Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions. Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents. Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models. Pathway inhibition in response to FGFR inhibitor treatment was assessed in cell lines (both in vitro and in vivo) and in samples from patients treated with the FGFR inhibitor JNJ-42756493 (erdafitinib). Frequency of FGFR aberrations was assessed in a panel of NSCLC, breast, prostate, ovarian, colorectal, and melanoma human tumor tissue samples. FGFR translocations and gene amplifications present in clinical specimens were shown to display potent transforming activity associated with constitutive pathway activation. Tumor cells expressing these FGFR activating mutants displayed sensitivity to the selective FGFR inhibitor erdafitinib and resulted in suppression of FGFR phosphorylation and downstream signal transduction. Clinically, patients receiving erdafitinib showed decreased Erk phosphorylation in tumor biopsies and elevation of serum phosphate. In a phase I study, a heavily pretreated bladder cancer patient with an FGFR3-TACC3 translocation experienced a partial response when treated with erdafitinib. This preclinical study confirmed pharmacodynamics and identified new predictive biomarkers to FGFR inhibition with erdafitinib and supports further clinical evaluation of this compound in patients with FGFR genetic alterations.
Autocrine or paracrine constitutive Wnt pathway activation occurs at a high frequency in several tumor types. The R-spondin (RSPO) protein family is comprised of four secreted growth factors. The four paralogs share 40-60% pairwise amino acid sequence identity and are predicted to share substantial structural homology. RSPO proteins are involved in vertebrate development and their ligand-type activities overlap substantially with those of canonical Wnt ligands. A characteristic feature of all four RSPO members is their ability to activate β-catenin signaling and enhance WNT-mediated β-catenin activation. It has recently been described that recurrent gene fusions involving RSPO family members RSPO2 and RSPO3 occur in ∼10% of colon tumors. In this study we developed a TaqMan qRT-PCR-based approach to evaluate the expression of these three (3) RSPO fusion transcripts in formalin-fixed paraffin embedded tissue (FFPET) samples. We examined 324 lung cancer, 81 colorectal cancer, 71 head & neck, 11 esophageal, 92 ovarian cancer, and 103 breast cancer FFPET samples for the presence of EIF3E(e1)-RSPO2(e1), PTPRK(e1)-RSPO3(e2), and PTPRK(e7)-RSPO3(e2). EIF3E(e1)-RSPO2(e1), a fusion which is expected to produce a functional RSPO2 protein driven by the EIF3E promoter, was identified in ∼1-2% of most of cancer types with the exception of breast cancer. The PTPRK(e1)-RSPO3(e2) fusion was expressed by ∼1-11% of the samples in the different cancers, making it the most prevalent of the fusions. PTPRK(e1)-RSPO3(e2) fusion is an in-frame fusion that preserves the entire coding sequence of RSPO3 and replaces its secretion signal sequence with that of PTPRK. The PTPRK(e7)-RSPO3(e2) fusion is also an in-frame fusion in which the RSPO3 native signal peptide is replaced by the secretion signal of PTPRK. The PTPRK(e7)-RSPO3(e2) was the least prevalent of all the fusions, positive samples were found exclusively in the head and neck (∼2%) and breast cancer samples (∼2%). All of the fusions detected were mutually exclusive. The RSPO gene fusions identified may provide new potential opportunities for therapeutic intervention. Citation Format: Gabriela Martinez Cardona, Katherine Bell, Joseph Portale, Dana Gaffney, Christopher Moy, Suso Platero, Matthew V. Lorenzi, Jayaprakash Karkera. Identification of R-Spondin fusions in various types of human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2408. doi:10.1158/1538-7445.AM2014-2408
Autocrine Wnt signaling has been reported in a significant fraction of NSCLC. The R-spondin (RSPO) protein family is a small family of four secreted growth factors. The four paralogs share 40–60% pairwise amino acid sequence identity and are predicted to share substantial structural homologies. RSPO proteins are involved in vertebrate development and their ligand-type activities overlap substantially with those of canonical Wnt ligands. A characteristic feature of all four RSPO members is their ability to activate β-catenin signaling and enhance WNT-mediated β-catenin activation. It has recently been described that recurrent gene fusions involving RSPO family members of RSPO2 and RSPO3 that occur in ~10% of colon tumors and are mutually exclusive with other WNT pathway genetic alterations. In this study we developed a TaqMan qRT-PCR-based approach to evaluate systematically the expression of these three (3) RSPO fusion transcripts in formalin-fixed paraffin embedded tissue (FFPET) samples. We examined 324 NSCLC samples that included 197 squamous and 127 adenocarcinoma subtypes for the presence of EIF3E(e1)-RSPO2(e1), PTPRK(e1)-RSPO3(e2), PTPRK(e7)-RSPO3(e2). EIF3E(e1)-RSPO2(e1) was identified in 1% and this fusion transcript is expected to produce a functional RSPO2 protein driven by the EIF3E promoter. The PTPRK(e1)–RSPO3(e2) transcript found in 2% and is an in-frame fusion that preserves the entire coding sequence of RSPO3 and replaces its secretion signal sequence with that of PTPRK. Interestingly, all the fusions were detected only in the squamous subtype of NSCLC. These findings suggest an important role for dysregulated Wnt-β-catenin signaling in lung cancer and identify a new driver segment in NSCLC for therapeutic intervention. Citation Format: Jayaprakash Karkera, Gabriela Martinez, Katherine Bell, Joseph Portale, Dana Gaffney, Matthew V. Lorenzi, Suso Platero. Identification of R-spondin fusions in NSCLC. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B03.
Protein arginine methyltransferase 5 (PRMT5), a type II methyltransferase, is responsible for symmetric arginine di-methylation of multiple cellular proteins involved in the regulation of cellular transcription. PRMT5 is involved in cellular processes such as survival, proliferation, and apoptosis, and an elevated tumor PRMT5 protein level has recently been correlated with poor survival of cancer patients. JNJ-64619178, a selective PRMT5 inhibitor, showed inhibition of cellular growth in several cell lines representing multiple cancer histologies in vitro. From this, a broad selection of xenograft models was chosen to demonstrate potent anti-tumor efficacy. Xenograft models representing small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), and non-Hodgkin lymphoma were chosen to demonstrate anti-tumor efficacy. Biologically significant tumor growth inhibition up to 99% was observed in both solid and hematological xenograft models, including an aggressive disseminated model of AML, with oral doses of 1 to 10 mg/kg, once daily. Importantly, continued inhibition of tumor growth was observed for several weeks following dosing cessation. Dosing of JNJ-64619178 results in inhibition of Sym-Arg di-methylation of SMD1/3 proteins, core components of the spliceosome in the tumor, and general Sym-Arg di-methylation of serum proteins. These serve as pharmacodynamic markers of PRMT5 inhibition in xenograft models. Potent and prolonged inhibition of SMD1/3 di-methylation was observed in the SCLC model, during and after the dosing period. This has led to the exploration of alternative dosing regimens preclinically. PRMT5 inhibitor JNJ-64619178 is currently being investigated in a Phase I clinical trial, based on its high selectivity and potency, favorable pharmacokinetics and safety properties, and strong preclinical efficacy and pharmacodynamic data. Citation Format: Hillary J. Millar, Dirk Brehmer, Tinne Verhulst, Nahor Haddish-Berhane, Tony Greway, Dana Gaffney, An Boeckx, Erika Van Heerde, Thomas Nys, Joseph Portale, Ulrike Philippar, Tongfei Wu, Sylvie Laquerre, Kathryn Packman. In vivo efficacy and pharmacodynamic modulation of JNJ-64619178, a selective PRMT5 inhibitor, in human lung and hematologic preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 950.
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