles initially in a discovery cohort of 23 mCRPC patients. The sequences from fastq files were mapped to human miRBase (release 19) for known miRNA read counts. A software package (miRDeep2) was used for novel miRNA prediction. Cox regression was used for association of candidate miRNAs with overall survival (OS), defined as time from development of mCRPC to death or last follow up after adjusting for Gleason Score (GS) and time on androgen deprivation (AD) for hormone sensitive disease. miRNAs significantly associated with OS (FDR<0.05) were then validated in an independent cohort of 100 mCRPC subjects using univariate Cox regression. Results: RNA sequencing generated >10 million mappable reads per specimen in the discovery cohort. Among these reads ~50% were known miRNAs which included 1237 unique RNA sequences. Due to low abundance of most RNA transcripts, only miRNAs (n=250) with >/= 32 reads (on average) were analyzed. Four mRNAs (miR-1290, -1246, -375 and a predicted miRNA on chr. 12) were associated with OS(FDR<0.05). These were evaluated as prognotic markers in the independent cohort (N=100) using real time RT-PCR. Median time on AD for this cohort prior to progression to mCRPC was 35.7 (range: 3.5-136) months; median GS was 7; median follow up after mCRPC development was 12.5 (1-41) months at which time 28 patients had died. Elevated expression for miR-1290 and -375 were associated with shorter OS after adjusting for GS and AD time with a Hazard Ratio (HR) for miR-375 of 1.19 (CI: 1.006-1.18); (p=0.04) and a HR for miR1290 of 1.58 (CI:1.01-2.4); (p=0.04). A stronger association with shorter OS was observed for elevated expression of both miRs-HR of 2.02 (CI: 1.1-3.6) (p=0.01). Conclusions: Blood-based nucleic acid assays are easily accessible for biomarker development in mCRPC. Results from this study suggest specific exosomal miRs are of prognostic value in mCRPC and should be validated in larger cohorts.