61.
62.
Initial testing of the multitargeted kinase inhibitor pazopanib by the pediatric preclinical testing program
Keir, Stephen T.; Morton, Christopher L.; Wu, Jianrong ...
Pediatric blood & cancer,
September 2012, Letnik:
59, Številka:
3
Journal Article
Pazopanib is an oral angiogenesis inhibitor targeting vascular growth factor receptor‐1, ‐2, and ‐3, platelet derived growth factor receptor‐α, platelet derived growth factor receptor‐β, and KIT that ...
has demonstrated activity against a variety of adult cancer xenografts. Pazopanib was tested against a panel of pediatric rhabdomyosarcoma and Ewing sarcoma xenografts at a dose of 108 mg/kg/day or 100 mg/kg twice daily, administered orally for 28 days. While no objective responses were observed, pazopanib induced statistically significant differences in event‐free survival compared to controls in approximately one‐half of the sarcoma xenograft models tested. Though well tolerated, pazopanib showed limited activity against the sarcoma models evaluated, with the best tumor responses being growth delay. Pediatr Blood Cancer 2012;59:586–588. © 2011 Wiley Periodicals, Inc.
več
63.
Initial testing (stage 1) of the anti-microtubule agents cabazitaxel and docetaxel, by the Pediatric Preclinical Testing Program
Reynolds, C. Patrick; Kang, Min H.; Maris, John M. ...
Pediatric blood & cancer,
November 2015, Letnik:
62, Številka:
11
Journal Article
Background
Although microtubule‐destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule‐stabilizing taxanes are uncommonly used to treat childhood ...
cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug‐resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts.
Procedures
Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1 μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5 mg/kg on an every 4 days × 3 I.V. schedule.
Results
In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47 nM and 0.88 nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel.
Conclusions
Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.
več
64.
IRS-1: Auditing the effectiveness of mTOR inhibitors
Easton, John B.; Kurmasheva, Raushan T.; Houghton, Peter J.
Cancer cell,
03/2006, Letnik:
9, Številka:
3
Journal Article
Rapamycin analogs that inhibit mTOR signaling have antitumor activity against certain lymphomas, but treatment of solid tumors has been less encouraging despite inhibition of mTOR function. Two ...
recent papers give insight into the potential use of mTOR inhibitors. O'Reilly et al. provide evidence that poor tumor response to rapamycins is the result of relieving mTOR-mediated feedback inhibition of insulin receptor substrate 1, and activation of Akt-mediated survival. In the second paper, Kaper et al. address the impact of pathway activation on hypoxia-mediated downregulation of mTOR signaling, raising the possibility that rapalogs could selectively inhibit hypoxic cells.
več
65.
Initial testing (stage 1) of the investigational mTOR kinase inhibitor MLN0128 by the pediatric preclinical testing program
Kang, Min H.; Reynolds, C. Patrick; Maris, John M. ...
Pediatric blood & cancer,
August 2014, Letnik:
61, Številka:
8
Journal Article
MLN0128 is an investigational small molecule ATP‐competitive inhibitor of the serine/threonine kinase mTOR. MLN0128 was tested against the in vitro panel at concentrations ranging from 0.1 nM to 1 μM ...
and against the PPTP in vivo panels at a dose of 1 mg/kg administered orally daily × 28. In vitro the median relative IC50 concentration was 19 nM. In vivo MLN0128 induced significant differences in EFS in 24/31 (77%) solid tumor models, but 0/7 ALL xenografts. The modest activity observed for MLN0128 against the PPTP preclinical models is similar to that previously reported for another TOR kinase inhibitor. Pediatr Blood Cancer 2014; 61:1486–1489. © 2014 Wiley Periodicals, Inc.
več
66.
Initial testing (Stage 1) of the antibody-maytansinoid conjugate, IMGN901 (Lorvotuzumab mertansine), by the pediatric preclinical testing program
Wood, Andrew C.; Maris, John M.; Gorlick, Richard ...
Pediatric blood & cancer,
November 2013, Letnik:
60, Številka:
11
Journal Article
ABSTRACT
Background
IMGN901 (lorvotuzumab mertansine) is an antibody‐drug conjugate composed of a humanized antibody that specifically binds to CD56 (NCAM, neural cell adhesion molecule) and that is ...
conjugated to the maytansinoid, DM1 (a microtubule targeting agent).
Procedures
IMGN901 and DM1‐SMe (unconjugated DM1 as a mixed disulfide with thiomethane to cap its sulfhydryl group) were tested in vitro at concentrations ranging from 0.01 nM to 0.1 µM and 0.3 pM to 3 nM, respectively. IMGN901 was tested against a subset of PPTP solid tumor xenografts focusing on those with high CD56 expression.The combination of IMGN901 with topotecan was also evaluated.
Results
Neuroblastoma models expressed CD56 at or above the median expression level for all PPTP xenografts and cell lines. Neuroblastoma cell lines demonstrated relatively low sensitivity to DM1‐SMe compared to other cell lines, but the sensitivity of neuroblastoma cell lines to IMGN901 was comparable to that of non‐neuroblastoma cell lines. In vivo, objective responses were observed in 9 of 24 (38%) models including, three of seven neuroblastoma xenografts, and two of seven rhabdomyosarcoma xenografts. All xenografts with objective responses showed homogeneous high‐level staining by IHC for CD56, but not all xenografts with homogenous high‐level staining had objective responses. Combined with topotecan, IMGN901 demonstrated therapeutic enhancement against two of four neuroblastoma models.
Conclusions
IMGN901 has anti‐tumor activity against some CD56 expressing pediatric cancer models. High expression of CD56 is a biomarker for in vivo response, but resistance mechanisms to IMGN901 in some high CD56 expressing lines need to be defined. Pediatr Blood Cancer 2013;60:1860–1867. © 2013 Wiley Periodicals, Inc.
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67.
Initial testing (stage 1) of temozolomide by the pediatric preclinical testing program
Keir, Stephen T.; Maris, John M.; Reynolds, C. Patrick ...
Pediatric blood & cancer,
20/May , Letnik:
60, Številka:
5
Journal Article
Background
The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood ...
cancer. Temozolomide was tested against the PPTP solid tumor and ALL models.
Procedures
Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000 µM and was tested against the PPTP in vivo panels at doses from 22 to 100 mg/kg administered orally daily for 5 days, repeated at day 21.
Results
In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380 µM against the PPTP cell lines (range 1 to > 1,000 µM). The three lines with rIC50 values lesser than 10 µM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100 mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR MCR, 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66 mg/kg temozolomide and with tumor regressions at 22 and 44 mg/kg restricted to models with low MGMT expression.
Conclusions
Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression. Pediatr Blood Cancer 2013; 60: 783–790. © 2013 Wiley Periodicals, Inc.
več
68.
Initial testing (stage 1) by the pediatric preclinical testing program of RO4929097, a γ-secretase inhibitor targeting notch signaling
Kolb, E. Anders; Gorlick, Richard; Keir, Stephen T. ...
Pediatric blood & cancer,
20/May , Letnik:
58, Številka:
5
Journal Article
RO4929097 is a potent and selective inhibitor of γ‐secretase and as a result is able to inhibit Notch pathway signaling. The activity of RO4929097 was evaluated against the in vivo panels of the ...
Pediatric Preclinical Testing Program (PPTP). RO4929097 induced significant differences in event‐free survival (EFS) distribution compared to control in 6 of 26 (23%) of the evaluable solid tumor xenografts and in 0 of 8 (0%) of the evaluable ALL xenografts. The most consistent tumor growth delay effects were noted in the osteosarcoma panel. RO4929097 at the dose and schedule evaluated demonstrated little antitumor activity against childhood cancer xenografts. Pediatr Blood Cancer 2012; 58: 815–818. © 2011 Wiley Periodicals, Inc.
več
69.
Initial testing (stage 1) of BAL101553, a novel tubulin binding agent, by the pediatric preclinical testing program
Kolb, E. Anders; Gorlick, Richard; Keir, Stephen T. ...
Pediatric blood & cancer,
June 2015, Letnik:
62, Številka:
6
Journal Article
BAL101553 is a highly water soluble prodrug of BAL27862 that arrests tumor cell proliferation and induces cell death in cancer cells through disruption of the microtubule network. In vitro BAL27862 ...
demonstrated potent activity, with the median relative IC50 (rIC50) of 13.8 nM (range 5.4–25.2 nM). The in vitro activity of BAL27862 against the PPTP cell lines is distinctive from that previously described for vincristine. BAL101553 induced significant differences in EFS distribution compared to control in 16 of 30 (53%) solid tumor xenografts and in two of four (67%) of the evaluable ALL xenografts. No objective responses were observed. Pediatr Blood Cancer 2015;62:1106–1109. © 2014 Wiley Periodicals, Inc.
več
70.
Initial testing (stage 1) of the phosphatidylinositol 3′ kinase inhibitor, SAR245408 (XL147) by the pediatric preclinical testing program
Reynolds, C. Patrick; Kang, Min H.; Carol, Hernan ...
Pediatric blood & cancer,
20/May , Letnik:
60, Številka:
5
Journal Article
Background
Activation of the PI3 kinase pathway occurs frequently in many adult cancers and is implicated in tumor cell proliferation, survival, and resistance to chemotherapy and radiotherapy. ...
However, less is known regarding the relevance of this pathway in pediatric cancers. Here we have evaluated SAR245408, a novel small molecule PI3K inhibitor, against childhood cancer cell lines and xenografts.
Procedures
SAR245408 was tested against the PPTP in vitro cell line panel at concentrations from 10 to 100 µM and against the PPTP in vivo xenograft panels at a dose of 100 mg/kg administered orally daily × 14.
Results
In vitro SAR245408 demonstrated cytotoxic activity, with a median relative IC50 value of 10.9 µM (range 2.7–24.5 µM). SAR245408 was well tolerated in vivo, and all 44 tested xenograft models were evaluable for efficacy. SAR245408 induced significant differences in EFS distribution compared to control in 29 of 37 (79%) of solid tumor xenografts and in two of seven (29%) ALL xenografts. SAR245408 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity (EFS T/C > 2) in 4 of 37 (11%) solid tumor xenografts. Intermediate EFS T/C activity was also observed for two of seven (29%) evaluable ALL xenografts. Objective responses were not observed for solid tumor or for ALL xenografts.
Conclusions
Under the conditions evaluated in this study, SAR245408 achieved modest single‐agent activity against most PPTP preclinical models. Further exploration of SAR245408 in combination with standard agents or with other signaling inhibitors could be considered. Pediatr Blood Cancer 2013; 60: 791–798. © 2012 Wiley Periodicals, Inc.
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