Activity of the Src-kinase inhibitor AZD0530 in androgen-independent prostate cancer (AIPC): Pre-clinical rationale for a phase II trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14542-14542 ◽  
Author(s):  
C. P. Evans ◽  
P. N. Lara ◽  
H. Kung ◽  
J. C. Yang
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Src Kinase ◽  
Soft Agar ◽  
Growth Reduction ◽  
Abl Kinase

14542 Background: Cells with neuroendocrine (NE) differentiation are found in prostate cancer and may facilitate the transition to AI by supplying alternate growth factors. Androgen deprivation further induces a subgroup of AI NE cells by transdifferentiation. We hypothesized that androgen receptor (AR)- and src kinase-mediated signaling participates in this NE progression, and tested inhibition using the src kinase inhibitor AZD0530. Methods: The neuropeptide gastrin-releasing peptide (GRP) was minimally expressed in androgen-sensitive LNCaP cells. LNCaP-GRP clones demonstrated androgen- and anchorage-independent growth, developed orthotopic tumors in castrated SCID mice & activated PSA with nuclear localization of AR. LNCap-GRP clones & xenografts showed activation of src kinase. Xenografts were recultured (LNCaP-Pro) & grown in androgen-free soft agar or tissue culture either alone, with synthetic androgen R1881 or with inhibitors including: GRP monoclonal antibody 2A11, 10 μM antiandrogen bicalutamide, Src kinase inhibitors AZM475271, AZD0530 (5 μM) and PP2 (10 μM). Mice bearing orthotopic LNCaP-GRP tumors were treated orally with 50 mg/kg AZD0530 daily for 6 weeks. Results: Androgen-depleted soft agar colony counts showed that LNCaP-Pro cell proliferation was not stimulated by R1881 but was partially inhibited by 2A11 antibody or bicalutamide, when compared to controls. A combination of 2A11 & bicalutamide resulted in significant growth reduction (p < 0.05). R1881 mostly reversed the 2A11 inhibition. The Src kinase inhibitors AZM475271 & PP2 showed greatest colony formation inhibition (p < 0.05). AZD0530 inhibited growth in culture (not tested in soft agar) at micromolar concentrations. Testing in vivo inhibited primary tumor growth in 5 of 7 dosed mice (71%), but completely inhibited metastasis in all AZD0530-treated mice (compared with metastasis in 100% of controls). Conclusions: Neuropeptide-mediated AIPC growth is dependent on both GRP and AR. There appears to be a beneficial role for Src kinase inhibition in this model. A CTEP-sponsored phase II trial of the dual Src/Abl kinase inhibitor AZD0530 in AIPC has been initiated. (KO8 DK60748–01, 2RO1 DK/AG52659–04, DOD PC10520, Astra-Zeneca, NO1 CM17101). [Table: see text]

scholarly journals A phase II trial of the Src-kinase inhibitor AZD0530 in patients with advanced castration-resistant prostate cancer: a California Cancer Consortium study

2009 ◽  
Vol 20 (3) ◽  
pp. 179-184 ◽  
Author(s):  
Primo N. Lara ◽  
Jeff Longmate ◽  
Christopher P. Evans ◽  
David I. Quinn ◽  
Przemyslaw Twardowski ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Src Kinase ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

scholarly journals A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621

Lung Cancer ◽  
2014 ◽  
Vol 85 (2) ◽  
pp. 245-250 ◽  
Author(s):  
Julian R. Molina ◽  
Nathan R. Foster ◽  
Thanyanan Reungwetwattana ◽  
Garth D. Nelson ◽  
Andrew V. Grainger ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Src Kinase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Extensive Stage

Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 5025-5025 ◽  
Author(s):  
Andrew J. Armstrong ◽  
Susan Halabi ◽  
Patrick Healy ◽  
Joshi J. Alumkal ◽  
Evan Y. Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Pi3 Kinase ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

A phase II trial of regorafenib (REGO) in patients (pts) with advanced Ewing sarcoma and related tumors (EWS) of soft tissue and bone: SARC024 trial results.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11005-11005 ◽  
Author(s):  
Steven Attia ◽  
Vanessa Bolejack ◽  
Kristen N. Ganjoo ◽  
Suzanne George ◽  
Mark Agulnik ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Phase Ii Trial ◽  
Common Grade ◽  
Duration Of Response ◽  
The Difference ◽  
Line Of Therapy

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.

In Vitro and In Vivo Activity of the Src/Abl Kinase Inhibitor AP23464 and Analogs Against Activation Loop Mutants of KIT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 793-793 ◽  
Author(s):  
Amie S. Corbin ◽  
Shadmehr Demehri ◽  
Ian J. Griswold ◽  
Chester A. Metcalf ◽  
William C. Shakespeare ◽  
...  
Keyword(s):  
Cell Lines ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Activation Loop ◽  
Wild Type ◽  
Abl Kinase ◽  
Ic50 Values

Abstract Oncogenic mutations of the KIT receptor tyrosine kinase have been identified in several malignancies including gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM), seminomas/dysgerminomas and acute myelogenous leukemia (AML). Mutations in the regulatory juxtamembrane domain are common in GIST, while mutations in the activation loop of the kinase (most commonly D816V) occur predominantly in SM and at low frequency in AML. Several ATP-competitive kinase inhibitors, including imatinib, are effective against juxtamembrane KIT mutants, however, the D816V mutant is largely resistant to inhibition. We analyzed the sensitivities of cell lines expressing wild type KIT, juxtamembrane mutant KIT (V560G) and activation loop mutant KIT (D816V,F,Y and murine D814Y) to a potent Src/Abl kinase inhibitor, AP23464, and analogs. IC50 values for inhibition of cellular KIT phosphorylation by AP23464 were 5–11 nM for activation loop mutants, 70 nM for the juxtamembrane mutant and 85 nM for wild type KIT. Consistent with this, IC50 values in cell proliferation assays were 3–20 nM for activation loop mutants and 100 nM for wild type KIT and the juxtmembrane mutant. In activation loop mutant-expressing cell lines, AP23464, at concentrations ≤50 nM, induced apoptosis, arrested the cell cycle in G0/G1 and down-regulated phosphorylation of Akt and STAT3, signaling pathways critical for the transforming capacity of mutant KIT. In contrast, 500 nM AP23464 was required to induce equivalent effects in wild-type KIT and juxtamembrane mutant-expressing cell lines. These data demonstrate that activation loop KIT mutants are considerably more sensitive to inhibition by AP23464 than wild type or juxtamembrane mutant KIT. Non-specific toxicity in parental cells occurred only at concentrations above 2 μM. Additionally, at concentrations below 100 nM, AP23464 did not inhibit formation of granulocyte/macrophage and erythrocyte colonies from normal bone marrow, suggesting that therapeutic drug levels would not impact normal hematopoiesis. We also examined in vivo target inhibition in a mouse model. Mice were subcutaneously injected with D814Y-expressing (D816V homologous) murine mastocytoma cells. Once tumors were established, compound was administered three-times daily by oral gavage. One hour post treatment we observed >90% inhibition of KIT phosphorylation in tumor tissue. Following a three-day treatment regimen, there was a statistically significant difference in tumor size compared to controls. Thus, AP23464 analogs effectively target D816-mutant KIT both in vitro and in vivo and inhibit activation loop KIT mutants more potently than the wild type protein. These data provide evidence that this class of kinase inhibitors may have therapeutic potential for D816V-expressing malignancies such as SM or AML.

scholarly journals Abl kinase deficiency promotes AKT pathway activation and prostate cancer progression and metastasis

2020 ◽  
Author(s):  
Melissa A Marchal ◽  
Devon L Moose ◽  
Afshin Varzavand ◽  
Destiney Taylor ◽  
James A Brown ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Kinase Inhibitor ◽  
Akt Pathway ◽  
Prostate Cancer Progression ◽  
Castration Resistant Prostate Cancer ◽  
Abl Kinase ◽  
Abl Kinases ◽  
Pathway Activation

AbstractAbl family kinases function as proto-oncogenes in various leukemias, and pro-tumor functions have been discovered for Abl kinases in solid tumors as well. However, a growing body of evidence indicates that Abl kinases can function to suppress tumor cell proliferation, motility, and in vivo tumor growth in some settings. To investigate the role of Abl kinases in prostate cancer, we generated Abl-deficient cells in a pre-clinical model of spontaneously metastatic, androgen-indifferent prostate cancer. Loss of Abl family kinase expression resulted in a highly aggressive, metastatic phenotype in vivo that was associated with AKT pathway activation, increased growth on 3D collagen matrix, and enhanced cell motility in vitro. Treatment of Abl kinase-expressing cells with the Abl kinase inhibitor imatinib phenocopied the malignant phenotypes observed in Abl-deficient tumor cells. In addition, inhibiting AKT pathway signaling abolished the increased 3D growth of Abl-deficient cells. Our data reveal that Abl family kinases can function as suppressors of prostate cancer progression and metastasis by restraining AKT signaling, a signaling pathway known to be associated with emergence of metastatic castration-resistant prostate cancer.

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

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