Autoantibody Cancer Biomarker: Extracellular Protein Kinase A

Nesterova, Maria; Johnson, Natalie R.; Cheadle, Christopher; Bates, Susan E.; Mani, Sridhar; Stratakis, Constantine A.; Kahn, Islam; Gupta, Rishab K.; Cho‐Chung, Yoon S.

doi:10.1158/0008-5472.can-06-1049

Cited by 53 publications

(45 citation statements)

References 15 publications

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“…This enzyme-triggered release could be achieved with enzyme concentrations on the order of 0.1 nM; such nanomolar or subnanomolar sensitivity would be crucial for biomedical application. Though the exact concentration and activity of extracellular protein kinase A in tumors varies among patients, its ability to be quantifiably assayed in the total serum of human cancer patients 49 suggests that the local concentration at the tumor is quite high and could provide a means to specifically target drug release from PA nanostructures at these regions of higher enzyme concentrations.…”

Section: Resultsmentioning

confidence: 99%

Switching of self-assembly in a peptide nanostructure with a specific enzyme

Webber

Newcomb

Bitton³

et al. 2011

Soft Matter

142

141

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Peptide self-assembly has been shown to be a useful tool for the preparation of bioactive nanostructures, and recent work has demonstrated their potential as therapies for regenerative medicine. In principle, one route to make these nanostructures more biomimetic would be to incorporate in their molecular design the capacity for biological sensing. We report here on the use of a reversible enzymatic trigger to control the assembly and disassembly of peptide amphiphile (PA) nanostructures. The PA used in these studies contained a consensus substrate sequence specific to protein kinase A (PKA), a biological enzyme important for intracellular signaling that has also been shown to be an extracellular cancer biomarker. Upon treatment with PKA, this PA molecule becomes phosphorylated causing the high aspect-ratio filamentous PA nanostructures to disassemble. Treatment with an enzyme to cleave the phosphate group results in reformation of the filamentous nanostructures. We also show that disassembly in the presence of PKA allows the enzyme-triggered release of an encapsulated cancer drug. In addition, these drug-loaded nanostructures were found to induce preferential cytotoxicity in a cancer cell line that is known to secrete high levels of PKA. This ability to control nanostructure through an enzymatic switch could allow for the preparation of highly sophisticated and biomimetic materials that incorporate a biological sensing capability to enable therapeutic specificity.

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Section: Resultsmentioning

confidence: 99%

Switching of self-assembly in a peptide nanostructure with a specific enzyme

Webber

Newcomb

Bitton³

et al. 2011

Soft Matter

142

141

View full text Add to dashboard Cite

show abstract

“…Since previous studies have detected PKA in the peripheral blood of cancer patients (38), this chimera may represent a diagnostic marker for FL-HCC. Surgical resection remains the cornerstone of therapy and patients who present with advanced stage or metastatic disease have few treatment options.…”

Section: Main Textmentioning

confidence: 90%

Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma

Honeyman

Simon

Robine

et al. 2014

Science

433

455

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Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver tumor affecting adolescents and young adults who have no history of primary liver disease or cirrhosis. We performed RNA sequencing on FL-HCC tumors and identified a chimeric transcript that was expressed in all tumor samples but not in adjacent normal liver. The chimeric RNA was confirmed by RT-PCR and Sanger Sequencing. Based on the results of whole genome sequencing, the chimeric transcript is the result of a ~400 kilobase deletion on chromosome 19. The chimera was predicted to code for a protein with the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A. The presence of this chimera protein was established by immunoprecipitation and Western Blot analysis. Expression of the chimera in human cell culture demonstrates that it retains kinase activity. Evidence for a DNAJB1-PRKACA chimeric transcript in 15 out of 15 FL-HCC patients suggests that it contributes to tumor pathogenesis.

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“…Many tumor-specific autoantibodies have been identified in the sera of patients with breast cancer 4,5 . Of these, several have been analyzed in detail with hundreds of serum samples, including p53 antigen 6 , her2/neu 7 , MUC1 8 ,c-myc 9 , ECPKA 10 , and NY-ESO-1 11,12 . While the specificity of these antigens for cancer is high (>90%), the sensitivities of individual antigens are low (10-20%).…”

Section: Introductionmentioning

confidence: 99%

Application of Protein Microarrays for Multiplexed Detection of Antibodies to Tumor Antigens in Breast Cancer

et al. 2008

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There is strong preclinical evidence that cancer, including breast cancer, undergoes immune surveillance. This continual monitoring, by both the innate and the adaptive immune systems, recognizes changes in protein expression, mutation, folding, glycosylation, and degradation. Local immune responses to tumor antigens are amplified in draining lymph nodes, and then enter the systemic circulation. The antibody response to tumor antigens, such as p53 protein, are robust, stable, and easily detected in serum, may exist in greater concentrations than their cognate antigens, and are potential highly specific biomarkers for cancer. However, antibodies have limited sensitivities as single analytes, and differences in protein purification and assay characteristics have limited their clinical application. For example, p53 autoantibodies in the sera are highly specific for cancer patients, but are only detected in the sera of 10-20% of patients with breast cancer. Detection of p53 autoantibodies is dependent on tumor burden, p53 mutation, rapidly decreases with effective therapy, but is relatively independent of breast cancer subtype. Although antibodies to hundreds of other tumor antigens have been identified in the sera of breast cancer patients, very little is known about the specificity and clinical impact of the antibody immune repertoire to breast cancer. Recent advances in proteomic technologies have the potential for rapid identification of immune response signatures for breast cancer diagnosis and monitoring. We have adapted programmable protein microarrays for the specific detection of autoantibodies in breast cancer. Here, we present the first demonstration of the application of programmable protein microarray ELISAs for the rapid identification of breast cancer autoantibodies.

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Autoantibody Cancer Biomarker: Extracellular Protein Kinase A

Cited by 53 publications

References 15 publications

Switching of self-assembly in a peptide nanostructure with a specific enzyme

Switching of self-assembly in a peptide nanostructure with a specific enzyme

Detection of a Recurrent DNAJB1-PRKACA Chimeric Transcript in Fibrolamellar Hepatocellular Carcinoma

Application of Protein Microarrays for Multiplexed Detection of Antibodies to Tumor Antigens in Breast Cancer

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