The Obama Administration's Cancer Moonshot: A Call for Proteomics

Conrads, Thomas P.; Petricoin, Emanuel F.

doi:10.1158/1078-0432.ccr-16-0688

Cited by 14 publications

(8 citation statements)

References 17 publications

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“…Nonetheless, the identification of the true molecular drivers in any given patient’s tumor can be extremely challenging because genomic analysis often fails to identify actionable alterations due to low prevalence rates, or uncovers multiple genomic alterations within the same tumor making it impossible to know which, if any, of the alterations found is causally significant as a targetable event. However, the addition of functional, phosphoprotein-based, drug target activation mapping could provide key missing information to the identification and selection of a molecularly rationalized therapy regimen (55). In this context, the development of quantitative, standardized, CAP/CLIA-accredited platforms suitable for measuring the activation level of drug targets and downstream substrates, including RPPA-based analysis of specific phosphoprotein levels, are becoming invaluable for capturing the molecular landscape of malignant lesions (21, 56, 57).…”

Section: Discussionmentioning

confidence: 99%

Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Pierobon

Ramos

Wong

et al. 2017

Clinical Cancer Research

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Purpose Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K–AKT–mTOR pathway is associated with specific sites of breast cancer metastasis. Experimental Design Next-generation sequencing–based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K–AKT–mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K–AKT–mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions. Results PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P < 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P < 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P < 0.01, mTOR (S2448) P < 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined. Conclusions Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K–AKT–mT OR signaling network.

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Section: Discussionmentioning

confidence: 99%

Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Pierobon

Ramos

Wong

et al. 2017

Clinical Cancer Research

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“…Proteins have historically been the most widely used and most successful type of biomarkers for use in cancer patients, although they are generally applied in diagnostic rather than screening settings (7,8). Major advances in proteomics have inspired renewed efforts to develop improved biomarkers for ovarian and other cancers (9)(10)(11)(12). Some of the most sophisticated of these use unbiased approaches wherein proteins from cancer patients and normal individuals are proteolytically digested and the resultant peptides are assessed via MS technologies.…”

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confidence: 99%

Selected reaction monitoring approach for validating peptide biomarkers

Wang

Zhang

Tomita

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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We here describe a selected reaction monitoring (SRM)-based approach for the discovery and validation of peptide biomarkers for cancer. The first stage of this approach is the direct identification of candidate peptides through comparison of proteolytic peptides derived from the plasma of cancer patients or healthy individuals. Several hundred candidate peptides were identified through this method, providing challenges for choosing and validating the small number of peptides that might prove diagnostically useful. To accomplish this validation, we used 2D chromatography coupled with SRM of candidate peptides. We applied this approach, called sequential analysis of fractionated eluates by SRM (SAFE-SRM), to plasma from cancer patients and discovered two peptides encoded by the peptidyl-prolyl isomerase A (PPIA) gene whose abundance was increased in the plasma of ovarian cancer patients. At optimal thresholds, elevated levels of at least one of these two peptides was detected in 43 (68.3%) of 63 women with ovarian cancer but in none of 50 healthy controls. In addition to providing a potential biomarker for ovarian cancer, this approach is generally applicable to the discovery of peptides characteristic of various disease states.

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“…In this study we conducted a first-of-its kind comparison between two popular cellular isolation techniques that are being extensively used in a number of important precision oncology programs such as the U.S. Department of Defense APOLLO program [61][62][63] and the I-SPY2 TRIAL series. Several prior precision studies have compared reproducibility, sampling heterogeneity, and laser effects for the LCM process, as well as accuracy studies comparing LCM generated HER2 and activated HER2 to FISH and IHC [8,47,48,64,65].…”

Section: Discussionmentioning

confidence: 99%

The impact of ultraviolet- and infrared-based laser microdissection technology on phosphoprotein detection in the laser microdissection-reverse phase protein array workflow

et al. 2020

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Reversible protein phosphorylation represents a key mechanism by which signals are transduced in eukaryotic cells. Dysregulated phosphorylation is also a hallmark of carcinogenesis and represents key drug targets in the precision medicine space. Thus, methods that preserve phosphoprotein integrity in the context of clinical tissue analyses are crucially important in cancer research. Here we investigated the impact of UV laser microdissection (UV LMD) and IR laser capture microdissection (IR LCM) on phosphoprotein abundance of key cancer signaling protein targets assessed by reverse-phase protein microarray (RPPA). Tumor epithelial cells from consecutive thin sections obtained from four high-grade serous ovarian cancers were harvested using either UV LMD or IR LCM methods. Phosphoprotein abundances for ten phosphoproteins that represent important drug targets were assessed by RPPA and revealed no significant differences in phosphoprotein integrity from those obtained using higher-energy UV versus the lowerenergy IR laser methods.

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The Obama Administration's Cancer Moonshot: A Call for Proteomics

Cited by 14 publications

References 17 publications

Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Enrichment of PI3K-AKT–mTOR Pathway Activation in Hepatic Metastases from Breast Cancer

Selected reaction monitoring approach for validating peptide biomarkers

The impact of ultraviolet- and infrared-based laser microdissection technology on phosphoprotein detection in the laser microdissection-reverse phase protein array workflow

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