Citations

Abstract Purpose: Growing mechanistic and epidemiologic evidence suggests that both metformin and statins have anti-cancer effects and are associated with reduced pancreatic cancer mortality. However, the joint effect of combination statin/metformin on pancreatic cancer mortality is unknown. By applying a robust analytic approach, we aim to examine the association between metformin and/or statin use and overall survival in a large cohort of patients with primary pancreatic adenocarcinoma (PDAC). Patients and Methods: 12,572 elderly patients with primary PDAC diagnosed between 2008 and 2012 were identified by using the Surveillance, Epidemiology, and End Results (SEER), and the detailed information on metformin and statin use was extracted from Medicare Part D. A Cox proportional hazard model with time-varying covariate adjusted for the propensity score was applied to assess the association of metformin and /or statin use with overall survival while controlling for potential confounders. Results: Of total 12,572 PDAC patients (median age = 76 years), 11,526 (91.77%) patients died before the study ended with a median follow-up of 3.8 months (interquartile range: 1.4-10.1). By the time-varying covariate analysis, statin use was significantly associated with an improved overall survival [Hazard ratio (HR), 0.938; 95% confidence interval (CI), 0.898 to 0.979], and more pronounced in post-diagnosis statin users (HR, 0.693; 95% CI, 0.555 to 0.864). However, metformin use was not significantly associated with overall survival (HR, 1.011; 95% CI, 0.939 to 1.091), neither in pre-diagnosis users (HR, 1.015; 95% CI, 0.970 to 1.061) nor in post-diagnosis users (HR, 0.990; 95% CI, 0.866 to 1.131). Additionally, no superior beneficial effect was observed for dual users (HR, 0.998; 95% CI, 0.947 to 1.053). Conclusions: Exposures to statin, not metformin, was significantly associated with reduced overall mortality of PDAC, indicating potential benefits of statin use on improving survival among PDAC patients. Further prospective validation is required to confirm these findings. Citation Format: Jian-Yu E, Shou-En Lu, Yong Lin, Judith M. Graber, David Rotter, Lanjing Zhang, Gloria M. Petersen, Kitaw Demissie, Grace Lu-Yao, Xiang-Lin Tan. Effects of concomitant metformin and statins on overall survival of pancreatic cancer patients: results from SEER-Medicare data analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2017-3288

Abstract Background: Published evidence indicates that individual use of metformin and statin is associated with reduced cancer mortality. However, their differential and joint effects on pancreatic cancer survival are inconclusive. Methods: We identified a large population-based cohort of 12,572 patients ages 65 years or older with primary pancreatic ductal adenocarcinoma (PDAC) diagnosed between 2008 and 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. Cox proportional hazards models with time-varying covariates adjusted for propensity scores were used to assess the association while controlling for potential confounders. Results: Of 12,572 PDAC patients, 950 (7.56%) had used metformin alone, 4,506 (35.84%) had used statin alone, and 2,445 (19.45%) were dual users. Statin use was significantly associated with improved overall survival [HR, 0.94; 95% confidence interval (CI), 0.90–0.98], and survival was more pronounced in postdiagnosis statin users (HR, 0.69; 95% CI, 0.56–0.86). Metformin use was not significantly associated with overall survival (HR, 1.01; 95% CI, 0.94–1.09). No beneficial effect was observed for dual users (HR, 1.00; 95% CI, 0.95–1.05). Conclusions: Our findings suggest potential benefits of statins on improving survival among elderly PDAC patients; further prospective studies are warranted to corroborate the putative benefit of statin therapy in pancreatic cancer. Impact: Although more studies are needed to confirm our findings, our data add to the body of evidence on potential anticancer effects of statins. Cancer Epidemiol Biomarkers Prev; 26(8); 1225–32. ©2017 AACR.

LBA4 Background: Daratumumab (D), a human anti-CD38 IgGκ mAb, induces deep and durable responses with a favorable safety profile in RRMM pts. We report a pre-specified interim analysis of the first randomized controlled study of D (CASTOR; NCT02136134). Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of bortezomib (V)/dexamethasone (d) (V: 1.3 mg/m2sc on Days 1, 4, 8, 11; d: 20 mg po on Days 1, 2, 4, 5, 8, 9, 11, 12) ± D (16 mg/kg iv qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Primary endpoint was PFS. Results: 498 pts (DVd, 251; Vd, 247) were randomized. Baseline demographics and disease characteristics were well balanced. Pts received a median of 2 prior lines of therapy (range 1-10). 66% received prior V; 76% received prior IMiD; 48% received prior PI and IMiD; 33% were IMiD-refractory; 32% were refractory to last line of prior therapy. With median follow-up of 7.4 months, D significantly improved median PFS (61% reduction in risk of progression) and TTP for DVd vs Vd (Table). D significantly increased ORR (83% vs 63%, P <0.0001), and doubled rates of ≥VGPR (59% vs 29%, P <0.0001), and ≥CR (19% vs 9%, P= 0.0012) for DVd vs Vd, respectively; median duration of response was NR vs 7.9 months, respectively. Most common (>25%) AEs (DVd/Vd) were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhea (32%/22%) and anemia (26%/31%). Most common grade 3/4 AEs (>10%) were thrombocytopenia (45%/33%), anemia (14%/16%), neutropenia (13%/4%). 7%/9% of pts discontinued due to a TEAE. D-associated infusion-related reactions (45% of pts) mostly occurred during the first infusion; most were grade 1/2 (grade 3/4, 9%/0%). Conclusions: D significantly improved PFS, TTP, and ORR in combination with Vd vs Vd alone. DVd doubled both VGPR and sCR/CR rates vs Vd alone. Safety of DVd is consistent with the known safety profile of D and Vd. The addition of D to Vd should be considered a new standard of care for RRMM pts currently receiving Vd alone. Clinical trial information: NCT02136134. [Table: see text]

ABSTRACT In addition to humans, only certain nonhuman primates are naturally susceptible to measles virus (MeV) infection. Disease severity is species dependent, ranging from mild to moderate for macaques to severe and even lethal for certain New World monkey species. To investigate if squirrel monkeys ( Saimiri sciureus ), which are reported to develop a course of disease similar to humans, may be better suited than macaques for the identification of virulence determinants or the evaluation of therapeutics, we infected them with a green fluorescent protein-expressing MeV. Compared to cynomolgus macaques ( Macaca fascicularis ) infected with the same virus, the squirrel monkeys developed more-severe immunosuppression, higher viral load, and a broader range of clinical signs typical for measles. In contrast, infection with an MeV unable to interact with the epithelial receptor nectin-4, while causing immunosuppression, resulted in only a mild and transient rash and a short-lived elevation of the body temperature. Similar titers of the wild-type and nectin-4-blind MeV were detected in peripheral blood mononuclear cells and lymph node homogenates, but only the wild-type virus was found in tracheal lavage fluids and urine. Thus, our study demonstrates the importance of MeV interactions with nectin-4 for clinical disease in the new and better-performing S. sciureus model of measles pathogenesis. IMPORTANCE The characterization of mechanisms underlying measles virus clinical disease has been hampered by the lack of an animal model that reproduces the course of disease seen in human patients. Here, we report that infection of squirrel monkeys ( Saimiri sciureus ) fulfills these requirements. Comparative infection with wild-type and epithelial cell receptor-blind viruses demonstrated the importance of epithelial cell infection for clinical disease, highlighting the spread to epithelia as an attractive target for therapeutic strategies.

AbstractControl of knee motion in small animal models is necessary to study the effect of mechanical load on the healing process. This can be especially challenging in mice, which are being increasingly used for various orthopedic reconstruction models. We explored the feasibility of botulinum toxin (Botox; Allergan, Dublin, Ireland) paralysis and a newly designed external fixator to restrict motion of the knee in mice undergoing anterior cruciate ligament (ACL) reconstruction. Nineteen C57BL/6 mice were allocated to two groups: (1) Botox group (n = 9) and (2) external fixator group (n = 10). Mice in Botox group received two different doses of Botox: 0.25 unit (n = 3) and 0.5 unit (n = 6). Injection was performed 72 hours prior to ACL reconstruction into the quadriceps, hamstring, and calf muscles of the right hind leg. Mice in external fixator group received an external fixator following ACL reconstruction. Mice were monitored for survival, tolerance, and achievement of complete knee immobilization. All mice were meant for sacrifice on day 14 postoperatively. No perceptible change in gait was observed with 0.25 unit of Botox. All mice that received 0.5 unit of Botox had complete hind limb paralysis documented by footprint analysis 2 days after injection but failed to tolerate anesthesia and were euthanized 24 hours after operation due to their critical condition. In contrast, the external fixator was well tolerated and effectively immobilized the limb. There was a single occurrence of intraoperative technical error in the external fixator group that led to euthanasia. No mechanical failure or complication was observed. Botox paralysis was not a viable option for postoperative restriction of motion and joint loading in mice. However, external fixation was an effective method for complete knee immobilization and can be used in murine models requiring postoperative control of knee loading. This study introduces a robust research tool to allow control of postoperative joint loading in animal models such as ACL reconstruction, permitting study of the effects of mechanical load on the biologic aspects of tendon-to-bone healing.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per‐allele relative risks (with the non‐breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two‐sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome‐wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Abstract Introduction: Liver metastasis of pancreatic or colorectal tumors is a major cause of cancer-related death worldwide. When cancer cells reach the liver parenchyma and make a direct contact with the surrounding extracellular matrix (ECM), β1-integrin-FAK signaling is activated allowing the cells attach, migration, and proliferate. Thus, the β1-integrin-FAK signaling axis is key for cancer cells to colonize the liver. However, mechanisms governing β1-integrin activation and how this pathway promotes liver metastasis remain incompletely understood. Aim: We sought to test the hypothesis that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, regulates the β1-integrin-FAK signaling axis, thereby, promoting liver metastasis of GI cancer. Methods: We employed lentiviruses encoding different VASP shRNAs to knockdown (KD) VASP in human GI cancer cells. We used a Matrigel-based 3-dimensional (3D) cell culture model and intrasplenic tumor injection mouse model to assess the role of VASP for cancer cells in vitro and in vivo. Immunofluorescence (IF) was used to study localization of VASP and active β1-integrin (using Huts-4 antibody), and Western blot analysis (WB) was used to quantitate protein levels of active β1-integrin and YAP1/TAZ. Additionally, we performed VASP immunohistochemistry (IHC) to analyze VASP immunoreactivity in 116 colorectal or pancreatic adenocarcinomas of patients. Results: In the Matrigel-based 3D-culture model, a single cancer cell gave arise to a 3D-cancer spheroid after being cultured for 6-8 days. Using KM12L4, HCT116, or HT29 colorectal cancer cells, and L3.6 or MIA PaCa-1 pancreatic cancer cells, we found that VASP KD reduced the sizes of the 3D-cancer spheroids grown on Matrigel (P&lt;0.05 by t-test for each cell line). IF and WB show that VASP KD reduced levels of Huts-4 (active β1-integrin) in KM12L4, HCT116 colorectal cancer cells and in L3.6, MIA PaCa-1 pancreatic cancer cells. VASP KD also reduced the protein levels of P-FAK and YAP1/TAZ in the 4 cell lines tested. Additionally, YAP1/TAZ protein levels were reduced by PF-228, a FAK inhibitor that blocks the β1-integrin-FAK signaling. In the intrasplenic tumor implanation mouse model, VASP KD suppressed liver metastasis of GI cancer as well as reduced Huts-4 and YAP1 signals of their liver metastases in mice (P&lt;0.05 by t-test). IHC of patient's samples reveals that VASP protein levels were upregulated in cancer cells in 81% of colorectal tumors (51/63) and pancreatic tumors (43/53), with higher VASP levels being associated with liver metastasis of colorectal cancer (P&lt;0.01 by Fisher exact test). Conclusions: VASP promotes ECM-mediated β1-integrin-FAK-YAP1/TAZ signaling axis of GI cancer. We propose that VASP and the β1-integrin-FAK-YAP1/TAZ signaling axis represent potential new therapeutic targets for liver metastasis of pancreatic or colorectal cancer. Citation Format: Xiaoyu Xiang, Jinhua Piao, Selvaraj Muthusamy, Lei Wang, Yibin Deng, Shengbing Huang, Raul Urrutia, Jinping Lai, Ningling Kang. Vasodilator-stimulated phosphoprotein promotes β1-integrin-FAK-YAP1/TAZ signaling axis that is required for liver metastasis of GI cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1633.