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Toll-like receptors (TLRs) in the innate immune system recognize specific pathogen-associated molecular patterns derived from microbes. Synthetic small molecule TLR7 agonists have been extensively evaluated as topical agents for antiviral and anticancer therapy, and as adjuvants for vaccine. However, safe and reproducible administration of synthetic TLR7 ligands has been difficult to achieve due to undesirable pharmacokinetics and unacceptable side effects. Here, we conjugated a versatile low molecular weight TLR7 ligand to various polysaccharides in order to improve its water solubility, enhance its potency, and maintain low toxicity. The synthetic TLR7 ligand, 2-methoxyethoxy-8-oxo-9-(4-carboxy benzyl)adenine, designated 1V209, was stably conjugated to primary amine functionalized Ficoll or dextran using benzoic acid functional groups. The conjugation ratios using specified equivalents of TLR7 ligand were dose responsive and reproducible. The zeta potential value of the polysaccharides was decreased in inverse proportion to the ratio of conjugated TLR7 ligand. These conjugates were highly water-soluble, stable for at least 6 months at room temperature in aqueous solution, and easy to lyophilize and reconstitute without altering potency. In vitro studies with murine mononuclear leukocytes showed that the TLR7 agonist conjugated to polysaccharides had 10- to 1000-fold higher potencies than the unconjugated TLR7 ligand. In vivo pharmacodynamics studies after injection indicate that the conjugates induced systemic cytokine production. When the conjugates were used as vaccine adjuvants, they enhanced antigen specific humoral and cellular immune responses to a much greater extent than did unconjugated TLR7 ligands. These results indicated that small molecule TLR7 ligands conjugated to polysaccharides have improved immunostimulatory potency and pharmacodynamics. Polysaccharides can be conjugated to a variety of molecules such as antigens, peptides, and TLR ligands. Therefore, such conjugates could represent a versatile platform for the development of vaccines against cancer and infectious diseases.

We have found that ERBB4 activates sterol regulatory element binding protein-2 (SREBP-2) to enhance expression of genes essential for cholesterol metabolism including mevalonate pathway enzymes and the low-density lipoprotein receptor (LDLR). ERBB4 is unusual among receptor kinases in undergoing ligand-induced proteolytic cleavage to release a soluble intracellular domain that enters the nucleus and modifies transcription. Expression of the ERBB4 intracellular domain or activation of ERBB4 with the ligand Neuregulin 1 (NRG1) in mammary epithelial cells induced expression of SREBP target genes involved in cholesterol biosynthesis including HMGCR, HMGCS1, and LDLR beyond amounts induced through lipoprotein depletion. ERBB4 increased expression of cholesterogenic genes by enhancing abundance of the mature form of SREBP-2. NRG1 activated SREBP-2 through ERBB family kinases and PI3K, but independent from AKT or mTORC1 activity. NRG1 increased cholesterol metabolism by 1) increasing de novo biosynthesis through the mevalonate pathway, and 2) enhancing LDL binding and uptake through the LDLR. As all EGFR family receptors can appropriate ERBB4 signaling by cross-activating ERBB4, these data show that the ERBBs are linked to SREBP-regulated cholesterol metabolism, with potential impact on dyslipidemia and cancer.

Introduction: A novel CD74-NRG2a fusion has recently been identified in NSCLC. We surveyed a large tumor database comprehensively profiled by whole transcriptome sequencing to investigate the incidence and distribution of NRG2 fusions among various solid tumors. Methods: Tumor samples submitted for clinical molecular profiling at Caris Life Sciences (Phoenix, AZ) that underwent whole transcriptome sequencing (NovaSeq [Illumina, San Diego, CA]) were retrospectively analyzed for NRG2 fusion events. All NRG2 fusions with sufficient reads (> three junctional reads spanning ! seven nucleotides) were identified for manual review, characterization of fusion class, intact functional domains, EGF-like domain isoforms, breakpoints, frame retention, and co-occurring alterations by next-generation sequencing (NextSeq [Illumina, San Diego, CA], 592 genes).Results: Seven inframe functional (containing the intact EGF-like domain) NRG2a fusions were identified, namely, the following: (1) NSCLC (two of 9600, 0.

Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC). Materials and Methods: Odds ratios (OR) and hazard ratios (HR) of TE were calculated from meta-analysis and time-to-event analysis respectively for either ALK+ or ROS1+ NSCLC patients. Results: We identified eight studies (766 ALK+, 143 ROS1+, 2314 non-ALK+ and non-ROS1+ NSCLC patients) for the meta-analysis. For ALK+ NSCLC, the pooled OR was 2.00 (95% CI: 1.60-2.50) for total TE (TTE) by random-effects model, 2.10 (95% CI: 1.70-2.60) for venous thromboembolism (VTE), and 1.24 (95% CI: 0.80-1.91) for arterial thromboembolism (ATE). For ROS1+ NSCLC, the pooled OR was 3.08 (95% CI: 1.95-4.86) for TTE, and 3.15 (95% CI: 1.83-5.43) for VTE. Six studies (739 ALK+, 137 ROS1+, 561 EGFR+, 714 "wildtype" NSCLC patients) were included in the time-to-event analysis. The TTE incidence rate was 17.4 (95% CI: 15.3-19.5) per 100 pateint-years for ALK+ NSCLC, and 32.1 (95% CI: 24.6-39.6) per 100 patient-years for ROS1+ NSCLC with a 50 % cumulative incidence rate at year 3 of diagnosis. HR for TTE was 2.35 (95% CI: 1.90-2.92, p < 0.001) and 3.23 (95% CI: 2.40-4.34, p < 0.001) for ALK+ and ROS1+ NSCLC, respectively. Comparing ROS1+ NSCLC to ALK+ NSCLC, HR for TTE was 1.37 (95% CI: 1.05-1.79, p = 0.020). Conclusions: ALK+ and ROS1+ NSCLC patients had an increased risk of TE. ROS1+ NSCLC had further increased risk of TE over ALK+ NSCLC.

The EGFR exon 20 insertion (EGFRex20ins) mutations are the third most common EGFR mutations seen in non-small cell lung cancer (NSCLC). More than 50 variants of EGFRex20ins mutations have been identified with A767_V769dupASV being the most common variant across multiple surveys. Treatment with currently available EGFR tyrosine kinase inhibitors (TKIs) including osimertinib is generally ineffective. Amivantamab (JNJ-372), a bispecific monoclonal antibody against EGFR and MET, has recently been approved by the US FDA for patients with advanced or metastatic NSCLC harboring EGFRex20ins mutations after disease progression on platinum-based chemotherapy. Among all the TKIs in clinical development, mobocertinib (TAK-788) has been granted priority review by the FDA for the same indication as amivantamab. Here, we provide a concise review on mobocertinib, with a focus on its chemical structure, preclinical data, and phase 1/2 trial results. Future directions will likely focus on combination approach such as TKI plus chemotherapy in the first-line setting, designing drugs with CNS activity, and exploring disease characteristics of various EGFRex20ins mutation variants and how they may affect treatment response.