Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease

Milenic, Diane E.; Garmestani, Kayhan; Brady, Erik D.; Albert, Paul S.; Abdulla, Alia; Flynn, Joseph M.; Brechbiel, Martin W.

doi:10.1158/1078-0432.ccr-06-2300

Cited by 67 publications

(79 citation statements)

References 42 publications

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“…This overall tumor response was similar to mice pretreated with GEM prior to injection with 212 Pb-trastuzumab. 4 GEM increases the survival of mice receiving either 212 Pb-labeled cetuximab or trastuzumab by 1.6-fold. Treatment of tumor-bearing mice with carboplatin appears to inhibit or suppress the therapeutic efficacy of 212 Pb-cetuximab.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Milenic

Baidoo

Kim

et al. 2015

mAbs

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Section: Discussionmentioning

confidence: 99%

“…Radiolabeling of CHX-A"-cetuximab (50 mg in 100 mL of 0.15 M NH 4 OAc buffer, pH 7.0) with 111 In (PerkinElmer) has been detailed elsewhere. 23 For these studies, 212 Pb was obtained from a 224 Ra/ 212 Pb generator (AlphaMed, Inc..).…”

Section: Radiolabelingmentioning

confidence: 99%

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Milenic

Baidoo

Kim

et al. 2015

mAbs

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“…[13][14][15][16][17] The starting dose level for this first cohort in a Phase I trial was low compared to theoretical tolerance and experience in other species but was consistent with the starting dose for another a particle radioimmunotherapy trial using 211 At. 20 This dose allowed monitoring of blood, urine, and imaging with minimal exposure to laboratory personnel.…”

Section: Discussionmentioning

confidence: 59%

“…IP administration of 212 Pb-TCMC-trastuzumab in a preclinical setting has demonstrated therapeutic activity against a variety of human tumor xenografts, and has allowed assessment of redistribution from the peritoneal cavity. [13][14][15][16][17] Those studies provided the information required to progress to this initial clinical trial of IP 212 Pb-TCMC-trastuzumab.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Imaging of²¹²Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients

Meredith

Torgue

Azure

et al. 2014

Cancer Biotherapy and Radiopharmaceuticals

120

103

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Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212 Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. Experimental Design: IP 212 Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. Results: Imaging studies after 0.2 mCi/m 2 (7.4 MBq/m 2 ) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was < 23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was £ 6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212 Pb physical decay (T 1/2 = 10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m 2 IP 212 Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, £ 6% urinary excretion, and good tolerance.

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“…All showed therapeutic efficacy in HER2-expressing xenografts. In addition, a combination of RIT and radiosensitizing chemotherapy was shown to potentiate the therapeutic effect of 212 Pb-radiolabeled trastuzumab, resulting in prolonged median survival in HER2-positive xenograft models (65). RIT with 90 Ytrastuzumab was even found to be applicable to BC expressing small amounts of HER2 (61).…”

Section: Her2-targeted Therapy With Radioactive Anti-her2 Probesmentioning

confidence: 99%

Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

et al. 2016

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Since the approval of trastuzumab, a humanized monoclonal antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2), 3 other HER2-targeting agents have gained regulatory approval: lapatinib, pertuzumab, and trastuzumab-emtansine. These agents have revolutionized the management of HER2-positive breast cancer, highlighting the concept that targeted therapies are successful when patients exhibit tumor-selective expression of a molecular target-in this case, HER2. However, response prediction and innate or acquired resistance remain serious concerns. Predictive biomarkers of a response-which could help in the selection of patients who might benefit from a selected targeted therapy-are currently lacking. Molecular imaging with anti-HER2 probes allows the noninvasive, whole-body assessment of HER2 tumor burden and has the potential to improve patient selection, optimize the dose and schedule, and rationalize assessment of the response to anti-HER2 therapies. Furthermore, unlike biopsy-based HER2 assessment, this approach can reveal inter-or intratumoral heterogeneity as well as variations in HER2 expression over time. This review summarizes the available literature and the current status of molecular imaging as a tool for the assessment of HER2 (target) expression or the prediction of an early treatment response in early and advanced HER2-positive breast cancer. Human epidermal growth factor receptor 2 (HER2) is overexpressed in several cancers, including breast, gastric, ovary, prostate, bladder, and lung cancers, and is a proven therapeutic target in the first 2 tumor types (1,2). In breast cancer (BC), in particular, HER2 overexpression is found in 15%-25% of patients and is associated with a clinically aggressive course. Successful targeting of HER2 with a range of anti-HER2 drugs has resulted in markedly improved patient outcomes in both advanced and early disease settings (3).However, the presence of a target (in this case, HER2) does not always guarantee benefit from matched targeted therapies because downstream signaling resistance or escape can occur. In HER2-overexpressing BC, it has been estimated that about 50% of patients with metastases do not benefit from anti-HER2 therapies (4), and not a single biomarker for identifying nonresponding patients has yet been validated (5).Furthermore, there is increasing evidence of temporal and spatial heterogeneity in BC HER2 overexpression. Patients with negative test results at diagnosis can have positive test results later in the disease course and vice versa, a fact that explains why biopsy of metastatic disease is a strong recommendation of many clinical treatment guidelines (6). Heterogeneity in biomarker expression at metastatic sites is only beginning to be recognized, with growing appreciation for molecular imaging.This article focuses on HER2-positive BC and provides a comprehensive overview of the present and future roles of molecular imaging in improving target mapping, predicting benefit from chemotherapy with or without ...

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Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease

Abstract: Purpose: Recent studies from this laboratory with 212

Cited by 67 publications

References 42 publications

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Pharmacokinetics and Imaging of²¹²Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients

Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

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Potentiation of High-LET Radiation by Gemcitabine: Targeting HER2 with Trastuzumab to Treat Disseminated Peritoneal Disease

Abstract: Purpose: Recent studies from this laboratory with 212

Cited by 67 publications

References 42 publications

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Evaluation of cetuximab as a candidate for targeted α-particle radiation therapy of HER1-positive disseminated intraperitoneal disease

Pharmacokinetics and Imaging of212Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients

Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

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Product

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Pharmacokinetics and Imaging of²¹²Pb-TCMC-Trastuzumab After Intraperitoneal Administration in Ovarian Cancer Patients