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Clin Cancer Res. 2015 Jun 15;21(12):2811-9. doi: 10.1158/1078-0432.CCR-14-2685. Epub 2015 Mar 16.

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient-Derived Xenograft Models.

Author information

1
Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
2
AstraZeneca, Cambridge, United Kingdom.
3
AstraZeneca, Alderley Park, United Kingdom.
4
Xentech, Evry, France.
5
Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts. Celina.Dcruz@astrazeneca.com.

Abstract

PURPOSE:

Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.

EXPERIMENTAL DESIGN:

Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).

RESULTS:

AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death.

CONCLUSIONS:

Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.

PMID:
25779944
DOI:
10.1158/1078-0432.CCR-14-2685
[Indexed for MEDLINE]
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