Lessons learned: Clinically applicable tools are needed for treatment selection and repurposing of available protein kinase inhibitors (PKIs) in patients with advanced solid tumors refractory to standard treatment.Using a tyrosine kinase peptide substrate microarray, observed inhibitory activity in vitro could not sufficiently predict clinical benefit of treatment with the selected PKI.
Background: This exploratory molecular profiling study determined the feasibility and benefit of the selection of protein kinase inhibitors (PKIs) based on kinase activity profiling in patients with refractory solid malignancies.
Methods: Adult patients with biopsy-accessible refractory solid tumors were eligible. Per patient, the inhibitory potency of sunitinib, dasatinib, erlotinib, sorafenib, everolimus, and lapatinib was determined in tumor lysates from fresh biopsies using a tyrosine kinase peptide substrate microarray. The most active PKI in this in vitro assay was selected for treatment.
Results: Thirteen patients were enrolled in the feasibility part and underwent tumor biopsy. Of 12 patients in whom kinase activity profiling was performed, 11 started treatment with a selected PKI: dasatinib in 8, sunitinib in 2, and erlotinib in 1 patient(s). Eight patients were evaluable for response. One patient had stable disease (SD) >4 months on sunitinib; one patient had SD at 6 weeks but progressive disease (PD) at 12 weeks. The remaining patients had PD after 6 weeks of treatment.
Conclusion: Kinase inhibition profiles of multiple PKIs can be reliably determined using fresh tumor biopsies from patients with refractory solid tumors. However, the current in vitro microarray selection approach insufficiently predicted clinical benefit of PKI treatment in these patients.
经验获取
• 在标准疗法难以治疗的晚期实体瘤患者中,需要临床适用的工具来选择疗法及再利用现行的蛋白激酶抑制剂 (PKI)。
• 使用酪氨酸激酶肽基微阵列体外观察抑制剂活性不能充分预测用所选 PKI 进行治疗的临床疗效。
摘要
背景。本探索性分子表达谱研究确定了根据难治性恶性实体瘤患者激酶活性谱选择的蛋白激酶抑制剂 (PKI) 的可行性和优势。
方法。可活检的难治性实体瘤的成人患者符合本研究的条件。采用酪氨酸激酶肽基微阵列通过新鲜活组织检查测定每位患者体内肿瘤裂解物中舒尼替尼、达沙替尼、厄洛替尼、索拉非尼、依维莫司和拉帕替尼的抑制效力。选择该体外测定中活性最高的 PKI 用于进行治疗。
结果。13 名患者参与了可行性部分,并接受了肿瘤活检。对其中的 12 名患者进行了激酶活性谱分析,对 11 名患者开始进行所选 PKI 的治疗:8 名患者服用达沙替尼,2 名患者服用舒尼替尼,1 名患者服用厄洛替尼。8 名患者的缓解程度可评估。1 名患者在服用舒尼替尼后病情稳定 (SD) 时间超过 4 个月;1 名患者在 6 周时SD,但在 12 周时出现疾病进展(PD)。其余患者在治疗6周后出现PD。
结论。通过新鲜肿瘤活组织检查可以可靠地测定难治性实体瘤患者体内多种 PKI 的激酶抑制谱。但是,当前的体外微阵列选择法未充分预测 PKI 治疗对上述患者的临床疗效。
Trial registration: ClinicalTrials.gov NCT01190241.
© AlphaMed Press; the data published online to support this summary are the property of the authors.