A Study of RXDX-106, an Oral Immunomodulatory TYRO3, AXL, and MER (TAM) Tyrosine Kinase Inhibitor, in Patients With Locally Advanced or Metastatic Solid Tumors

This is a first-in-human, open label, multicenter, dose escalation study of RXDX-106 in patients with locally advanced or metastatic solid tumors, who have no available therapy likely to convey clinical benefit.
This study will examine the safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of RXDX 106.

开始日期2018-02-15

申办/合作机构

Hoffmann-La Roche, Inc.

100 项与 RXDX-106 相关的临床结果

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100 项与 RXDX-106 相关的转化医学

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100 项与 RXDX-106 相关的专利（医药）

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项与 RXDX-106 相关的文献（医药）

2023-09-01·Journal of dental research

Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction

Article

作者: Taichman, R. ; Inohara, N. ; Sugai, J. ; Kaigler, D. ; Decker, J.T. ; Martin, K. ; Matsumoto, M. ; Shea, L.D. ; Decker, A.M. ; Núñez, G. ; Roh, A.

Regeneration of alveolar bone is an essential step in restoring healthy function following tooth extraction. Growth of new bone in the healing extraction socket can be variable and often unpredictable when systemic comorbidities are present, leading to the need for additional therapeutic targets to accelerate the regenerative process. One such target is the TAM family (Tyro3, Axl, Mertk) of receptor tyrosine kinases. These proteins have been shown to help resolve inflammation and maintain bone homeostasis and thus may have therapeutic benefits in bone regeneration following extraction. Treatment of mice with a pan-TAM inhibitor (RXDX-106) led to accelerated alveolar bone fill following first molar extraction in a mouse model without changing immune infiltrate. Treatment of human alveolar bone mesenchymal stem cells with RXDX-106 upregulated Wnt signaling and primed the cells for osteogenic differentiation. Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. First molar extractions in Mertk–/– mice had increased alveolar bone regeneration in the extraction socket relative to wild type controls 7 d postextraction. Flow cytometry of 7-d extraction sockets showed no difference in immune cell numbers between Mertk –/– and wild type mice. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk –/– mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury.

2022-04-01·Molecular cancer research : MCR2区 · 医学

Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration

2区 · 医学

Article

作者: Stroud, Mia ; Smith, Matthew A. ; Meyer, Benjamin S. ; Creixell, Marc ; Agarwal, Shruti ; Saller, James J. ; Hosseinian, Sina ; Majumder, Anurima ; Zhang, Guolin ; Stewart, Paul A. ; Welsh, Eric A. ; Haura, Eric B. ; Meyer, Aaron S. ; Adhikari, Emma ; Kinose, Fumi ; Koomen, John M. ; Boyle, Theresa A. ; Bowers, Kiah ; Fang, Bin

Abstract:

To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration. Global phosphoproteomics show that AXL inhibition decreases phosphorylation of peptides involved in phosphatidylinositol-mediated signaling and cell adhesion/migration. Comparison of three AXL inhibitors reveals that TKI RXDX-106 inhibits pAXL, pAKT, and migration/invasion of these cells without reducing their viability, while bemcentinib exerts AXL-independent phenotypic effects on viability. Proteomic characterization of these TKIs demonstrates that they inhibit diverse targets in addition to AXL, with bemcentinib having the most off-targets. AXL and EGFR TKI cotreatment did not reverse resistance in cell line models of erlotinib resistance. However, a unique vulnerability was identified in one resistant clone, wherein combination of bemcentinib and erlotinib inhibited cell viability and signaling. We also show that AXL is overexpressed in approximately 30% to 40% of nonsmall but rarely in small cell lung cancer. Cell lines have a wide range of AXL expression, with basal activation detected rarely.

Implications::

Our study defines mechanisms of action of AXL in lung cancers which can be used to establish assays to measure drug targetable active AXL complexes in patient tissues and inform the strategy for targeting it's signaling as an anticancer therapy.

2019-04-15·Cancer research1区 · 医学

Immuno-oncological Efficacy of RXDX-106, a Novel TAM (TYRO3, AXL, MER) Family Small-Molecule Kinase Inhibitor

1区 · 医学

Article

作者: Walsh, Colin ; Fagan, Patrick C. ; Bui, Jack D. ; Diliberto, Amy ; Yokoyama, Yumi ; Seelige, Ruth ; Tucker, Kathleen D. ; Albert, Amanda ; Oh, Joanne ; Vaaler, Heather ; Smith, Kristen M. ; Lew, Erin D. ; Nevarez, Robin ; Li, Gary ; Chen, Marissa ; Lee, Jack Y. ; Tindall, Elizabeth A.

Abstract:

Expression of the TAM (TYRO3, AXL, MER) family of receptor tyrosine kinases (RTK) has been associated with cancer progression, metastasis, and drug resistance. In immune cells, TAM RTKs can dampen inflammation in favor of homeostatic wound-healing responses, thus potentially contributing to the evasion of cancer cells from immune surveillance. Here we characterize the small-molecule RXDX-106 as a selective and potent pan-TAM RTK inhibitor with slow dissociation kinetics and significant antitumor activity in multiple syngeneic tumor models. Expression of AXL and MER on both immune and tumor cells increased during tumor progression. Tumor growth inhibition (TGI) following treatment with RXDX-106 was observed in wild-type mice and was abrogated in immunodeficient mice, suggesting that the antitumor activity of RXDX-106 is, in part, due to the presence of immune cells. RXDX-106–mediated TGI was associated with increased tumor-infiltrating leukocytes, M1-polarized intratumoral macrophages, and activation of natural killer cells. RXDX-106 proportionally increased intratumoral CD8+ T cells and T-cell function as indicated by both IFNγ production and LCK phosphorylation (pY393). RXDX-106 exhibited its effects via direct actions on TAM RTKs expressed on intratumoral macrophages and dendritic cells, leading to indirect activation of other immune cells in the tumor. RXDX-106 also potentiated the effects of an immune checkpoint inhibitor, α-PD-1 Ab, resulting in enhanced antitumor efficacy and survival. Collectively, these results demonstrate the capacity of RXDX-106 to inhibit tumor growth and progression and suggest it may serve as an effective therapy against multiple tumor types.

Significance::

The pan-TAM small-molecule kinase inhibitor RXDX-106 activates both innate and adaptive immunity to inhibit tumor growth and progression, indicating its clinical potential to treat a wide variety of cancers.

100 项与 RXDX-106 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期恶性实体瘤	临床1期	美国	Hoffmann-La Roche, Inc.	2018-02-15
实体瘤	临床1期	美国	F. Hoffmann-La Roche Ltd.	2018-02-15
肿瘤	临床1期	-	F. Hoffmann-La Roche Ltd.	-
肿瘤	临床1期	-	Teva Pharmaceutical Industries Ltd.	-
肿瘤	临床1期	-	Daiichi Sankyo Co., Ltd.	-