Targeting of extracellular proteases required for the progression of pancreatic cancer

Ardito, Christine M.; Briggs, Courtney D; Crawford, Howard C.

doi:10.1517/14728222.12.5.605

Cited by 10 publications

(3 citation statements)

References 139 publications

(144 reference statements)

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“…We found that angiogenesis genes tended to be significantly downregulated in BRCA (Breast invasive carcinoma) and UCES(Uterine Corpus Endometrial Carcinoma), but upregulated in PAAD (Pancreatic adenocarcinoma), GBM (Glioblastoma multiforme). These findings are consistent with several previous studies (Ardito et al, 2008;Liu et al, 2019). For example, SPP1 was upregulated in most tumor types.…”

Section: Correlations Between Angiogenesis Score and Immunological Genessupporting

confidence: 93%

Association of Angiogenesis Gene Expression With Cancer Prognosis and Immunotherapy Efficacy

et al. 2022

Front. Cell Dev. Biol.

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Background: Several new blood vessels are formed during the process of tumor development. These new blood vessels provide nutrients and water for tumour growth, while spreading tumour cells to distant areas and forming new metastases in different parts of the body. The available evidence suggests that tumour angiogenesis is closely associated with the tumour microenvironment and is regulated by a variety of pro-angiogenic factors and/or angiogenic inhibitors.Methods: In the present study, a comprehensive characterization of angiogenesis genes expression was performed in a pan-cancer analysis across the 33 human cancer types. Further, genetic data from several public databases were also used in the current study. An angiogenesis score was assigned to The Cancer Genome Atlas (TCGA) pan-cancer data, with one angiogenesis score as per sample for each tumour.Results: It was found that angiogenesis genes vary across cancer types, and are associated with a number of genomic and immunological features. Further, it was noted that macrophages and iTreg infiltration were generally higher in tumours with high angiogenesis scores, whereas lymphocytes and B cells showed the opposite trend. Notably, NK cells showed significantly different correlations among cancer types. Furthermore, results of the present study showed that a high angiogenesis score was associated with poor survival and aggressive types of cancer in most of the cancer types.Conclusion: In conclusion, the current study evidently showed that the expression of angiogenesis genes is a key feature of tumour biology that has a major impact on prognosis of patient with cancers.

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Section: Correlations Between Angiogenesis Score and Immunological Genessupporting

confidence: 93%

Association of Angiogenesis Gene Expression With Cancer Prognosis and Immunotherapy Efficacy

et al. 2022

Front. Cell Dev. Biol.

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“…The recognition of MMPs as disease biomarkers has stimulated the development of imaging strategies targeting these proteases, aiming for improved diagnosis or application in image-guided surgery. Commonly used approaches for MMP imaging are based on targeting with antibodies or smallmolecule ligands (5)(6)(7)(8)(9). For example, radiolabeled MMP binding ligands have been developed for the detection of upregulated MMP levels by means of SPECT or PET (10)(11)(12).…”

mentioning

confidence: 99%

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Duijnhoven¹,

Robillard²,

Nicolay³

et al. 2011

J Nucl Med

106

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Activatable cell-penetrating peptides (ACPPs) are a new class of promising molecular imaging probes for the visualization of enzymes in vivo. The cell-penetrating function of a polycationic peptide is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a cleavable linker present between the polycationic cell-penetrating peptide and polyanionic peptide affords dissociation of both domains and enables the activated cell-penetrating peptide to enter cells. Here, we aimed to develop an ACPP sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for nuclear imaging purposes. Methods: MMP-2/9 ACPPs and nonactivatable cell-penetrating peptides (non-ACPP) were prepared by 9-fluorenylmethyloxycarbonyl solid-phase peptide synthesis and labeled with 177 Lu or 177 Lu/ 125 I for dual-isotope studies. The in vivo biodistribution of these probes was assessed in MMP-2/9-positive tumor-bearing mice (n 5 6) and healthy mice (n 5 4) using g-counting. Furthermore, a radiolabeled cell-penetrating peptide serving as a positive control was evaluated in tumorbearing mice (n 5 6). Results: Biodistribution studies showed a 5-fold-higher retention of ACPP in tumor than in muscle (P , 0.01) and a 6-fold-higher tumor retention relative to non-ACPP (P , 0.01), supporting earlier studies on fluorescently labeled ACPPs proposing activation by tumor-associated MMP-2/9. Surprisingly, however, the uptake of ACPP was significantly higher than that of non-ACPP in almost all tissues (P , 0.01). To unravel the activation process of ACPP in vivo, we developed dual-isotope ACPP analogs (dACPPs) that allowed us to discriminate between uncleaved dACPP and activated dACPP. In vivo biodistribution of dACPP indicated that the tissue-associated counts originated from activated dACPP. Interestingly, dACPP administration to healthy mice, compared with MMP-2/9-positive tumor-bearing mice, resulted in a similar dACPP biodistribution. Furthermore, a radiolabeled cell-penetrating peptide showed tumor-to-tissue ratios equal to those found for ACPP (P . 0.05). Conclusion: This study demonstrates that the tumor targeting of radiolabeled MMP-2/9 ACPPs is most likely caused by the activation in the vascular compartment rather than tumor-specific activation, as suggested earlier.The results in the present paper indicate that different and more tissue-specific enzyme-ACPP combinations are needed to unleash the full potential of the elegant ACPP concept in living animals.

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“…Epidermal growth factor receptor (EGFR) has a relevant physiological function regulating epithelial tissue development. Aberrant activation of EGFR plays a key role in PC through the activation of downstream cascades that promotes cell survival and proliferation [ 7 , 8 ]. One of the most important EGFR-downstream protein is the focal adhesion kinase (FAK).…”

Section: Introductionmentioning

confidence: 99%

Phospho-Aspirin (MDC-22) inhibits pancreatic cancer growth in patient-derived tumor xenografts and KPC mice by targeting EGFR: Enhanced efficacy in combination with irinotecan

Lanzi¹,

Wei²,

Luo³

et al. 2022

Neoplasia

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Novel therapeutic strategies are needed in the fight against pancreatic cancer. We have previously documented the chemopreventive effect of MDC-22 in preclinical models of pancreatic cancer. In the present work, we examined the therapeutic effects of MDC-22 in patient-derived tumor xenografts (PDTXs) and in LSL-Kras G12D/+, LSL-Trp53 R172H/+, Pdx1-Cre (KPC) genetically engineered mice, two complementary and clinically relevant animal models of pancreatic cancer. In addition, we evaluated whether MDC-22 could synergize with current chemotherapeutic drugs used in the clinic. MDC-22 reduced the growth of various human pancreatic cancer cell lines in a concentration-dependent manner. In vivo , MDC-22 strongly reduced patient-derived pancreatic tumor xenograft growth by 50%, and extended survival of LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre (KPC) mice by over a month (5.3 months versus 7.0 months). In both models, MDC-22 inhibited EGFR activation and its downstream signals, including ERK and FAK phosphorylation. In human pancreatic cancer cell lines, MDC-22 enhanced the growth inhibitory effect of irinotecan, and to a lesser degree those of gemcitabine and nab-paclitaxel. Normal human pancreatic epithelial cells were more resistant to the cytotoxic effects of, both, MDC-22 alone or in combination with irinotecan, indicating selectivity. Furthermore, MDC-22 enhanced irinotecan's effect on cell migration, in part, by inhibiting EGFR/FAK signaling. Collectively, our results indicate that MDC-22 is an effective anticancer drug in preclinical models of pancreatic cancer, and suggest that MDC-22 plus irinotecan as drug combination strategy for pancreatic cancer treatment, which warrants further evaluation.

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Targeting of extracellular proteases required for the progression of pancreatic cancer

Cited by 10 publications

References 139 publications

Association of Angiogenesis Gene Expression With Cancer Prognosis and Immunotherapy Efficacy

Association of Angiogenesis Gene Expression With Cancer Prognosis and Immunotherapy Efficacy

Tumor Targeting of MMP-2/9 Activatable Cell-Penetrating Imaging Probes Is Caused by Tumor-Independent Activation

Phospho-Aspirin (MDC-22) inhibits pancreatic cancer growth in patient-derived tumor xenografts and KPC mice by targeting EGFR: Enhanced efficacy in combination with irinotecan

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