Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer

Rajeshkumar, N. V.; Tan, Aik Choon; Oliveira, Elizabeth De; Womack, Chris; Wombwell, Helen; Morgan, Shethah; Warren, Madhuri; Walker, Jill; Green, Tim P.; Jimeno, Antonio; Messersmith, Wells A.; Hidalgo, Manuel

doi:10.1158/1078-0432.ccr-08-3021

Cited by 76 publications

(62 citation statements)

References 40 publications

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“…In mice treated with saracatinib, a significant delay in xenograft tumor growth was measurable after 21 days of drug administration. These data confirm the efficacy of an Src-targeted approach as an efficient strategy to counteract tumor progression, and are consistent with previous works conducted on gastric (35) and pancreatic (8) carcinoma xenograft models.…”

Section: Discussionsupporting

confidence: 91%

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Cavalloni

Peraldo-Neia

Sarotto

et al. 2012

Molecular Cancer Therapeutics

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Biliary tract carcinoma (BTC) has a poor prognosis due to limited treatment options. There is, therefore, an urgent need to identify new targets and to design innovative therapeutic approaches. Among potential candidate molecules, we evaluated the nonreceptor tyrosine kinase Src, observing promising antitumor effects of its small-molecule inhibitor saracatinib in BTC preclinical models. The presence of an active Src protein was investigated by immunohistochemistry in 19 surgical samples from patients with BTC. Upon saracatinib treatment, the phosphorylation of Src and of its downstream transducers was evaluated in the BTC cell lines TFK-1, EGI-1, HuH28, and TGBC1-TKB. The effect of saracatinib on proliferation and migration was analyzed in these same cell lines, and its antitumor activity was essayed in EGI-1 mouse xenografts. Saracatinibmodulated transcriptome was profiled in EGI-1 cells and in tumor samples of the xenograft model. Src was activated in about 80% of the human BTC samples. In cultured BTC cell lines, low-dose saracatinib counteracted the activation of Src and of its downstream effectors, increased the fraction of cells in G 0 -G 1 phase, and inhibited cell migration. At high concentrations (median dose from 2.26-6.99 mmol/L), saracatinib was also capable of inhibiting BTC cell proliferation. In vivo, saracatinib treatment resulted in delayed tumor growth, associated with an impaired vascular network. Here, we provide a demonstration that the targeted inhibition of Src kinase by saracatinib is of therapeutic benefit in preclinical models of BTC. We propose our results as a basis for the design of saracatinib-based clinical applications.

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Section: Discussionsupporting

confidence: 91%

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Cavalloni

Peraldo-Neia

Sarotto

et al. 2012

Molecular Cancer Therapeutics

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“…It has also been suggested that LRRC19 and IGFBP2 identified by the K-TSP classifier are potential predictive biomarkers for saracatinib sensitivity in pancreatic cancer (31). Furthermore, Src overexpression was suggested as genotype-associated indicator of sensitivity to Src inhibitor such as saracatinib and dasatinib in ovarian, breast, NSCLC, or prostate cancers (32).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

Nam

et al. 2013

Molecular Cancer Therapeutics

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Src is a nonreceptor tyrosine kinase involved in the cross-talk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration, and tumorigenesis. Increased Src activity has been reported in many types of human cancer, including gastric cancer. Therefore, this factor has been identified as a promising therapeutic target for cancer treatments, and targeting Src in gastric cancer is predicted to have potent effects. We evaluated the antitumor effect of a c-Src/Abl kinase inhibitor, saracatinib (AZD0530), alone or combined with chemotherapeutic agents in gastric cancer cell lines and a NCI-N87 xenograft model. Among 10 gastric cancer cell lines, saracatinib specifically inhibited the growth and migration/invasion of SNU216 and NCI-N87 cells. Saracatinib blocked the Src/FAK, HER family, and oncogenic signaling pathways, and it induced G 1 arrest and apoptosis in SNU216 and NCI-N87 cells. Apoptosis required induction of the proapoptotic BCL2 family member Bim. Knockdown of Bim using siRNA decreased apoptosis induced by treatment with saracatinib, suggesting that Bim has an important role in saracatinibinduced apoptosis. Saracatinib enhanced the effects of lapatinib, an EGFR/HER2 dual inhibitor, in SNU216 and NCI-N87 cells. Furthermore, combined treatment with saracatinib and 5-fluorouracil (5-FU) or cisplatin exerted synergistic effects in both saracatinib-sensitive and saracatinib-resistant cells. Consistent with our in vitro findings, cotreatment with saracatinib and 5-FU resulted in enhanced antitumor activity in the NCI-N87 xenografts. These data indicate that the inhibition of Src kinase activity by saracatinib alone or in combination with other agents can be a strategy to target gastric cancer.

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“…27). There have also been several studies with putative predictive biomarkers from preclinical studies (28)(29)(30). On the basis of the results of this trial, pretreated patients with advanced breast cancer have been treated with oral bosutinib 400 mg/day in a phase II trial (31) and 2 phase II trials in combination with aromatase inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

Daud

Krishnamurthi

Saleh

et al. 2012

Clinical Cancer Research

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Purpose: Bosutinib, a potent ATP-competitive, quinolinecarbonitrile Src/Abl kinase inhibitor, was tested in this first-in-human phase I trial in patients with advanced solid tumor malignancies.Patients and Methods: This trial was conducted in 2 parts. In part 1 (dose escalation), increasing oral bosutinib doses were administered using a 3 þ 3 design. In part 2 (dose expansion), approximately 30 patients each with refractory colorectal, pancreas, or non-small cell lung cancer were treated at the recommended phase II dose (RP2D). Primary efficacy endpoints for part 2 were median progression-free survival (colorectal and non-small cell lung) and median overall survival (pancreas).Results: In part 1, dose-limiting toxicities of grade 3 diarrhea (two patients) and grade 3 rash occurred with bosutinib 600 mg/day and the maximum tolerated dose identified was 500 mg/day. However, the majority of patients treated with 500 mg/day had grade 2 or greater gastrointestinal toxicity, and 400 mg/day was identified as the RP2D. The most common bosutinib-related adverse events were nausea (60% patients), diarrhea (47%), vomiting (40%), fatigue (38%), and anorexia (36%). Bosutinib had a mean half-life of 19 to 20 hours at the RP2D. A partial response (breast) and unconfirmed complete response (pancreas) were observed; 8 of 112 evaluable patients had stable disease for 22 to 101 weeks. However, the primary efficacy endpoints for part 2 were not met.Conclusions: Bosutinib was generally well tolerated in patients with solid tumors, with the main toxicity being gastrointestinal. The RP2D was 400 mg/day orally. Further study of bosutinib is planned in combination regimens.

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Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer

Cited by 76 publications

References 40 publications

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Antitumor Activity of Src Inhibitor Saracatinib (AZD-0530) in Preclinical Models of Biliary Tract Carcinomas

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

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