Marianna B. Ruzinova

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Purpose: Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC. Experimental Design: We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells in vitro and in vivo. Results: p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Conclusions: Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. Clin Cancer Res; 23(7); 1748–59. ©2016 AACR.

High frequency of KRAS mutation in early onset colorectal adenocarcinoma: implications for pathogenesis.

While the incidence of sporadic early onset (defined here as ≤40 years of age) colorectal cancer is increasing, its molecular pathogenesis remains unclear. In particular, previous studies have suggested that the genetic initiating events in these patients may be distinct from those observed in older colorectal cancer patients. We aimed to study clinical, histopathological, and molecular features of early onset colorectal cancer. We identified 68 consecutive sporadic early onset colorectal cancer cases with available molecular data treated in our institution between 2007 and 2014. Consistent with previous reports, the majority of sporadic early onset colorectal cancer patients had left-sided tumors, which were predominantly of low histologic grade, but advanced clinical stage. A subset of tumors (<40%) contained mucinous or signet ring cell features. DNA mismatch repair pathway, commonly associated with Lynch syndrome, was abnormal only in a minor subset of cases. In contrast to the low prevalence (<30%) of KRAS mutations reported by previous studies, we found that a significantly higher proportion (54%) of early onset colorectal cancer cases harbored KRAS mutations, a finding that was independent of tumor stage. The high prevalence of KRAS mutation in early onset colorectal cancer suggests that it shares common genetic initiating events with colorectal cancer in older patients.

Perioperative Therapy for Surgically Resectable Pancreatic Adenocarcinoma

It is estimated that 10% to 20% of patients with pancreatic cancer present with resectable disease. Although surgery offers curative intent, the median survival after curative resection is less than 2 years. To improve clinical outcomes in this patient population, clinical studies have investigated the role of perioperative therapy, including neoadjuvant and adjuvant treatment in resectable pancreatic cancer. The role of adjuvant therapy has been well established by large randomized phase III studies, whereas benefit of the neoadjuvant approach remains inconclusive. Here, we review various treatment modalities and their clinical benefits in resectable pancreatic cancer.

Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.

Distinct clinical and magnetic resonance features of metastatic hepatocellular carcinoma treated with pembrolizumab: A case report of late response after pseudoprogression

There are few effective therapies for unresectable or metastatic hepatocellular carcinoma. Recent data have demonstrated efficacy of immune checkpoint blockade in this difficult to treat disease; however, clinical experience is limited. We report a case of hepatocellular carcinoma displaying pseudoprogression followed by a late response with novel magnetic resonance imaging features following treatment with the anti‐programmed cell death protein 1 agent pembrolizumab. (Hepatology Communications 2018;2:148–151)

Tumor-stroma IL-1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC.Significance: Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. Cancer Res; 78(7); 1700-12. ©2018 AACR.

Abstract 181: Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic cancer

Constitutive activation of the NF-κb transcription factor is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of pancreatic cancer. Understanding the molecular mechanisms that activate NF-κB will provide novel therapeutic opportunities to improve the dismal outcome of pancreatic cancer patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated in a majority of pancreatic cancer cell lines and patients samples, and are major drivers of NF-κB activity. Notably, we found that constitutive phosphorylation of IRAK4 is associated with poor patient prognosis. Suppression of IRAK1 and IRAK4 with small molecule inhibitor or RNA-interference in pancreatic cancer cells significantly reduces NF-κB activity, three-dimensional growth, invasiveness, production of inflammatory, and augment their sensitivity to chemotherapeutic agents in vitro. Notably, we showed that the NF-κB activity of pancreatic cancer cell with IRAK4 ablated using CRISPR technology can be restored with wild-type, but not kinase-dead IRAK4 mutant, supporting development of IRAK4 inhibitor as a novel therapeutic agent in pancreatic cancer. Silencing of IRAK1 or IRAK4, and more potently both, significantly abrogated the tumorigenic potential of human and murine pancreatic cancer cells as xenograft in mice. Lastly, we showed that IRAK1/4 inhibitor augments the therapeutic effect of gemcitabine in tumor-bearing mice by suppressing proliferation and increasing apoptosis of neoplastic cells, and reducing stromal fibrosis. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in pancreatic cancer. Citation Format: Daoxiang Zhang, Lin Li, Hongmei Jiang, Jinsheng Yu, Brett Knolhoff, Richard Head, Albert C. Lockhart, David G. DeNardo, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK1/4 kinase activation contributes to NF-kB activity and chemoresistance in pancreatic 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 181.