Exploration of a Class of Aryl Imidazolyl Ureas As Potent Acid Ceramidase Inhibitors for the Treatment of Fibrotic Diseases.

Acid ceramidase (aCDase) is an essential enzyme in sphingolipid metabolism and has been linked to various pathological conditions, including cancer and fibrosis. In our previous studies, we observed that inhibiting aCDase with B13 () helped alleviate liver fibrosis in mouse models and in ex vivo human precision-cut liver slices. However, B13 () showed limited potency, prompting us to search for more effective aCDase inhibitors.

The immortality mechanism of TERT promoter mutant cancers is self-reinforcing and reversible.

Activating mutations in the telomerase reverse transcriptase (TERT) promoter are prevalent in cancer and enable limitless cell division characteristic of immortal cells. Solving the immortality mechanism represents a major step toward selective reversal in cancer cells. TERT promoter (TERTp) mutations create a de novo E26 transformation-specific (ETS) transcription factor binding motif.

Neratinib Alone or in Combination with Immune Checkpoint Inhibitors with or without Mammalian Target of Rapamycin Inhibitors in Patients with Fibrolamellar Carcinoma.

Introduction: Fibrolamellar carcinoma (FLC) displays upregulation of several oncogenes, including , and multiple immune-suppressive mechanisms. We investigated the efficacy and safety of the pan-HER tyrosine kinase inhibitor neratinib as monotherapy (SUMMIT phase 2 basket study) or with immune checkpoint and/or mammalian target of rapamycin (mTOR) inhibitors (compassionate-use program) in patients with FLC.

Methods: Patients received neratinib 240 mg/day orally in SUMMIT, or as doublet or triplet combinations with pembrolizumab 2 mg/kg intravenously every 3 weeks, nivolumab 240 mg intravenously every 2 weeks, everolimus 7.

HBV Remodels PP2A Complexes to Rewire Kinase Signaling in Hepatocellular Carcinoma.

Hepatitis B virus (HBV) infections promote liver cancer initiation by inducing inflammation and cellular stress. Despite a primarily indirect effect on oncogenesis, HBV is associated with a recurrent genomic phenotype in hepatocellular carcinoma (HCC), suggesting that it impacts the biology of established HCC. Characterization of the interaction of HBV with host proteins and the mechanistic contributions of HBV to HCC initiation and maintenance could provide insights into HCC biology and uncover therapeutic vulnerabilities.

Changes in alpha-fetoprotein across the systemic therapy continuum in advanced hepatocellular carcinoma-a real-world, multicenter study.

Background: Early changes in alpha-fetoprotein (AFP) are a promising surrogate endpoint for systemic treatment outcomes in hepatocellular carcinoma (HCC).

Objectives: We sought to investigate the utility of AFP response across first-line sorafenib (1L SOR) and later-line checkpoint inhibitor (CPI) therapies.

Design: We conducted a multicenter, retrospective cohort study of patients with advanced HCC who received 1L SOR and any subsequent CPI.

Protein kinase A and local signaling in cancer.

Protein kinase A (PKA) is a basophilic kinase implicated in the modulation of many cell-signaling and physiological processes. PKA also contributes to cancer-relevant events such as growth factor action, cell cycle control, cell migration and tumor metabolism. Germline and somatic mutations in PKA, gene amplifications, and chromosome rearrangements that encode kinase fusions, are linked to a growing number of malignant neoplasms.

Cataracts Associated With Fibroblast Growth Factor Receptor Inhibitors for Cholangiocarcinoma.

Importance: Since fibroblast growth factor receptor inhibitors (FGFRi) are used for treatment of intrahepatic cholangiocarcinoma (iCCA), understanding potential complications following longer-term use in clinical practice settings is warranted. This study describes cataract formation or progression as a complication of FGFRi use for the treatment of iCCA, even after treatment discontinuation.

Objective: To describe cases of cataract formation or worsening in patients with iCCA treated with FGFRi and to characterize the ophthalmologic features, risk factors, and outcomes for FGFRi-associated cataracts.

DNAJB1-PRKACA Fusion Drives Fibrolamellar Liver Cancer through Impaired SIK Signaling and CRTC2/p300-Mediated Transcriptional Reprogramming.

This work combines functional studies in model systems and examination of human tumor specimens to define a central oncogenic pathway driven by DNAJB1-PRKACA fusions in FLC. DNAJB1-PRKACA-mediated inactivation of the SIK stimulates CRTC2-p300-mediated transcription to drive tumor growth. The findings illuminate pathogenic mechanisms and inform therapeutic development.

Emerging Therapies for the Management of Human Epidermal Growth Factor Receptor 2-/-Altered Advanced Biliary Tract Cancers.

Journal Journal of Clinical Oncology

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis.

Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline Update.

Purpose: To update an evidence-based guideline to assist in clinical decision-making for patients with advanced hepatocellular carcinoma (HCC).

Methods: ASCO convened an Expert Panel to update the 2020 guideline on systemic therapy for HCC. The panel updated the systematic review to include randomized controlled trials (RCTs) published through October 2023 and updated recommendations.

New Opportunities to Individualize Frontline Therapy in Advanced Stages of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally and is rising in incidence. Until recently, treatment options for patients with advanced stages of HCC have been limited to antiangiogenic therapies with modest improvements in overall survival. The emerging role of immunotherapy with immune checkpoint inhibitors (ICI) in oncology has led to a rapid expansion in treatment options and improvements in outcomes for patients with advanced stages of HCC.

Defining incidence and complications of fibrolamellar liver cancer through tiered computational analysis of clinical data.

The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is a rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of the electronic medical record and national payer data and found that FLC incidence is likely five to eight times higher than previous estimates.

Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms.

Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer.

Methods to assess small molecule allosteric modulators of the STRAD pseudokinase.

With the increased appreciation of the biological relevance of pseudokinase (PSK) allostery, the broadening of small molecule strategies to target PSK function is of particular importance. We and others have pursued the development of small molecule allosteric modulators of the STRAD pseudokinase by targeting its ATP binding pocket. The purpose of this effort is to modulate the function of the LKB1 tumor suppressor kinase, which exists in a trimer with the STRAD PSK and the adaptor protein MO25.

EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.

Unlabelled: FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies.

Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1.

The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling.

Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling.

Background: The mammalian target of rapamycin () pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose.

A protein interaction landscape of breast cancer.

Cancers have been associated with a diverse array of genomic alterations. To help mechanistically understand such alterations in breast-invasive carcinoma, we applied affinity purification–mass spectrometry to delineate comprehensive biophysical interaction networks for 40 frequently altered breast cancer (BC) proteins, with and without relevant mutations, across three human breast cell lines. These networks identify cancer-specific protein-protein interactions (PPIs), interconnected and enriched for common and rare cancer mutations, that are substantially rewired by the introduction of key BC mutations.

Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma.

Hepatitis B virus (HBV) infection contributes to hepatocellular carcinoma (HCC) initiation and is associated with worse outcomes. Many prior studies of HBV-related HCC have not accounted for potential heterogeneity among HBV-related tumors by assessing whether HBV activity is present in tumor tissue. Here, we measured tumor HBV RNA, a proxy for viral activity, and investigated the association between HBV RNA status and several clinicogenomic characteristics.

Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline.

Purpose: To develop an evidence-based clinical practice guideline to assist in clinical decision making for patients with advanced hepatocellular carcinoma (HCC).

Methods: ASCO convened an Expert Panel to conduct a systematic review of published phase III randomized controlled trials (2007-2020) on systemic therapy for advanced HCC and provide recommended care options for this patient population.

Results: Nine phase III randomized controlled trials met the inclusion criteria.