Abstract Acquired drug resistance is a long-standing problem of cancer therapeutics, for example chemoresistance to temozolomide occurs in >90% of recurrent gliomas. The issue has become even more vexing with the development of highly selective targeted agents; e.g. agents targeting the epidermal and hepatocyte growth factor (EGF and HGF, respectively) pathways; resistance to gefitinib and erlotinib has already been frequently demonstrated in lung adenocarcinomas. Thus, anticipating acquired resistance and understanding its basis may help us develop clinical strategies to prevent or circumvent its occurrence. HGF, through its receptor tyrosine kinase Met, regulates mitogenesis, motogenesis, and morphogenesis in a range of cellular targets during development and homeostasis. HGF/Met signaling also contributes to oncogenesis and tumor progression in many prevalent human malignancies, including glioblastoma. Rilotumumab (AMG102) is a fully human neutralizing monoclonal antibody against HGF tested in multiple Phase 2 clinical trials, including mono therapy in renal cell carcinoma and Glioblastoma, as well as combination trials in gastric, colorectal and small cell lung cancers and castrate resistant prostate cancer. To generate a cellular model of acquired resistance to rilotumumab, the HGF/Met dependent human glioblastoma-derived cell line U87-MG, was grown in continuous exposure to 600 nM rilotumumab for 120 days. Growth rate, HGF secretion, Met content and Met activation state were 10-fold, 10,000-fold, 10-fold and 80-fold higher than the parental cell values, respectively. The HGF and MET coding sequences and the HGF promoter DATE region, where truncation reportedly increases HGF expression level, were found to have normal sequence and length in both parental and resistant cell lines. Quantitative PCR studies to determine mRNA levels of all HGF isoforms revealed a dramatic increase in full-length HGF transcript. CGH array studies indicated amplification within both HGF and MET genes. Xenograft studies confirmed that tumor growth was resistant to rilotumumab, however the resistant cell line and tumors remained sensitive to a highly selective Met tyrosine kinase inhibitor suggesting that resistance was achieved via increased HGF/Met signaling rather than mutation or activation of alternate pathways. Microarray expression analysis demonstrated transcript profiles that were consistent with HGF/Met pathway activation. Thus the molecular basis of acquired resistance in this model differs from those prevalent in: [1] lung cancers treated with EGFR inhibitors and medulloblastomas treated with hedgehog inhibitors, where nearly all cases acquire secondary mutations in the targeted kinase; [2] breast cancers treated with HER2 inhibitors, where PTEN loss, p27 downregulation, and activation of other receptors are primary causes; or [3] malignant melanoma treated with BRAF inhibitors, where increased signaling by ARAF, CRAF, IGFR1, PDGFR, and other sources lead to PI3K- and/or MEK-mediated reactivation of the MAPK pathway. In addition to the importance of HGF/Met pathway activity in selecting glioblastoma patients for HGF-targeted therapeutics, our results suggest that monitoring Met pathway activity could provide early indications of acquired resistance to these agents, and that Met kinase inhibitors may still be efficacious when resistance occurs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A204.
<p>Figure S1. Kinase interaction map for AMG 337; Figure S2. In a large unbiased cancer cell line viability screen only MET-amplified cell lines were sensitive to treatment with an analogue of AMG 337 (Compound 5); Figure S3: AMG 337 inhibits the phosphorylation of MET and but not its downstream effectors in MET-amplified, KRAS mutant NSCLC cell line NCI-H1573; Figure S4. Cell lines harboring MET FISH scores >3 exhibited sensitivity to AMG 337. MET FISH analysis was performed on a subset of cancer cell lines exhibiting elevated MET gene copy number; Figure S5. Selective inhibition of MET exhibits partial effects on the viability of U-87 MG glioblastoma cells harboring an HGF/MET autocrine loop; Figure S6. Increases in MET gene number correlate with high levels of total MET protein; Figure S7. AMG 337 inhibits Gab-1 phosphorylation in a concentration dependent manner in the TPR-MET mouse tumor model.</p>
This brief report describes the effect of an automatic therapeutic interchange program on patients' discharge medications. Pharmacists at a medical center were authorized to convert various nonformulary medications to formulary equivalents. To determine which medications were prescribed to the patients upon hospital discharge, automatic interchanges during June 2001 to September 2001 were identified. Of those identified, 94 met study inclusion criteria. Complete information was obtained for 46 patients. Inpatient and outpatient pharmacy records were reviewed retrospectively for a 3-month period postdischarge. In the majority (67.4%) of cases, the patient's preadmission medication was continued on an outpatient basis. In 17.4% of the cases, the therapeutic interchange medication was continued on an outpatient basis. In 15.3% of the cases, patients were prescribed medications that were neither preadmission nor the interchanged medications. These results demonstrate that an automatic interchange program has the potential to influence outpatient therapy.
We show that both the lipopolysaccharide (LPS)-induced activation of NF-kappa DNA binding and kappa gene expression are blocked by treating murine pre-B lymphocyte 70Z/3 cells with 5'-methylthioadenosine (MTA), an inhibitor of several S-adenosylmethionine-dependent methylation reactions. We further show that the LPS-induced incorporation of radioactivity from [methyl-3H]methionine into methyl ester-like linkages on a group of membrane polypeptides is also inhibited by MTA treatment, suggesting the involvement of protein methylation reactions in the LPS signal transduction pathway. We also find that NF-kappa B and kappa gene activation in LPS-treated 70Z/3 cells is blocked by mevinolin, an inhibitor that prevents protein isoprenylation. Interestingly, mevinolin-treated cells also exhibited a marked reduction in the methylation of membrane proteins. Neither MTA nor mevinolin significantly inhibited NF-kappa B activation by phorbol myristate acetate, suggesting that these agents act early in signal transduction. These results provide the first evidence that carboxyl methylated and/or isoprenylated proteins play an essential role in the LPS-signaling pathway.
8014 Background: Elranatamab (PF-06863135) is a bispecific molecule that activates and redirects the T-cell mediated immune response against multiple myeloma (MM), a plasma cell dyscrasia characterized by expression of B-cell maturation antigen (BCMA). MagnetisMM-1 (NCT03269136), the ongoing Phase 1 first-in-human study for elranatamab, was designed to characterize safety, pharmacokinetics (PK), pharmacodynamics, and efficacy for patients (pts) with relapsed or refractory MM. Methods: Elranatamab was given subcutaneously (SC) at doses from 80 to 1000µg/kg either weekly or every 2 weeks (Q2W). Treatment-emergent adverse events (TEAEs) were graded by Common Terminology Criteria for Adverse Events (v4.03) and cytokine release syndrome (CRS) by American Society for Transplantation and Cellular Therapy criteria. PK, cytokine and soluble BCMA profiling, and lymphocyte subset analyses were performed. Response was assessed by International Myeloma Working Group (IMWG) criteria. Minimal residual disease (MRD) was assessed by next generation sequencing at a sensitivity of 1×10 -5 in accordance with IMWG criteria. Results: A total of 55 pts received single-agent elranatamab SC at a dose ≥215μg/kg as of 1-Nov-2021. Median age was 64 (range 42-80) years, and 27% of pts were Black/African American or Asian. Median number of prior regimens was 6 (range 2-15), 91% were triple-class refractory, 56% had prior stem cell transplantation, 27% had high cytogenetic risk, and 22% received prior BCMA-targeted therapy. The most common TEAEs regardless of causality included CRS, neutropenia, anemia, injection site reaction, and lymphopenia. With pre-medication and a single priming dose (600µg/kg or 44mg), the overall incidence of CRS at the recommended dose (1000µg/kg or 76mg) was 67% and limited to Grade 1 (33%) or Grade 2 (33%), with no events Grade 3 or higher. Exposure was dose dependent and Q2W dosing achieved exposure associated with anti-myeloma efficacy. Cytokine increases occurred with the first dose and were reduced by pre-medication. Soluble BCMA decreased with disease response, elranatamab therapy was associated with increased peripheral T cell proliferation, and median time to response was 36 days (range 7-73). With a median follow-up of 8.1 months (range 0.3-21) and including only IMWG confirmed responses, 31% of pts achieved complete response or better and the overall response rate was 64% (95% CI 50-75%). For responders (n = 35), median duration of response was not yet reached, but the probability of being event-free at 6 months was 91% (95% CI 73-97%). Single-agent elranatamab induces durable clinical and molecular responses, and updated data including MRD assessment will be presented. Conclusions: Elranatamab shows a manageable safety profile and achieves durable clinical and molecular responses for pts with relapsed or refractory MM. Clinical trial information: NCT03269136.
NF-kappa B activation is a crucial late step in the induction of immunoglobulin kappa light-chain gene expression in pre-B cells by lipopolysaccharide (LPS). We have analyzed NF-kappa B activation in three independent mutant lines of 70Z/3 pre-B cells which are unresponsive to LPS. All three variant cell lines failed to activate NF-kappa B when induced with LPS or the phorbol ester 12-O-tetradecanoylphorbol 13-acetate. However, all three cell lines contained functional NF-kappa B, as revealed by detergent treatment of cytoplasmic extracts. Moreover, cycloheximide induced limited activation of NF-kappa B comparable to that in wild-type 70Z/3 pre-B cells in two of the three variant lines. These results indicate that the mutations blocking kappa gene induction in these variant 70Z/3 pre-B-cell lines affect NF-kappa B activation.
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