• EPR effect
• clinical translation
• nanomedicine
• tumor microenvironments

• NRF-2022M3H4A1A03067401 National Research Foundation of Korea

• Doxorubicin
• Ifosfamide
• Olaratumab
• Safety
• Soft tissue sarcoma

Autologous platelet rich plasma (PRP) has significant benefits facilitating improved graft take on wound beds due to hemostasis, adhesive and healing properties. This study aimed at effective use of PRP in wound beds on graft take irrespective of etiology as compared to conventional methods of mechanical fixation using sutures and staples.

Forty cases including 20 in control and 20 in PRP groups admitted to the Department of Plastic Surgery at Vydehi Institute of Medical Sciences and Research Centre, Bangalore were enrolled between October 2015 and September 2017. Freshly prepared autologous PRP was applied on wound beds in the treated group, while conventional mechanical fixation methods like staples and sutures were used in the control group for the fixation of the skin grafts.

Most significant result was the instant graft take to the wound bed irrespective of the etiology besides hemostasis and healing properties in the PRP treated group which resulted in considerable reduction of surgeon’s time required for the removal of sutures and staples at the final stages. Also, only 10% with graft edema were noted in the PRP treated patients as compared to 68% in the control group. The inner dressings and skin graft were dry in the PRP group and the post-operative etching, weeping and pain at the graft site reduced.

The cosmetic appearance of this scar was better in the PRP group besides post-operative edema and graft loss. The study recommends use of PRP at the recipient site of split thickness skin graft.

• Autologous
• Graft
• Platelet rich plasma
• Split thickness skin graft
• Wound

• Liposomal doxorubicin
• Olaratumab
• Ovarian cancer
• Platinum refractory
• Platinum resistant

• IMC-3G3
• Soft tissue sarcoma
• anti-PDGFRα monoclonal antibody
• olaratumab
• sarcoma

• CP-673451
• Cisplatin
• NSCLC
• Nrf2
• PDGFRβ

• Pathology Section
• airway remodeling
• asthma
• neuropilin 1
• platelet-derived growth factor
• semaphorin 3A

Constitutive STAT3 activation by tyrosine phosphorylation of mutated or amplified tyrosine kinases (pYSTAT3) is critical for cancer initiation, progression, invasion, and motility of carcinoma cells. We showed that AF1q is associated with STAT3 signaling in breast cancer cells. In xenograft models, enhanced AF1q expression activated STAT3 and promoted tumor growth and metastasis in immunodeficient NSG mice. The cytokine secretory phenotype of MDA-MB-231LN breast cancer cells with altered AF1q expression revealed changes in expression of platelet-derived growth factor subunit B (PDGF-B). AF1q-induced PDGF-B stimulated motility, migration, and invasion of MDA-MB-231LN cells, and AF1q up-regulated platelet-derived growth factor receptor (PDGFR) signaling. Further, AF1q-induced PDGFR signaling enhanced STAT3 activity through Src kinase activation, which could be blocked by the Src kinase inhibitor PP1. Moreover, AF1q up-regulated tyrosine kinase signaling through PDGFR signaling, which was blockable by imatinib. In conclusion, we demonstrated that enhanced AF1q expression contributes to persistent and oncogenic pYSTAT3 levels in invasive carcinoma cells by activating Src kinase through activation of the PDGF-B/PDGFR cascade. Therefore, AF1q plays an essential role as a cofactor in PDGF-B-driven STAT3 signaling.

• AF1q
• PDGF
• PDGFR
• STAT3
• Src

• Soft tissue sarcoma
• chemotherapy
• olaratumab
• platelet derived growth factor
• platelet derived growth factor receptor

• NSCLC
• Olaratumab
• PDGFR
• Paclitaxel/carboplatin

• PDGFRA
• PDGFRα
• diagnostics
• immunohistochemistry
• pathology

• Nilotinib
• PDGF
• aorta
• cholesterol
• liver

• soft tissue sarcoma
• olaratumab
• monoclonal antibody
• doxorubicin

• Adult
• Aged
• Aged, 80 and over
• Antibiotics, Antineoplastic/administration & dosage
• Antibiotics, Antineoplastic/therapeutic use
• Antibodies, Monoclonal/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Disease-Free Survival
• Doxorubicin/administration & dosage
• Doxorubicin/therapeutic use
• Drug Administration Schedule
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Patient Selection
• Sarcoma/drug therapy
• Treatment Outcome
• United States

• P30 CA008748 NCI NIH HHS
• P50 CA140146 NCI NIH HHS

• GZD856
• Lung cancer
• Metastasis
• PDGFRα/β inhibitor
• Stromal

Glioblastoma is the most common type of malignant human brain tumor. Currently available chemotherapies for glioblastoma focus on targeting tyrosine kinases. However, the existing inhibitors of tyrosine kinases have not produced the therapeutic outcomes that were anticipated. In order to investigate the viability alternative chemotherapeutic agents in this disease, the present study examined the anticancer effects of tyrphostin AG 1296, focusing on its involvement in apoptosis in glioblastoma cells. The study aimed to identify whether tyrphostin AG 1296 affects glioblastoma cell growth by inducing cell apoptosis. To achieve this, cell viability, propidium iodide analysis and cell invasion assay were used to measure cell growth, cell apoptosis and cell migration of human glioblastoma cells. The results showed that tyrphostin AG 1296 treatment reduced cell viability and suppressed migration of human glioblastoma cells. It was also demonstrated that tyrphostin AG 1296 induced cell apoptosis in vitro. Finally, tyrphostin AG 1296 was also shown to significantly inhibit the growth of glioblastoma cells and to increase tumor cell apoptosis in vivo. These findings suggest that tyrphostin AG 1296 induces apoptosis, thereby reducing cell viability and capacity for migration of glioblastoma cells.

• cancer therapy
• glioblastoma
• platelet-derived growth factor receptor inhibitor
• tyrphostin AG 1296

• Hsp90
• cancer
• homology modeling
• molecular docking
• molecular dynamics
• quantitative structure-activity relationship
• virtual screening

• pdgfrα
• 3g3
• uterine cancer

• Animals
• Antibodies, Monoclonal/immunology
• Antibodies, Monoclonal/pharmacology
• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Blotting, Western
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Immunohistochemistry
• Mice, Nude
• Mitogen-Activated Protein Kinases/metabolism
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Neovascularization, Pathologic/prevention & control
• Oligonucleotide Array Sequence Analysis
• Phosphorylation/drug effects
• Proto-Oncogene Proteins c-akt/metabolism
• Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors
• Receptor, Platelet-Derived Growth Factor alpha/immunology
• Receptor, Platelet-Derived Growth Factor alpha/metabolism
• Signal Transduction/drug effects
• Transcriptome/drug effects
• Uterine Neoplasms/drug therapy
• Uterine Neoplasms/genetics
• Uterine Neoplasms/metabolism
• Xenograft Model Antitumor Assays

• P30 CA016672 NCI NIH HHS
• R01 CA109298 NCI NIH HHS
• CA016672 NCI NIH HHS
• P50 CA098258 NCI NIH HHS
• P50 CA083639 NCI NIH HHS
• R01 CA128797 NCI NIH HHS
• P50CA083639 NCI NIH HHS
• T32 CA101642 NCI NIH HHS
• CA109298 NCI NIH HHS
• CA128797 NCI NIH HHS
• U54 CA151668 NCI NIH HHS
• RC2 GM092599 NIGMS NIH HHS

• Cell migration
• Epidermal growth factor
• Metastasis
• Pancreatic cancer
• Receptor tyrosine kinases

• PDGF
• metastasis
• targeted therapy
• tumor growth
• tumor microenvironment

In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR).

This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes.

Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail.

The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy.

ClinicalTrials.gov NCT01011075

• molecular biology
• oncogenes
• tumor biology

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Humans
• Mutation
• Neoplasms/drug therapy
• Neoplasms/physiopathology
• Oncogene Proteins v-sis/chemistry
• Platelet-Derived Growth Factor/antagonists & inhibitors
• Platelet-Derived Growth Factor/chemistry
• Platelet-Derived Growth Factor/physiology
• Protein Isoforms/physiology
• Receptors, Platelet-Derived Growth Factor/genetics

Increased CCL5 levels are markers of an unfavourable outcome in patients with melanoma, breast, cervical, prostate, gastric or pancreatic cancer. Here, we have assessed the role played by CCL5/CCR5 interactions in the development of colon cancer. To do so, we have examined a number of human colorectal carcinoma clinical specimens and found CCL5 and its receptors over-expressed within primary as well as liver and pulmonary metastases of patients compared to healthy tissues. In vitro, CCL5 increased the growth and migratory responses of colon cancer cells from both human and mouse origins. In addition, systemic treatment of mice with CCL5-directed antibodies reduced the extent of development of subcutaneous colon tumors, of liver metastases and of peritoneal carcinosis. Consistently, we found increased numbers of CD45-immunoreactive cells within the stroma of the remaining lesions as well as at the interface with the healthy tissue. In contrast, selective targeting of CCR5 through administration of TAK-779, a CCR5 antagonist, only partially compromised colon cancer progression. Furthermore, CCL5 neutralization rendered the tumors more sensitive to a PDGFRβ-directed strategy in mice, this combination regimen offering the greatest protection against liver metastases and suppressing macroscopic peritoneal carcinosis. Collectively, our data demonstrate the involvement of CCL5 in the pathogenesis of colorectal carcinoma and point to its potential value as a therapeutic target.

• Amides/pharmacology
• Animals
• Antibodies, Neutralizing/immunology
• CHO Cells
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Chemokine CCL5/antagonists & inhibitors
• Chemokine CCL5/immunology
• Chemokine CCL5/metabolism
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Cricetinae
• Cricetulus
• Disease Progression
• Female
• HT29 Cells
• Humans
• Leukocytes/drug effects
• Leukocytes/immunology
• Mice
• Molecular Targeted Therapy
• Neoplasm Metastasis
• Quaternary Ammonium Compounds/pharmacology
• Receptor, Platelet-Derived Growth Factor beta/genetics
• Receptor, Platelet-Derived Growth Factor beta/metabolism
• Receptors, CCR5/metabolism
• Treatment Outcome

Pancreatic cancer does not respond to a single-agent imatinib therapy. Consequently, multimodality treatments are contemplated. Published data indicate that in colorectal cancer, imatinib and radioimmunotherapy synergize to delay tumor growth. In pancreatic cancer, the tumor response is additive. This disparity of outcomes merited further studies because interactions between these modalities depend on the imatinib-induced reduction of the tumor interstitial fluid pressure. The examination of human and murine PDGFr-β/PDGF-B pathways in SW1990 pancreatic cancer xenografts revealed that the human branch is practically dormant in untreated tumors but the insult on the stromal component produces massive responses of human cancer cells. Inhibition of the stromal PDGFr-β with imatinib activates human PDGFr-β/PDGF-B signaling loop, silent in untreated xenografts, via an apparent paracrine rescue pathway. Responses are treatment-and time-dependent. Soon after treatment, levels of human PDGFr-β, compared to untreated tumors, are 3.4×, 12.4×, and 5.7× higher in imatinib-, radioimmunotherapy + imatinib-, and radioimmunotherapy-treated tumors, respectively. A continuous 14-day irradiation of imatinib-treated xenografts reduces levels of PDGFr-β and phosphorylated PDGFr-β by 5.3× and 4×, compared to earlier times. Human PDGF-B is upregulated suggesting that the survival signaling via the autocrine pathway is also triggered after stromal injury. These findings indicate that therapies targeting pancreatic cancer stromal components may have unintended mitogenic effects and that these effects can be reversed when imatinib is used in conjunction with radioimmunotherapy.

We have previously shown that small molecule PDGF receptor tyrosine kinase inhibitors (RTKI) can drastically attenuate radiation-induced pulmonary fibrosis if the drug administration starts at the time of radiation during acute inflammation with present but limited effects against acute inflammation. To rule out interactions of the drug with acute inflammation, we investigated here in an interventive trial if a later drug administration start at a time when the acute inflammation has subsided - has also beneficial antifibrotic effects.

Whole thoraces of C57BL/6 mice were irradiated with 20 Gy and treated with the RTKI imatinib starting either 3 days after radiation (during acute inflammation) or two weeks after radiation (after the acute inflammation has subsided as demonstrated by leucocyte count). Lungs were monitored and analyzed by clinical, histological and in vivo non-invasive computed tomography as a quantitative measure for lung density and lung fibrosis.

Irradiation induced severe lung fibrosis resulting in markedly reduced mouse survival vs. non-irradiated controls. Both early start of imatinib treatment during inflammation and late imatinib start markedly attenuated the development of pulmonary fibrosis as demonstrated by clinical, histological and qualitative and quantitative computed tomography results such as reduced lung density. Both administration schedules resulted in prolonged lifespans. The earlier drug treatment start resulted in slightly stronger beneficial antifibrotic effects along all measured endpoints than the later start.

Our findings show that imatinib, even when administered after the acute inflammation has subsided, attenuates radiation-induced lung fibrosis in mice. Our data also indicate that the fibrotic fate is not only determined by the early inflammatory events but rather a complex process in which secondary events at later time points are important. Because of the clinical availability of imatinib or similar compounds, a meaningful attenuation of radiation-induced lung fibrosis in patients seems possible.