Showing papers by "Evan Y. Yu published in 2009"
TL;DR: Encouraging evidence is provided of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC and treatment-related adverse events were moderate.
Abstract: Purpose: Antiproliferative and antiosteoclastic activity from preclinical models show potential for dasatinib, an oral SRC and SRC family kinase inhibitor, as a targeted therapy for patients with prostate cancer. This phase II study investigated the activity of dasatinib in patients with metastatic castration-resistant prostate cancer (CRPC). Experimental Design: Chemotherapy-naive men with CRPC and increasing prostate-specific antigen were treated with dasatinib 100 or 70 mg twice daily. Endpoints included changes in prostate-specific antigen, bone scans, measurable disease (Response Evaluation Criteria in Solid Tumor), and markers of bone metabolism. Following Prostate Cancer Working Group 2 guidelines, lack of progression according to Response Evaluation Criteria in Solid Tumor and bone scan was determined and reported at 12 and 24 weeks. Results: Forty-seven patients were enrolled and received dasatinib (initial dose 100 mg twice daily, n = 25; 70 mg twice daily, n = 22), of whom 41 (87%) had bone disease. Lack of progression was achieved in 20 (43%) patients at week 12 and in 9 (19%) patients at week 24. Of 41 evaluable patients, 21 (51%) patients achieved ≥40% reduction in urinary N-telopeptide by week 12, with 33 (80%) achieving some level of reduction anytime on study. Of 15 patients with elevated urinary N-telopeptide at baseline, 8 (53%) normalized on study. Of 40 evaluable patients, 24 (60%) had reduction in bone alkaline phosphatase at week 12 and 25 (63%) achieved some reduction on study. Dasatinib was generally well tolerated and treatment-related adverse events were moderate. Conclusions: This study provides encouraging evidence of dasatinib activity in bone and reasonable tolerability in chemotherapy-naive patients with metastatic CRPC. (Clin Cancer Res 2009;15(23):7421–8)
207 citations
TL;DR: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel and inhibits osteolysis associated with CaP, a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK).
Abstract: Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis
90 citations
TL;DR: The PSA RR in both arms met criterion for further study and OS appears superior with DOC/OGX, and this combination warrants further evaluation.
Abstract: 5012 Background: Clusterin is a cytoprotective chaperone protein associated with CRPC progression. OGX is a 2'-methoxyethyl antisense that potentiates chemotherapy in xenografts and inhibits clusterin expression at doses of 60%) could be tested at 10% β and 10% α, Arm B the true PSA RR could be estimated with half-width of the 90% CI ...
32 citations
TL;DR: A 63-year-old man presented with 1 month of left flank pain, gross hematuria, urgency, and frequency; a large bladder mass was identified on cystoscopy and radical cystoprostatectomy with ileal loop diversion and pelvic lymphadenectomy was performed.
Abstract: A 63-year-old man presented with 1 month of left flank pain, gross hematuria, urgency, and frequency; a large bladder mass was identified on cystoscopy. No local extension, lymphadenopathy, or distant metastasis was identified on computed tomography (CT) imaging and bone scan. Transurethral resection of the bladder tumor demonstrated high-grade urothelial carcinoma invasive into the muscularis propria. Approximately 2 months later, work-up for neoadjuvant chemotherapy before cystoprostatectomy identified a WBC count of 42,000/uL with a manual differential of 37,000/uL neutrophils, without other abnormalities or blasts. Urine and blood cultures were negative for bacterial growth, and there were no clinical signs of infection. Neoadjuvant chemotherapy with high-dose methotrexate, vinblastine, doxorubicin, and cisplatin was initiated on days 1 and 2 on an every-2-week cycle for a total of four cycles. Although the first chemotherapy cycle was well tolerated, with significant improvement in urinary symptoms, neutropenia developed, and pegfilgrastim (recombinant granulocyte colony-stimulating growth factor [G-CSF]) was administered on day 3 of the remaining chemotherapy cycles to prevent neutropenic infection. Approximately 1 week before surgery, CT imaging of the chest, abdomen, and pelvis demonstrated a residual bladder mass (Fig 1A, arrows) without evidence of lymphadenopathy or distant metastasis (Fig 2A, coronal abdominal CT). The day before surgery, the leukocyte count was 29,500/uL, with predominantly mature neutrophils without significant left shift. There was no clinical or laboratory evidence of infection. Radical cystoprostatectomy with ileal loop diversion and pelvic lymphadenectomy was performed. The bladder contained a 7-cm, posteriorly located, exophytic, and partially necrotic tumor (Fig 1B, arrows), which invaded through the muscularis into the subserosal soft tissue but did not involve the serosa or soft tissue margin. This was histologically characterized as a high-grade urothelial carcinoma, with multifocal lymphatic space invasion, no identifiable lymph node metastasis, and a minimum pathological stage of pT3bN0Mx. The postoperative course was complicated by a Staphylococcus epidermis portacath infection successfully treated with intravenous vancomycin; however, a leukocytosis of 50,000/uL persisted at the time of hospital discharge. Three days after discharge and 3 weeks after the surgery, the patient was admitted to the hospital with fever, delirium, hypotension, and a clinical concern for sepsis. The leukocyte count was 100,000/uL with a predominance of mature neutrophils with Döhle bodies and toxic granulation, identified as a leukemoid reaction. Broad-spectrum antibiotic treatment was initiated. CT of the chest, abdomen, and pelvis identified numerous pulmonary nodules, hilar lymphadenopathy, and para-aortic lymphadenopathy (Fig 2B, arrows), which had not been identified on the presurgical staging CT approximately 1 month prior (Fig 2A). Blood, urine, CSF, stool, and bronchoalveolar lavage cultures were negative for bacterial or fungal growth. There were no cardiac vegetations identified on transthoracic and transesophageal echocardiography. The leukocyte count peaked at 121,000/uL, and flow cytometry of peripheral blood
31 citations
TL;DR: OGX-427 is a second generation ASO that inhibits Hsp27 expression which in preclinical models inhibited cell growth, induced apoptosis, and enhanced chemotherapy efficacy and was well tolerated.
Abstract: 3506 Background: Heat shock protein 27 (Hsp27) is a chaperone protein expressed in many cancers and implicated as a therapeutic “hyper-node” affecting multiple pathways in cancer progression. Overe...
17 citations
TL;DR: Preliminary clinical activity (tumor and PSA response; decreasing bone turnover [uNTX, BAP]), is now confirmed to be similar in pts treated with 100mg QD and BID dosing, which supports the relevance of further studies of dasatinib in metastatic CRPC.
Abstract: 5147 Background: Dasatinib is a potent oral SRC family kinase inhibitor that also inhibits c-KIT and PDGFR in vitro. The anti-proliferative/anti-metastatic activity as well as osteoclast inhibitory...
13 citations