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Neoadjuvant Dasatinib for Muscle-Invasive Bladder Cancer With Tissue Analysis of Biologic Activity

Neoadjuvant Dasatinib for Muscle-Invasive Bladder Cancer With Tissue Analysis of Biologic Activity

Noah M Hahn, Beatrice S Knudsen, Siamak Daneshmand, Michael O Koch, Richard Bihrle, Richard S Foster, Thomas A Gardner, Liang Cheng, Ziyue Liu, Timothy Breen, Mark T Fleming, Raymond Lance, Christopher L Corless, etc.

Urol Oncol. 2016 Jan;34(1):4.e11-7.

PMID: 26362343

Abstract:

Objectives:
Preclinical urothelial carcinoma models suggest activity of dasatinib, an oral SRC-family kinase (SFK) inhibitor. We sought to determine the feasibility and biologic activity of neoadjuvant dasatinib (Neo-D) in patients with muscle-invasive urothelial carcinoma of the bladder (miUCB) preceding radical cystectomy (RC).
Materials and methods:
A prospective multisite phase II trial was conducted. Key eligibility criteria included: resectable miUCB (T2-T4a, N0, M0), and Eastern Cooperative Oncology Group performance status 0 to 1. Patients received oral Neo-D 100mg once daily for 28±7 days followed by RC 8 to 24 hours after the last dose. The primary end point was feasibility, defined as≥60% of patients with miUCB completing therapy without treatment-related dose-limiting toxicity (DLT). Pre- and posttreatment tumor immunohistochemistry of phosphorylated SFK (pSFK), Ki-67, and cleaved caspase (Cas)-3 results were analyzed by paired t test.
Results:
The study completed full accrual with enrollment of 25 patients of whom 23 were evaluable for feasibility. The study achieved its primary end point with 15 patients (65%) completing therapy without treatment-related DLTs. DLTs included: fatigue (n = 2), pulmonary embolism, abdominal pain, supraventricular tachycardia, enteric fistula, hematuria, and dyspnea (n = 1 each). At RC, 5 patients (23%) hadConclusions:
Neo-D in miUCB patients was feasible and safe. Overall, significant inhibition of pSFK was observed without overall reduction of cellular proliferation or increase of apoptosis, although biologic anti-tumor activity may exist in a small subset of patients. These results highlight the potential utility of the neoadjuvant trial paradigm and suggest that clinical benefit of single-agent SFK inhibition in unselected patients with miUCB is unlikely.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP147837523	Caspase Inhibitor II - CAS 147837-52-3		147837-52-3	Price
AP459848352	Src Kinase Inhibitor II - CAS 459848-35-2		459848-35-2	Price

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