Derek J. Erstad

Targeting the NF-κB Pathway in Cancer Therapy

Most NF-κB inhibitors target the IKK complex, IκB proteins, or NF-κB transcription factors. The most promising classes of inhibitors include antioxidants, antiinflammatory compounds, natural compounds, statins, proteasome inhibitors, IKKβ inhibitors, biologics, gene therapy, and RNA interference. Targeting NF-κB is limited by intrinsic pathway complexity, cross-talk with other pathways, a lack of biomarkers, poor drug specificity, drug resistance, and difficulty with drug delivery. Future NF-κB targeting will be improved through better understanding of the pathway, more specific inhibitors, and multimodality therapies.

Gli1 Induces G2/M Arrest and Apoptosis in Hippocampal but Not Tumor-Derived Neural Stem Cells

Sonic hedgehog (Shh) is necessary for sustaining the proliferation of neural stem cells (NSCs), yet little is known about its mechanisms. Whereas Gli1, Gli2, and Gli3, the primary mediators of Shh signaling, were all expressed in hippocampal neural progenitors, Shh treatment of NSCs induced only Gli1 expression. Acute depletion of Gli1 in postnatal NSCs by short‐hairpin RNA decreased proliferation, whereas germline deletion of Gli1 did not affect NSC proliferation, suggesting a difference in mechanisms of Gli1 compensation that may be developmentally dependent. To determine whether Gli1 was sufficient to enhance NSC proliferation, we overexpressed this mitogen and were surprised to find that Gli1 resulted in decreased proliferation, accumulation of NSCs in the G2/M phase of cell cycle, and apoptosis. In contrast, Gli1‐expressing lineage‐restricted neural precursors demonstrated a 4.5‐fold proliferation enhancement. Expression analyses of Gli1‐expressing NSCs identified significant induction of Gadd45a and decreased cyclin A2 and Stag1 mRNA, genes involved in the G2‐M transition and apoptosis. Furthermore, Gadd45a overexpression was sufficient to partially recapitulate the Gli1‐induced G2/M accumulation and cell death of NSCs. In contrast to normal stem cells, tumor‐derived stem cells had markedly higher basal Gli1 expression and did not undergo apoptosis with further elevation of Gli1. Our data suggest that Gli1‐induced apoptosis may serve as a protective mechanism against premature mitosis and may give insight into mechanisms by which nonmalignant stem cells restrain hyperproliferation in the context of potentially transforming mitogenic signals. Tumor‐derived stem cells apparently lack these mechanisms, which may contribute to their unrestrained proliferation and malignant potential.

Mutational Analysis of Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy that is associated with a poor prognosis. The pathogenesis of MCC is not well understood, and despite a recent plethora of mutational analyses, we have yet to find a set of signature mutations implicated in the majority of cases. Mutations, including TP53, Retinoblastoma and PIK3CA, have been documented in subsets of patients. Other mechanisms are also likely at play, including infection with the Merkel cell polyomavirus in a subset of patients, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, posttranslational modifications and microRNAs. In this review, we summarize what is known about MCC genetic mutations and chromosomal abnormalities, and their clinical significance. We also examine aberrant protein function and microRNA expression, and discuss the therapeutic and prognostic implications of these findings. Multiple clinical trials designed to selectively target overexpressed oncogenes in MCC are currently underway, though most are still in early phases. As we accumulate more molecular data on MCC, we will be better able to understand its pathogenic mechanisms, develop libraries of targeted therapies, and define molecular prognostic signatures to enhance our clinicopathologic knowledge.

The DABBEC Phenotyping System: towards a mechanistic understanding of CP/CPPS

There is an urgent need to elucidate the mechanistic basis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), as the current methods of symptom-based diagnosis and treatment have failed. Here, we propose a phenotyping system that bridges the gap between the symptom-based diagnosis and treatment of the present and the mechanistic approach of the future. Our phenotyping system uses the Chronic Prostatitis Collaborative Research Network (CPCRN)-recommended algorithm in combination with the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) as a basis for diagnosis, while incorporating novel domains for quantitative assessment and stratification of CP/CPPS patients. We believe this novel system will serve to help advance our understanding of the roles of the patients genome and proteome in the etiology of CP/CPPS. We predict that, as we begin to understand the mechanistic basis of CP/CPPS pathology and progression, we will develop specific treatments that will aim to cure the disease, rather than merely quell the symptoms.

Prognostic and Predictive Biomarkers in Colorectal Cancer: Implications for the Clinical Surgeon

Colorectal cancer is a heterogeneous disease with a wide range of long-term outcomes and responses to treatment. Recent advances in the genetic and molecular characterization of tumors has yielded a set of prognostic and predictive biomarkers that aid the identification of patients at higher risk for disease recurrence and progression, and in some cases indicate the likelihood of response to a specific treatment. Increasingly, these biomarkers have become integral to the treatment algorithm for managing patients with colorectal cancer. Prognostic and predictive factors in colorectal cancer can broadly be categorized into treatment impact, clinicopathologic factors, and molecular markers. This review will focus primarily on molecular markers, which are foundational to the paradigmatic shift toward personalized cancer therapy.

The autotaxin-lysophosphatidic acid pathway emerges as a therapeutic target to prevent liver cancer

ABSTRACT Using transcriptome meta-analysis, we recently identified the autotaxin (ATX)-lysophosphatidic acid (LPA) pathway as a regulator of hepatocellular carcinoma (HCC) risk in human cirrhosis patients. Pharmacological targeting of this pathway reduced fibrosis progression and HCC development in animals, identifying ATX-LPA signaling as a novel chemoprevention strategy for cirrhosis and HCC.

Hepatocellular carcinoma: early-stage management challenges

Hepatocellular carcinoma (HCC) is a major cause of cancer death and is increasing in incidence. This review focuses on HCC surveillance and treatment of early-stage disease, which are essential to improving outcomes. Multiple societies have published HCC surveillance guidelines, but screening efforts have been limited by noncompliance and overall lack of testing for patients with undiagnosed chronic liver disease. Treatment of early-stage HCC has become increasingly complex due to expanding therapeutic options and better outcomes with established treatments. Surgical indications for HCC have broadened with improved preoperative liver testing, neoadjuvant therapy, portal vein embolization, and perioperative care. Advances in post-procedural monitoring have improved efficacies of transarterial chemoembolization and radiofrequency ablation, and novel therapies involving delivery of radiochemicals are being studied in small trials. Finally, advances in liver transplantation have allowed for expanded indications beyond Milan criteria with non-inferior outcomes. More clinical trials evaluating new therapies and multimodal regimens are necessary to help clinicians design better treatment algorithms and improve outcomes.

Molecular signatures in hepatocellular carcinoma: A step toward rationally designed cancer therapy: Molecular Signatures in HCC

Molecular characterization of hepatocellular carcinoma (HCC) has greatly improved our understanding of disease pathogenesis. Mutational analysis, RNA and microRNA expression profiling, and epigenetic characterization have revealed common aberrations in oncogenes and tumor suppressors that correlate with disease biology and serve as a guide for the rational design of targeted therapies. These approaches have also led to the discovery of novel targets, including mutations in isocitrate dehydrogenase and chromatin remodeling enzymes. With the advent of immunotherapy, RNA expression profiling of the tumor microenvironment has identified a subset of HCC with high lymphocyte infiltration that may benefit from checkpoint inhibitor therapy. Molecular signatures thus capture the biology of a tumor, providing a supplement to current staging schema, which are based on tumor size and number, for more accurate prognostication of recurrence risk and survival. Molecular signatures may also be used to guide interventional therapy by defining those most suitable for transplantation or locoregional therapy rather than surgical resection. Finally, a multiomics approach involves the aggregation and analysis of multiple signatures for a more comprehensive characterization of pathogenic mechanisms. This broader approach attempts to address issues with signaling pathway cross‐talk and redundancy, which have greatly limited the potential value of targeted therapies to date. Cancer 2018.

Manganese-Based Contrast Agents for Magnetic Resonance Imaging of Liver Tumors: Structure Activity Relationships and Lead Candidate Evaluation

Gd-based MRI contrast agents (GBCAs) have come under intense regulatory scrutiny due to concerns of Gd retention and delayed toxicity. Three GBCAs comprising acyclic Gd chelates, the class of GBCA most prone to Gd release, are no longer marketed in Europe. Of particular concern are the acyclic chelates that remain available for liver scans, where there is an unmet diagnostic need and no replacement technology. To address this concern, we evaluated our previously reported Mn-based MRI contrast agent, Mn-PyC3A, and nine newly synthesized derivatives as liver specific MRI contrast agents. Within this focused library the transient liver uptake and rate of blood clearance are directly correlated with log P. The complex Mn-PyC3A-3-OBn emerged as the lead candidate due to a combination of high relaxivity, rapid blood clearance, and avid hepatocellular uptake. Mn-PyC3A-3-OBn rendered liver tumors conspicuously hypo-intense in a murine model and is wholly eliminated within 24 h of injection.

Molecular magnetic resonance imaging accurately measures the antifibrotic effect of EDP‐305, a novel farnesoid X receptor agonist

We examined a novel farnesoid X receptor agonist, EDP‐305, for its antifibrotic effect in bile duct ligation (BDL) and choline‐deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) models of hepatic injury. We used molecular magnetic resonance imaging with the type 1 collagen‐binding probe EP‐3533 and the oxidized collagen‐specific probe gadolinium hydrazide to noninvasively measure treatment response. BDL rats (n = 8 for each group) were treated with either low or high doses of EDP‐305 starting on day 4 after BDL and were imaged on day 18. CDAHFD mice (n = 8 for each group) were treated starting at 6 weeks after the diet and were imaged at 12 weeks. Liver tissue was subjected to pathologic and morphometric scoring of fibrosis, hydroxyproline quantitation, and determination of fibrogenic messenger RNA expression. High‐dose EDP‐305 (30 mg/kg) reduced liver fibrosis in both the BDL and CDAHFD models as measured by collagen proportional area, hydroxyproline analysis, and fibrogenic gene expression (all P < 0.05). Magnetic resonance signal intensity with both EP‐3533 in the BDL model and gadolinium hydrazide in the CDAHFD model was reduced with EDP‐305 30 mg/kg treatment (P < 0.01). Histologically, EDP‐305 30 mg/kg halted fibrosis progression in the CDAHFD model. Conclusion: EDP‐305 reduced fibrosis progression in rat BDL and mouse CDAHFD models. Molecular imaging of collagen and oxidized collagen is sensitive to changes in fibrosis and could be used to noninvasively measure treatment response in clinical trials. (Hepatology Communications 2018;2:821‐835)