First-in-human, first-in-class phase 1 study of a novel oral multi-AGC kinase inhibitor AT13148 in patients (pts) with advanced solid tumors.

Kumar, Rajiv; Mateo, Joaquín; Smith, Alan D.; Khan, Khurum; Ruddle, Ruth; Swales, Karen E.; Decordova, Shaun; Backholer, Zoe; Jones, Paul S.; Tran, Christine; Seeramreddi, Satyanarayana; McLeod, Robert; Yap, Timothy A.; Raynaud, Florence I.; Garrett, Michelle D.; Banerji, Udai

doi:10.1200/jco.2014.32.15_suppl.2554

Cited by 7 publications

(7 citation statements)

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“…AT13148 is an orally available multi-AGC kinase inhibitor that was identified through a fragment-based screen and was found to potently inhibit ROCK1 and ROCK2 (Yap et al, 2012). AT13148 was shown to have anti-tumor effects in pre-clinical models of pancreatic (Rath et al, 2018), breast, prostate and uterine cancer (Yap et al, 2012) and was well tolerated in a phase I clinical trial in patients with advanced solid tumors (NCT01585701) (Kumar et al, 2014).…”

Section: Rho-associated Protein Kinases (Rocks)mentioning

confidence: 99%

Targeting Rho GTPase Signaling Networks in Cancer

Clayton

Ridley

2020

Front. Cell Dev. Biol.

139

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As key regulators of cytoskeletal dynamics, Rho GTPases coordinate a wide range of cellular processes, including cell polarity, cell migration, and cell cycle progression. The adoption of a pro-migratory phenotype enables cancer cells to invade the stroma surrounding the primary tumor and move toward and enter blood or lymphatic vessels. Targeting these early events could reduce the progression to metastatic disease, the leading cause of cancer-related deaths. Rho GTPases play a key role in the formation of dynamic actin-rich membrane protrusions and the turnover of cell-cell and cellextracellular matrix adhesions required for efficient cancer cell invasion. Here, we discuss the roles of Rho GTPases in cancer, their validation as therapeutic targets and the challenges of developing clinically viable Rho GTPase inhibitors. We review other therapeutic targets in the wider Rho GTPase signaling network and focus on the four best characterized effector families: p21-activated kinases (PAKs), Rho-associated protein kinases (ROCKs), atypical protein kinase Cs (aPKCs), and myotonic dystrophy kinase-related Cdc42-binding kinases (MRCKs).

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Section: Rho-associated Protein Kinases (Rocks)mentioning

confidence: 99%

Targeting Rho GTPase Signaling Networks in Cancer

Clayton

Ridley

2020

Front. Cell Dev. Biol.

139

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“…In addition, AT13148 was shown to slow the subcutaneous tumor growth of BT474 breast, PC3 prostate and MES-SA uterine human cancer cell lines, revealing its in vivo anti-tumor efficacy (21). Importantly, the therapeutic promise, satisfactory pharmacokinetic properties and selectivity profile of AT13148 contributed to its progression to phase 1 clinical trials (23).…”

Section: Introductionmentioning

confidence: 99%

Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth

et al. 2018

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The high mortality of pancreatic cancer demands that new therapeutic avenues be developed. The orally available small molecule inhibitor AT13148 potently inhibits ROCK1 and ROCK2 kinases that regulate the actomyosin cytoskeleton.We previously reported that ROCK kinase expression increases with human and mouse pancreatic cancer progression and that conditional ROCK activation accelerates mortality in a genetically modified LSL-KrasG12D; LSL-p53R172H; Pdx1-Cre; (KPC) mouse pancreatic cancer model. In this study, we show that treatment of KPC mouse and human TKCC5 patient-derived pancreatic tumor cells with AT13148, as well as the ROCK selective inhibitors Y27632 and H1152, act comparably in blocking ROCK substrate phosphorylation. AT13148, Y27632, and H1152 induced morphological changes and reduced cellular contractile force generation, motility on pliable discontinuous substrates, and three-dimensional collagen matrix invasion. AT13148 treatment reduced subcutaneous tumor growth and blocked invasion of healthy pancreatic tissue by KPC tumor cells in vivo without affecting proliferation, suggesting a role for local tissue invasion as a contributor to primary tumor growth. These results suggest that AT13148 has anti-tumor properties that may be beneficial in combination therapies or in the adjuvant setting to reduce pancreatic cancer cell invasion and slow primary tumor growth. AT13148 might also have the additional benefit of enabling tumor resection by maintaining separation between tumor and healthy tissue boundaries.

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“…We chose to determine the feasibility of using the Meso Scale Discovery ® (MSD ® ) multiplex electrochemiluminescence platform to measure total and phospho‐protein signals for AKT, GSK3β and P70S6K, in neuroblastoma cells and also platelet‐rich plasma (PRP), the latter as a surrogate tissue. These assays have been validated to meet Good Clinical Practice requirements and have been used by our laboratory to detect PI3K/AKT/mTOR activity in PRP as a surrogate tissue in five adult phase I clinical trials of PI3K/AKT/mTOR inhibitors including MK2206 and AZD5363 (Arkenau et al., 2014; Banerji et al., 2013; Kumar et al., 2014; Omlin et al., 2012; Yap et al., 2011), but have not been evaluated in the pediatric setting until now.…”

Section: Resultsmentioning

confidence: 99%

“…This methodology has been reported before for analysis of PI3K/AKT/mTOR pathway signals in PRP from adult clinical studies in our laboratory (Arkenau et al, 2014;Banerji et al, 2013;Kumar et al, 2014;Omlin et al, 2012;Yap et al, 2011). In brief, blood samples were collected in 2 Â 2.7 ml BD Vacutainer Ò tubes with sodium citrate.…”

Section: Measurement Of Pi3k/akt/mtor Pathway Signalsmentioning

confidence: 99%

“…We chose to determine the feasibility of using the Meso Scale Discovery Ò (MSD Ò ) multiplex electrochemiluminescence platform to measure total and phospho-protein signals for AKT, GSK3b and P70S6K, in neuroblastoma cells and also platelet-rich plasma (PRP), the latter as a surrogate tissue. These assays have been validated to meet Good Clinical Practice requirements and have been used by our laboratory to detect PI3K/AKT/mTOR activity in PRP as a surrogate tissue in five adult phase I clinical trials of PI3K/AKT/mTOR inhibitors including MK2206 and AZD5363 (Arkenau et al, 2014;Banerji et al, 2013;Kumar et al, 2014;Omlin et al, 2012; Firstly, we tested whether these assays reliably detect changes in PI3K/AKT/mTOR pathway activity in neuroblastoma cells following treatment with the TORC1/TORC2 inhibitor AZD8055. We confirmed that phospho-AKT, GSK3b and P70S6K signals decreased compared to total levels of each of the biomarkers following 3 h AZD8055 treatment of Kelly neuroblastoma cells ( Supplementary Figure S4A and B).…”

Section: 7mentioning

confidence: 99%

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Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathway signaling in children with neuroblastoma

et al. 2015

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There is an urgent need for improved therapies for children with high-risk neuroblastoma where survival rates remain low. MYCN amplification is the most common genomic change associated with aggressive neuroblastoma and drugs targeting PI3K/AKT/mTOR, to activate MYCN oncoprotein degradation, are entering clinical evaluation. Our aim was to develop and validate pharmacodynamic (PD) biomarkers to evaluate both proof of mechanism and proof of concept for drugs that block PI3K/AKT/mTOR pathway activity in children with neuroblastoma. We have addressed the issue of limited access to tumor biopsies for quantitative detection of protein biomarkers by optimizing a three-color fluorescence activated cell sorting (FACS) method to purify CD45À/GD2þ/CD56þ neuroblastoma cells from bone marrow. We then developed a novel quantitative measurement of MYCN protein in these isolated neuroblastoma cells, providing the potential to demonstrate proof of concept for drugs that inhibit PI3K/AKT/mTOR signaling in this disease. In addition we have established quantitative detection of three biomarkers for AKT pathway activity (phosphorylated and total AKT, GSK3b and P70S6K) in surrogate platelet-rich plasma (PRP) from pediatric patients. Together our new approach to neuroblastoma cell isolation for protein detection and suite of PD assays provides for the first time the opportunity for robust, quantitative measurement of proteinbased PD biomarkers in this pediatric patient population. These will be ideal tools to support clinical evaluation of PI3K/AKT/mTOR pathway drugs and their ability to target MYCN oncoprotein in upcoming clinical trials in neuroblastoma.

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First-in-human, first-in-class phase 1 study of a novel oral multi-AGC kinase inhibitor AT13148 in patients (pts) with advanced solid tumors.

Cited by 7 publications

References 0 publications

Targeting Rho GTPase Signaling Networks in Cancer

Targeting Rho GTPase Signaling Networks in Cancer

Rho Kinase Inhibition by AT13148 Blocks Pancreatic Ductal Adenocarcinoma Invasion and Tumor Growth

Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathway signaling in children with neuroblastoma

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