Using reverse-phase protein arrays as pharmacodynamic assays for functional proteomics, biomarker discovery, and drug development in cancer
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Yiling Lu, Shiyun Ling, Apurva M. Hegde, Lauren A. Byers, Kevin Coombes, Gordon B. Mills, Rehan Akbani Source Type: research
The root causes of pharmacodynamic assay failure
Robust pharmacodynamic assay results are valuable for informing go/no ‐go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contribut ors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing, and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Katherine V. Ferry-Galow, Hala R. Makhlouf, Deborah F. Wilsker, Scott M. Lawrence, Thomas D. Pfister, Allison M. Marrero, Kristina M. Bigelow, William H. Yutzy, Jiuping J. Ji, Donna O. Butcher, Brad A. Gouker, Shivaani Kummar, Alice P. Chen, Robert J. Kin Source Type: research
Pharmacodynamic analyses in a multi-laboratory network: lessons from the poly(ADP-ribose) assay
This report describes the process of making an immunoassay based on commercially available reagents “clinically ready”. The assay was developed to quantify poly(ADP-ribose) (PAR) levels as a marker of PAR polymerase inhibitor activity for a proof-of-concept phase 0 clinical trial at the National Cancer Institute (NCI) and subsequent clinical trials. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Katherine V. Ferry-Galow, Jiuping Ji, Robert Kinders, Yiping Zhang, R. Kenneth Czambel, John C. Schmitz, Josef Herzog, Yvonne A. Evrard, Ralph Parchment Source Type: research
Promise and limits of the CellSearch platform for evaluating pharmacodynamics in circulating tumor cells
We present representative data from three clinical trials with the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Lihua Wang, Priya Balasubramanian, Alice P. Chen, Shivaani Kummar, Yvonne A. Evrard, Robert J. Kinders Source Type: research
Using reverse-phase protein arrays as pharmacodynamic assays for functional proteomics, biomarker discovery, and drug development in cancer
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Yiling Lu, Shiyun Ling, Apurva M. Hegde, Lauren A. Byers, Kevin Coombes, Gordon B. Mills, Rehan Akbani Source Type: research
Translating Pharmacodynamic Biomarkers from Bench to Bedside: Analytical Validation and Fit-for-Purpose Studies to Qualify Multiplex Immunofluorescent Assays for use on Clinical Core Biopsy Specimens
Multiplex pharmacodynamic (PD) assays have the potential to increase sensitivity of biomarker-based reporting for new targeted agents, as well as revealing significantly more information about target and pathway activation than single-biomarker PD assays. Stringent methodology is required to ensure reliable and reproducible results. Common to all PD assays is the importance of reagent validation, assay and instrument calibration, and the determination of suitable response calibrators; however, multiplex assays, particularly those performed on paraffin specimens from tissue blocks, bring format-specific challenges adding a ...
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Allison Marrero, Scott Lawrence, Deborah Wilsker, Andrea Regier Voth, Robert Kinders Source Type: research
Promise and Limits of the CellSearch® Platform for Evaluating Pharmacodynamics in Circulating Tumor Cells (CTC)
We present representative data from three clinical trials with the PARP inhibitor veliparib (ABT-888) suggesting that CTCs can be used to measure PD effects, but our experience points to the difficulty in obtaining sufficient EpCAM-expressing CTCs from patients with advanced disease to reach statistically significant conclusions about PD effects from each trial, instead often leading to hypothesis generating information. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Lihua Wang, Priya Balasubramanian, Alice Chen, Shivaani Kummar, Yvonne A. Evrard, Robert Kinders Source Type: research
Using Reverse-Phase Protein Arrays (RPPAs) as Pharmacodynamic Assays for Functional Proteomics, Biomarker Discovery, and Drug Development in Cancer
The majority of the targeted therapeutic agents in clinical use target proteins and protein function. Although DNA and RNA analyses have been used extensively to identify novel targets and patients likely to benefit from targeted therapies, these are indirect measures of the levels and functions of most therapeutic targets. More importantly, DNA and RNA analysis is ill-suited for determining the pharmacodynamic effects of target inhibition. Assessing changes in protein levels and function is the most efficient way to evaluate the mechanisms underlying sensitivity and resistance to targeted agents. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Yiling Lu, Shiyun Ling, Apurva M. Hegde, Lauren A. Byers, Kevin Coombes, Gordon B. Mills, Rehan Akbani Source Type: research
The Root Causes of Pharmacodynamic Assay Failure
Robust pharmacodynamic assay results are valuable for informing go/no‐go decisions about continued development of new anti-cancer agents and for identifying combinations of targeted agents, but often pharmacodynamic results are too incomplete or variable to fulfill this role. Our experience suggests that variable reagent and specimen quality are two major contributors to this problem. Minimizing all potential sources of variability in procedures for specimen collection, processing and assay measurements is essential for meaningful comparison of pharmacodynamic biomarkers across sample time points. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Katherine V. Ferry-Galow, Hala R. Makhlouf, Deborah F. Wilsker, Scott M. Lawrence, Thomas D. Pfister, Allison M. Marrero, Kristina M. Bigelow, William H. Yutzy, Jiuping J. Ji, Donna O. Butcher, Brad A. Gouker, Shivaani Kummar, Alice P. Chen, Robert J. Kin Source Type: research
Pharmacodynamic Analyses in a Multi-laboratory Network: Lessons from the Poly(ADP-ribose) Assay
This report describes the process of making an immunoassay based on commercially available reagents “clinically ready”. The assay was developed to quantify poly(ADP-ribose) (PAR) levels as a marker of PAR polymerase inhibitor activity for a proof-of-concept phase 0 clinical trial at the NCI and subsequent clinical trials. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 13, 2016 Category: Cancer & Oncology Authors: Katherine V. Ferry-Galow, Jiuping Ji, Robert Kinders, Yiping Zhang, R. Kenneth Czambel, John C. Schmitz, Josef Herzog, Yvonne A. Evrard, Ralph Parchment Source Type: research
Critical parameters in targeted drug development: the pharmacological audit trail
The Pharmacological Audit Trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: (1) defining a patient population; (2) establishing pharmacokinetic characteristics; (3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; (4) determining intermediate biomarkers of response; (5) assessing tumor response; and (6) determining how to overcome resistance by combination or sequential therapy and new target/drug discovery. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 12, 2016 Category: Cancer & Oncology Authors: Udai Banerji, Paul Workman Source Type: research
Establishing proof of mechanism: Assessing target modulation in early-phase clinical trials
Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early-phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 12, 2016 Category: Cancer & Oncology Authors: Shivaani Kummar, Khanh Do, Geraldine O ’Sullivan Coyne, Alice Chen, Jiuping Ji, Larry Rubinstein, James H. Doroshow Source Type: research
Critical Parameters in Targeted Drug Development: The Pharmacological Audit Trail
The pharmacological audit trail (PhAT) comprises a set of critical questions that need to be asked during discovery and development of an anticancer drug. Key aspects include: 1) defining a patient population; 2) establishing pharmacokinetic characteristics; 3) providing evidence of target engagement, pathway modulation, and biological effect with proof of concept pharmacodynamic biomarkers; 4) determining intermediate biomarkers of response; 5) assessing tumor response; and 6) overcoming resistance by combination or sequential therapy and new target/drug discovery. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 12, 2016 Category: Cancer & Oncology Authors: Udai Banerji, Paul Workman Source Type: research
Establishing Proof of Mechanism: Assessing Target Modulation in Early-Phase Clinical Trials
Since modulation of the putative target and the observed anti-tumor effects form the basis for the clinical development of a molecularly targeted therapy, early phase clinical trials should be designed to demonstrate proof-of-mechanism in tissues of interest. In addition to establishing safety and the maximum tolerated dose, first-in-human clinical trials should be designed to demonstrate target modulation, define the proposed mechanism of action, and evaluate pharmacokinetic-pharmacodynamic relationships of a new anti-cancer agent. (Source: Seminars in Oncology)
Source: Seminars in Oncology - June 12, 2016 Category: Cancer & Oncology Authors: Shivaani Kummar, Khanh Do, Geraldine O’Sullivan Coyne, Alice Chen, Jiuping Ji, Larry Rubinstein, James H. Doroshow Source Type: research
ASCO Plenary Sessions: impact, legacy, future
The ASCO annual meeting draws a large crowd of physicians, cancer researchers, policy makers, and industry representatives. The crown jewel of the annual events is the Plenary session where impactful, influential and visible abstracts are selected for the largest audience. Plenary topics are frequently paired with concurrent New England Journal or Lancet publications. Here, we review 9 years of ASCO plenary sessions. Several themes emerge. First, many of the topics selected have indeed been practice changing, such as the use of ALK inhibitors for ALK rearranged NSCLC, or checkpoint inhibitors in metastatic melanoma....
Source: Seminars in Oncology - May 31, 2016 Category: Cancer & Oncology Authors: Andrae Vandross, Vinay Prasad, Sham Mailankody Source Type: research
