scholarly journals Cabozantinib Inhibits Photodynamic Therapy-Induced Auto- and Paracrine MET Signaling in Heterotypic Pancreatic Microtumors

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1401 ◽  
Author(s):  
Mans Broekgaarden ◽  
Ahmed Alkhateeb ◽  
Shazia Bano ◽  
Anne-Laure Bulin ◽  
Girgis Obaid ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Kinase Inhibitor ◽  
Treatment Resistance ◽  
Local Tumor Control ◽  
Ductal Adenocarcinoma ◽  
Tumor Control ◽  
Multi Agent ◽  
Therapeutic Mechanisms ◽  
Tumor Metastases

Extensive desmoplasia is a hallmark of pancreatic ductal adenocarcinoma (PDAC), which frequently associates with treatment resistance. Recent findings indicate that a combination of photodynamic therapy and the multi-kinase inhibitor cabozantinib achieved local tumor control and a significant decrease in tumor metastases in preclinical PDAC models, but the underlying therapeutic mechanisms remain unclear. This study elucidates the molecular basis of this multi-agent regimen, focusing on the role of MET signaling. Since MET activation stems from its interaction with hepatocyte growth factor (HGF), which is typically secreted by fibroblasts, we developed heterotypic PDAC microtumor models that recapitulate these interactions. In these models, MET signaling can be constitutively activated through paracrine and autocrine mechanisms. Photodynamic therapy caused significant elevations in HGF secretion by fibroblasts, suggesting it plays a complex role in the modulation of the paracrine HGF–MET signaling cascade in desmoplastic tumors. Blocking MET phosphorylation with adjuvant cabozantinib caused a significant improvement in photodynamic therapy efficacy, most notably by elevating spheroid necrosis at low radiant exposures. These findings highlight that adjuvant photodynamic therapy can augment chemotherapy efficacies, and potentially achieve improved management of desmoplastic PDAC in a more tolerable manner.

scholarly journals Photodynamic Therapy in Advanced Tracheobronchial Cancers

1999 ◽  
Vol 5 (4) ◽  
pp. 245-251 ◽  
Author(s):  
Tom G. Sutedja
Keyword(s):  
Photodynamic Therapy ◽  
Tracheobronchial Tree ◽  
Local Tumor Control ◽  
Treatment Modalities ◽  
Tumor Control ◽  
Tissue Necrosis ◽  
Endoscopic Techniques ◽  
Lung Cancer Patients ◽  
Secondary Tissue ◽  
Effectiveness Studies

Photodynamic therapy (PDT) has been introduced in the early eighties for treating patients with malignancies in the tracheobronchial tract. After intravenous injection of the photosensitizers, the tumor area in the tracheobronchial tree is illuminated bronchoscopically using a laser fiber to transmit light of a specific wavelength during the procedure. Secondary tissue necrosis ensues, because of the thrombosis of the tumor vasculature leading to late tissue hypoxia. Ample data have shown that PDT is effective to obtain full depth tissue necrosis with relative sparing of the normal tissue. Local tumor control can be achieved. Competitive endoscopic techniques such as lasers and electrocautery are applicable to debulk tumor in a less selective but more immediate manner. Skin photosensitivity is a potential morbidity of PDT, especially in using the first generation photosensitizers. This limits its palliative potential. More selective and more phototoxic sensitizers in combination with the use of portable diode laser, may improve the clinical usefulness of PDT in the management of lung cancer patients. However, cost-effectiveness studies comparing PDT and other local bronchoscopic treatment modalities such as thermal lasers, electrocautery, cryotherapy, brachytherapy, whether or not in addition to external radiotherapy and chemotherapy, should be conducted to define its definite role in the palliative treatment of advanced obstructive bronchial cancers.

scholarly journals Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control

2020 ◽  
pp. 1-11 ◽  
Author(s):  
Stephanie Schipmann ◽  
Michael Müther ◽  
Louise Stögbauer ◽  
Sebastian Zimmer ◽  
Benjamin Brokinkel ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Aminolevulinic Acid ◽  
Diffusion Tensor ◽  
Case Series ◽  
Local Tumor Control ◽  
Resection Margins ◽  
Tumor Control ◽  
Therapeutic Effects ◽  
Local Tumor ◽  
Continuous Irrigation

OBJECTIVEHigh-grade glioma (HGG) prognosis remains dismal, with inevitable, mostly local recurrence. Regimens for improving local tumor control are therefore needed. Photodynamic therapy (PDT) using porfimer sodium has been investigated but was abandoned due to side effects and lack of survival benefits. Intracellular porphyrins induced by 5-aminolevulinic acid (5-ALA) are approved for fluorescence-guided resections (FGRs), but are also photosensitizers. Activated by light, they generate reactive oxygen species with resultant cytotoxicity. The authors present a combined approach of 5-ALA FGR and PDT.METHODSAfter 5-ALA FGR in recurrent HGG, laser diffusors were strategically positioned inside the resection cavity. PDT was applied for 60 minutes (635 nm, 200 mW/cm diffusor, for 1 hour) under continuous irrigation for maintaining optical clarity and ventilation with 100% oxygen. MRI was performed at 24 hours, 14 days, and every 3 months after surgery, including diffusion tensor imaging and apparent diffusion coefficient maps.RESULTSTwenty patients were treated. One surgical site infection after treatment was noted at 6 months as the only adverse event. MRI revealed cytotoxic edema along resection margins in 16 (80%) of 20 cases, mostly annular around the cavity, corresponding to prior laser diffusor locations (mean volume 3.3 cm3). Edema appeared selective for infiltrated tissue or nonresected enhancing tumor. At the 14-day follow-up, enhancement developed in former regions of edema, in some cases vanishing after 4–5 months. Median progression-free survival (PFS) was 6 months (95% CI 4.8–7.2 months).CONCLUSIONSCombined 5-ALA FGR and PDT provides an innovative and safe method of local tumor control resulting in promising PFS. Further prospective studies are warranted to evaluate long-term therapeutic effects.

ATM- and ATR-Induced Primary Ciliogenesis Promotes Cisplatin Resistance in Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Yu-Ying Chao ◽  
Bu-Miin Huang ◽  
I-Chen Peng ◽  
Yi-Shyun Lai ◽  
Wen-Tai Chiu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanism ◽  
Primary Cilia ◽  
Kinase Inhibitor ◽  
Ductal Adenocarcinoma ◽  
Ataxia Telangiectasia Mutated ◽  
Development And Differentiation ◽  
Inhibitor Resistance

Abstract BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of its late diagnosis and chemoresistance. Primary cilia, the cellular antennae, are observed in most human cells to maintain development and differentiation. Primary cilia are gradually lost during the progression of pancreatic cancer and are eventually absent in PDAC. However, recent study showed that primary cilia regrowth contributes to the development of diverse kinase inhibitor resistance in lung cancer. We elucidated the role of regrowth primary ciliogenesis in PDAC chemoresistance and uncovered the underlying molecular mechanism.ResultsWe showed that cisplatin-resistant PDAC regrew primary cilia. Additionally, genetic or pharmacological disruption of primary cilia sensitized PDAC to cisplatin treatment. Mechanistically, ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR), tumor suppressors that initiate DNA damage responses, promoted the excessive formation of centriolar satellites (EFoCS) and autophagy activation. Disruption of EFoCS and autophagy inhibited primary ciliogenesis, sensitizing PDAC cells to cisplatin treatment. ConclusionsCollectively, our findings revealed an unexpected interplay among the DNA damage response, primary cilia, and chemoresistance in PDAC and deciphered the molecular mechanism by which ATM/ATR-mediated EFoCS and autophagy cooperatively regulate primary ciliogenesis.

scholarly journals A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin-mediated Photodynamic Therapy

2017 ◽  
Vol 93 (4) ◽  
pp. 1115-1122 ◽  
Author(s):  
Haixia Qiu ◽  
Michele M. Kim ◽  
Rozhin Penjweini ◽  
Jarod C. Finlay ◽  
Theresa M. Busch ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Local Tumor ◽  
Dose Metrics

scholarly journals STMO-17 Treatment outcome of photodynamic therapy using talaporfin sodium for recurrent high-grade glioma

2021 ◽  
Vol 3 (Supplement_6) ◽  
pp. vi14-vi14
Author(s):  
Makoto Ohno ◽  
Daisuke Kawauchi ◽  
Yoshiharu Hayashi ◽  
Kaishi Satomi ◽  
Yasuji Miyakita ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Treatment Outcome ◽  
Treatment Outcomes ◽  
High Grade Glioma ◽  
Local Tumor Control ◽  
Tumor Control ◽  
High Grade ◽  
Local Tumor ◽  
Limit Of Quantification ◽  
Talaporfin Sodium

Abstract Objective: Photodynamic therapy (PDT) using Talaporfin Sodium (TS) is a novel therapeutic strategy to improve local tumor control in high-grade glioma. TS is a photosensitizer that accumulates in tumor cells and produces highly toxic free radicals by intraoperative irradiation of laser with a 664nm wavelength. However, little is known about the treatment outcomes of PDT in recurrent high-grade gliomas (rHGG). In this study, we investigated the treatment outcome of PDT in rHGG and evaluated the correlation between intratumoral TS accumulation and outcomes. Methods: We included 21 patients with rHGG and 22 tumors, who were treated by PDT between June 2016 and March 2021. TS was transvenously administered 22–26 hours before PDT. Intratumoral TS concentrations were measured by liquid chromatography using frozen tissue. Results: The rHGGs included 10 glioblastoma, IDH1/2-wildtype (GBM, IDH1/2-WT: 45.5%), 3 GBM, IDH1/2-mutant (GBM, IDH1/2-Mut: 13.6%), 7 anaplastic oligodendroglioma, IDH1/2-Mut/codel (AO, IDH1/2-Mut/codel: 31.8%), 1 anaplastic astrocytoma, IDH1/2-WT (AA, IDH1/2-WT: 4.5%), 1 high-grade astrocytoma, IDH1/2-WT (4.5%). The median local progression free survival (PFS) time after PDT was 3.6 months and the median survival time from PDT was 19.4 months. The intratumoral TS concentrations of 7 tumors (TS(-): 31.8%) were below the limit of quantification, and the intratumoral TS concentrations of the remaining 15 tumors (TS(+)) were 43.5 ng/mg-protein (14.7–132 ng/mg-protein). The intratumoral TS concentrations were not significantly associated with IDH1/2 mutation status, cellularity, tumor grade, and pattern of enhancement. The median PFS from PDT tended to be longer in TS(+) than in TS(-) (TS(+): 6.3 vs TS(-): 1.4 months, p = 0.054). Conclusions: We found that the intratumoral TS concentrations were heterogeneous and 31.8% were below the limit of quantification. TS(+) tended to have better local tumor control than TS(-), suggesting the intratumoral TS accumulation have an impact of treatment outcomes of PDT.

The Role of Stereotactically Guided Conformal Radiotherapy for Local Tumor Control of Esthesioneuroblastoma

2002 ◽  
Vol 178 (4) ◽  
pp. 187-191 ◽  
Author(s):  
Angelika Zabel ◽  
Christoph Thilmann ◽  
Stefanie Milker-Zabel ◽  
Wolfgang Schlegel ◽  
Ivan Zuna ◽  
...  
Keyword(s):  
Conformal Radiotherapy ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Local Tumor

scholarly journals Contralateral Liver Hypertrophy and Oncological Outcome Following Radioembolization with 90Y-Microspheres: A Systematic Review

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 294 ◽  
Author(s):  
Emrullah Birgin ◽  
Erik Rasbach ◽  
Steffen Seyfried ◽  
Nils Rathmann ◽  
Steffen J. Diehl ◽  
...  
Keyword(s):  
Systematic Review ◽  
Oncological Outcome ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Liver Lobe ◽  
Kinetic Growth ◽  
Present Systematic Review ◽  
Definitive Role ◽  
90Y Microspheres

Radioembolization with 90Y-microspheres has been reported to induce contralateral liver hypertrophy with simultaneous ipsilateral control of tumor growth. The aim of the present systematic review was to summarize the evidence of contralateral liver hypertrophy and oncological outcome following unilateral treatment with radioembolization. A systematic literature search using the MEDLINE, EMBASE, and Cochrane libraries for studies published between 2008 and 2020 was performed. A total of 16 studies, comprising 602 patients, were included. The median kinetic growth rate per week of the contralateral liver lobe was 0.7% and declined slightly over time. The local tumor control was 84%. Surgical resection after radioembolization was carried out in 109 out of 362 patients (30%). Although the available data suggest that radioembolization prior to major hepatectomy is safe with a promising oncological outcome, the definitive role of radioembolization requires assessment within controlled clinical trials.

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