Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance... more Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation an...
Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of comput... more Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of computerized tomography, magnetic resonance and endoscopic ultrasound, novel imaging techniques have struggled to get established in the management of patients diagnosed with pancreatic adenocarcinoma for several reasons. Thus, imaging assessment of pancreatic cancer remains a field with scope for further improvement. In contrast to cross-sectional anatomical imaging methods, molecular imaging modalities such as positron emission tomography (PET) can provide information on tumour function. Particularly, tumour proliferation may be assessed by measurement of intracellular thymidine kinase 1 (TK1) activity level using thymidine analogues radiolabelled with a positron emitter for use with PET. This approach, has been widely explored with [(18)F]-fluoro-3'-deoxy-3'-l-fluorothymidine ((18)F-FLT) PET. This manuscript reviews the rationale and physiology behind (18)F-FLT PET imaging, with special focus on pancreatic cancer and other gastrointestinal malignancies. Potential benefit and challenges of this imaging technique for diagnosis, staging and assessment of treatment response in abdominal malignancies are discussed.
... UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348: 104954. 3. Al-Sarraf M, LeB... more ... UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348: 104954. 3. Al-Sarraf M, LeBlanc M, Giri PG et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. ...
Page 368. CHAPTER 19 TUMOR IMAGING APPLICATIONS IN THE TESTING OF NEW DRUGS Eric Ofori Aboagye Az... more Page 368. CHAPTER 19 TUMOR IMAGING APPLICATIONS IN THE TESTING OF NEW DRUGS Eric Ofori Aboagye Azeem Saleem Patricia M. Price Cancer Research Campaign PET Oncology Group Imperial College School ...
As cancer therapy becomes more effective, allowing patients to live longer, the long-term morbidi... more As cancer therapy becomes more effective, allowing patients to live longer, the long-term morbidity of treatment assumes greater significance. Trastuzumab (Herceptin 1 ), a monoclonal antibody that targets the epidermal growth factor, has proven efficacy in breast cancer patients but is also known to be cardiotoxic. Left ventricular ejection fraction (LVEF), a measure of cardiac function, is commonly used to evaluate patients receiving trastuzumab by Multiple Gated Acquisition (MUGA) isotope scans. In this paper, we have assessed the utility of previously published ventricular synchrony parameters in patients undergoing trastuzumab therapy. In addition, we apply Approximate Entropy (ApEn) to MUGA images, as a new measure of cardiac dysfunction and have evaluated its utility in the same patients. A significant change in LVEF (p = 0.015) and ApEn (p = 0.020) but not ventricular synchrony measures were observed over the course of treatment in these patients. The results suggest that ApEn provides a useful measure of cardiac function and synchrony. ß
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined w... more Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an
Nuclear Science Symposium Conference Record 2007 Nss 07 Ieee 2007, Oct 1, 2007
Page 1. Patient-Specific Noise-Equivalent-Counts from Repeated, Dose Varying [O-15]H2O PET Scans ... more Page 1. Patient-Specific Noise-Equivalent-Counts from Repeated, Dose Varying [O-15]H2O PET Scans Matthew D. Walker, Student Member, IEEE, Julian C. Matthews, Marie-Claude Asselin, Azeem Saleem, Pat Price and Terry Jones ...
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating... more Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 -a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([ 11 C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [ 11 C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen.
The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic act... more The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting.
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance... more Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation an...
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined w... more Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[ 18 F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K I ؍ 0.0033 ؎ 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K I ؍ 0.7313 ؎ 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66 -91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94 -98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing t... more AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and FDG-PET markers of glucose metabolism in tumor tissue to determine if FDG-PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Twelve patients were enrolled in three cohorts; all had dynamic FDG-PET scans and serial pharmacokinetic sampling at baseline, Week 2 (W2) and Week 4 (W4) with tumor biopsies pre-treatment and at W4. Response was evaluated by RECIST v1.1 and GCIG criteria. Biopsy samples were analyzed for mutations and protein expression. GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics (PK) and FDG-PET pharmacodynamic (PD) measures; however an exposure-response-relationship was seen bet...
Background: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positiv... more Background: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.
Scanning protocols in dynamic PET imaging can be optimised to improve the accuracy and precision ... more Scanning protocols in dynamic PET imaging can be optimised to improve the accuracy and precision of measurements of physiological parameters. For [O-15]H2O scans, one of the major factors that can be controlled is the injected dose, which affects the statistical quality of the PET data as well as its accuracy. We build upon a previous dose optimisation methodology that considers
The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic act... more The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed ...
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating... more Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney a...
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance... more Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation an...
Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of comput... more Pancreatic ductal adenocarcinoma is known for its poor prognosis. Since the development of computerized tomography, magnetic resonance and endoscopic ultrasound, novel imaging techniques have struggled to get established in the management of patients diagnosed with pancreatic adenocarcinoma for several reasons. Thus, imaging assessment of pancreatic cancer remains a field with scope for further improvement. In contrast to cross-sectional anatomical imaging methods, molecular imaging modalities such as positron emission tomography (PET) can provide information on tumour function. Particularly, tumour proliferation may be assessed by measurement of intracellular thymidine kinase 1 (TK1) activity level using thymidine analogues radiolabelled with a positron emitter for use with PET. This approach, has been widely explored with [(18)F]-fluoro-3&amp;amp;#39;-deoxy-3&amp;amp;#39;-l-fluorothymidine ((18)F-FLT) PET. This manuscript reviews the rationale and physiology behind (18)F-FLT PET imaging, with special focus on pancreatic cancer and other gastrointestinal malignancies. Potential benefit and challenges of this imaging technique for diagnosis, staging and assessment of treatment response in abdominal malignancies are discussed.
... UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348: 104954. 3. Al-Sarraf M, LeB... more ... UK Co-ordinating Committee on Cancer Research. Lancet 1996; 348: 104954. 3. Al-Sarraf M, LeBlanc M, Giri PG et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. ...
Page 368. CHAPTER 19 TUMOR IMAGING APPLICATIONS IN THE TESTING OF NEW DRUGS Eric Ofori Aboagye Az... more Page 368. CHAPTER 19 TUMOR IMAGING APPLICATIONS IN THE TESTING OF NEW DRUGS Eric Ofori Aboagye Azeem Saleem Patricia M. Price Cancer Research Campaign PET Oncology Group Imperial College School ...
As cancer therapy becomes more effective, allowing patients to live longer, the long-term morbidi... more As cancer therapy becomes more effective, allowing patients to live longer, the long-term morbidity of treatment assumes greater significance. Trastuzumab (Herceptin 1 ), a monoclonal antibody that targets the epidermal growth factor, has proven efficacy in breast cancer patients but is also known to be cardiotoxic. Left ventricular ejection fraction (LVEF), a measure of cardiac function, is commonly used to evaluate patients receiving trastuzumab by Multiple Gated Acquisition (MUGA) isotope scans. In this paper, we have assessed the utility of previously published ventricular synchrony parameters in patients undergoing trastuzumab therapy. In addition, we apply Approximate Entropy (ApEn) to MUGA images, as a new measure of cardiac dysfunction and have evaluated its utility in the same patients. A significant change in LVEF (p = 0.015) and ApEn (p = 0.020) but not ventricular synchrony measures were observed over the course of treatment in these patients. The results suggest that ApEn provides a useful measure of cardiac function and synchrony. ß
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined w... more Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an
Nuclear Science Symposium Conference Record 2007 Nss 07 Ieee 2007, Oct 1, 2007
Page 1. Patient-Specific Noise-Equivalent-Counts from Repeated, Dose Varying [O-15]H2O PET Scans ... more Page 1. Patient-Specific Noise-Equivalent-Counts from Repeated, Dose Varying [O-15]H2O PET Scans Matthew D. Walker, Student Member, IEEE, Julian C. Matthews, Marie-Claude Asselin, Azeem Saleem, Pat Price and Terry Jones ...
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating... more Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 -a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([ 11 C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [ 11 C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney and liver and lowest uptake was seen in lung and muscle. One patient underwent repeat analysis on day 15 of multiple dose therapy, during administration of LY2181308 (750mg), when altered tissue PKs and a favorable change in biodistribution was seen.
The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic act... more The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting.
Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance... more Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation an...
Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined w... more Tumor and normal tissue pharmacokinetics of 5-Fluorouracil (5-FU) in patients can be determined with positron emission tomography scanning. However, the data obtained are of limited value because of the inability to distinguish catabolites (inactive species) from parent 5-FU and anabolites (cytotoxic species). In this paper, we have blocked 5-FU catabolism in one arm of a paired study with eniluracil, an inactivator of dihydropyrimidine dehydrogenase, enabling catabolite correction and calculation of tissue pharmacokinetic parameters to be achieved. Using this novel approach, we report for the first time that the net clearance of 5-[ 18 F]FU from plasma into tumors (liver metastases and pancreatic tumor) of patients is low (K I ؍ 0.0033 ؎ 0.0005 ml plasma/ml tissue/min). In contrast, the initial (up to 10 min) clearance through catabolism in liver was high (K I ؍ 0.7313 ؎ 0.092 ml plasma/ml tissue/min). In the absence of eniluracil, catabolites in tumors accounted for 83% of total tumor exposure (range, 66 -91%), whereas catabolites in liver accounted for 96% of total liver exposure (range, 94 -98%). This study provides definitive evidence that the cytotoxicity of 5-FU in patients with gastrointestinal cancer could be compromised by its intrinsically low uptake by tumors, as well as decreased systemic availability through hepatic catabolism.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing t... more AKT (a serine/threonine-specific protein kinase) regulates many cellular processes contributing to cytotoxic drug resistance. This study's primary objective examined the relationship between GSK2141795, an oral, pan-AKT inhibitor, and FDG-PET markers of glucose metabolism in tumor tissue to determine if FDG-PET could be used to guide personalized dosing of GSK2141795. Biomarker analysis of biopsies was also undertaken. Twelve patients were enrolled in three cohorts; all had dynamic FDG-PET scans and serial pharmacokinetic sampling at baseline, Week 2 (W2) and Week 4 (W4) with tumor biopsies pre-treatment and at W4. Response was evaluated by RECIST v1.1 and GCIG criteria. Biopsy samples were analyzed for mutations and protein expression. GSK2141795 did not significantly influence blood glucose levels. No dose-response relationship was observed between GSK2141795 pharmacokinetics (PK) and FDG-PET pharmacodynamic (PD) measures; however an exposure-response-relationship was seen bet...
Background: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positiv... more Background: Brain metastases are common in human epidermal growth factor receptor (Her)-2-positive breast cancer. Drug access to brain metastases and normal brain is key to management of cranial disease. In this study, positron emission tomography (PET) scanning after administration of radiolabelled lapatinib was used to obtain direct evidence of cranial drug access.
Scanning protocols in dynamic PET imaging can be optimised to improve the accuracy and precision ... more Scanning protocols in dynamic PET imaging can be optimised to improve the accuracy and precision of measurements of physiological parameters. For [O-15]H2O scans, one of the major factors that can be controlled is the injected dose, which affects the statistical quality of the PET data as well as its accuracy. We build upon a previous dose optimisation methodology that considers
The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic act... more The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed ...
Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating... more Antisense oligonucleotides (ASOs) have potential as anti-cancer agents by specifically modulating genes involved in tumorigenesis. However, little is known about ASO biodistribution and tissue pharmacokinetics (PKs) in humans, including whether sufficient delivery to target tumor tissue may be achieved. In this preliminary study in human subjects, we used combined positron emission and computed tomography (PET-CT) imaging and subsequent modeling analysis of acquired dynamic data, to examine the in vivo biodistribution and PK properties of LY2181308 - a second generation ASO which targets the apoptosis inhibitor protein survivin. Following radiolabeling of LY2181308 with methylated carbon-11 ([(11)C]methylated-LY2181308), micro-doses (<1mg) were administered to three patients with solid tumors enrolled in a phase I trial. Moderate uptake of [(11)C]methylated-LY2181308 was observed in tumors (mean=32.5ng*h /mL, per mg administered intravenously). Highest uptake was seen in kidney a...
Uploads
Papers by Azeem Saleem