New Approaches to SCLC Therapy: From the Laboratory to the Clinic

Poirier, John T.; George, Julie; Owonikoko, Taofeek K.; Berns, Anton; Brambilla, Élisabeth; Byers, Lauren A.; Carbone, David P.; Chen, Huanhuan Joyce; Christensen, Camilla L.; Dive, Caroline; Farago, Anna F.; Govindan, Ramaswamy; Hann, Christine L.; Hellmann, Matthew D.; Horn, Leora; Johnson, Jane E.; Ju, Young Seok; Kang, Sumin; Krasnow, Mark A.; Lee, James; Lee, Se‐Hoon; Lehman, Jonathan M.; Lok, Benjamin H.; Lovly, Christine M.; MacPherson, David; McFadden, David G.; Minna, John D.; Oser, Matthew G.; Park, Keunchil; Park, Kwon-Sik; Pommier, ﻿Yves; Quaranta, Vito; Ready, Neal; Sage, Julien; Scagliotti, Giorgio Vittorio; Sos, Martin L.; Sutherland, Kate D.; Travis, William D.; Vakoc, Christopher R.; Wait, Sarah J.; Wistuba, Ignacio I.; Wong, Kwok Kin; Zhang, Hua; Daigneault, Jillian B.; Wiens, Jacinta; Rudin, Charles M.; Oliver, Trudy G.

doi:10.1016/j.jtho.2020.01.016

Cited by 133 publications

(136 citation statements)

References 153 publications

(231 reference statements)

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“…SCLC represents 13% of lung cancer cases, with a 5-year survival rate of only 5%. Due to the aggressive nature of the disease, together with its acquired resistance to chemotherapy, the standard care for advanced SCLC has essentially remained stagnant for more than 30 years, until only very recently with the introduction of immunotherapy (Poirier et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Wilson

Jannetti

Guru

et al. 2020

International Journal of Radiation Biology

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Purpose: 123 I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123 I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123 I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials. Materials and methods: 123 I-MAPi was prepared in a single step via 123 I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123 I-MAPi in a small cell lung cancer model. Results: 123 I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq mmol À1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation. Conclusions: Here, we have developed an improved radiosynthesis of 123 I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123 I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123 I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

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Section: Introductionmentioning

confidence: 99%

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Wilson

Jannetti

Guru

et al. 2020

International Journal of Radiation Biology

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“…Although systemic therapies including immunotherapy have begun to show promising outcomes in the past few years, the outcomes of SCLC patients remain to be substantially impacted [ 24 ]. Chemotherapy and radiation therapy are still the main stay approaches regardless of the stage of LD or ED [ 25 ].…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Hippo Pathway and CD133 in Radiation Resistance in Small-Cell Lung Cancer

Yang

et al. 2021

Journal of Oncology

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Although the Hippo pathway and CD133 have been reported to play pertinent roles in a variety of cancer, knowledge about their contribution to radiation resistance in small-cell lung cancer (SCLC) is limited. In this first-of-a-kind study, we have reported the expression of key Hippo pathway proteins in SCLC patients by immunohistochemical staining. We assessed the involvement of yes-associated protein 1 (YAP1) in radiation resistance by Cell Counting Kit-8 (CCK-8) and flow cytometry. In addition, we analysed the impact of CD133 on radiotherapy for SCLC. The mammalian Ste20-like serine/threonine kinase 2(MST2), pMST2, and pYAP1 in the Hippo pathway were not significantly associated with the disease stage and survival time in patients with SCLC. However, the pYAP1 expression showed some significance in the “YAP/TAZ subgroup” of SCLC patients. The proportion of CD133 in the SCLC cells was controlled by the YAP1 expression. The CD133 and YAP1 levels were significantly correlation with each other in tissues of SCLC patients. We sorted and isolated the CD133+ and CD133−cells in H69 and found that the cell surface glycoprotein may be associated with the radiation resistance of SCLC.In summary, we have firstly reported the expression of key Hippo pathway proteins in SCLC patients. Furthermore, we also identified that CD133 may be controlled by the expression of YAP1 in the Hippo pathway and that CD133 may be associated with the radiation resistance of SCLC.

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“…Sloman et al ( 12 ) investigated the role of several immunohistochemical markers, including synaptophysin and CD 44 in a small sample of 28 patients, and could not find a significant correlation concerning survival, whereas in an analysis by Drivsholm et al ( 47 ), the expression of chromogranin A in plasma correlated with a worse OS and the stage of disease. Recent studies have shown that SCLC has four different molecular subtypes with a different neuroendocrine character each identified by their key transcriptional regulator ( 3 , 48 ). A subset of small cell lung carcinomas shows loss of the typical neuroendocrine markers.…”

Section: Discussionmentioning

confidence: 99%

“…SCLC is an aggressive, high-grade neuroendocrine tumor associated with a short doubling time, a high growth fraction, and early development of widespread metastases, which contribute to the extremely poor prognosis of the disease ( 1 – 3 ). In an era of precision medicine, there is an increasing need for defining biomarkers that could assist in therapeutic decision making.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer

et al. 2020

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Background: The aim of the study was to evaluate the role of different immunohistochemical and radiomics features in patients with small cell lung cancer (SCLC). Methods: Consecutive patients with histologically proven SCLC with limited (n = 47, 48%) or extensive disease (n = 51, 52%) treated with radiotherapy and chemotherapy at our department were included in the analysis. The expression of different immunohistochemical markers from the initial tissue biopsy, such as CD56, CD44, chromogranin A, synaptophysin, TTF-1, GLUT-1, Hif-1 a, PD-1, and PD-L1, and MIB-1/KI-67 as well as LDH und NSE from the initial blood sample were evaluated. H-scores were additionally generated for CD44, Hif-1a, and GLUT-1. A total of 72 computer tomography (CT) radiomics texture features from a homogenous subgroup (n = 31) of patients were correlated with the immunohistochemistry, the survival (OS), and the progression-free survival (PFS). Results: The median OS, calculated from diagnosis, was 21 months for patients with limited disease and 13 months for patients with extensive disease. The expression of synaptophysin correlated with a better OS (HR 0.546 95% CI 0.308-0.966, p = 0.03). The expression of TTF-1 (HR 0.286, 95% CI: 0.117-0.698, p = 0.006) and a lower GLUT-1 H-score (median = 50, HR: 0.511, 95% CI: 0.260-1.003, p = 0.05) correlated with a better PFS. Patients without chromogranin A expression had a higher risk for developing cerebral metastases (p = 0.02) and patients with PD 1 expression were at risk for developing metastases (p = 0.02). Our radiomics analysis did not reveal a single texture feature that correlated highly with OS or PFS. Correlation coefficients ranged between −0.48 and 0.39 for OS and between −0.46 and 0.38 for PFS. Gkika et al. Immunohistochemistry and Radiomics in SCLC Conclusions: The role of synaptophysin should be further evaluated as synaptophysin-negative patients might profit from treatment intensification. We report an, at most, moderate correlation of radiomics features with overall and progression free survival and no correlation with the expression of different immunohistochemical markers.

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New Approaches to SCLC Therapy: From the Laboratory to the Clinic

Cited by 133 publications

References 153 publications

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Evaluation of Hippo Pathway and CD133 in Radiation Resistance in Small-Cell Lung Cancer

Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer

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New Approaches to SCLC Therapy: From the Laboratory to the Clinic

Cited by 133 publications

References 153 publications

Improved radiosynthesis of 123I-MAPi, an auger theranostic agent

Improved radiosynthesis of 123I-MAPi, an auger theranostic agent

Evaluation of Hippo Pathway and CD133 in Radiation Resistance in Small-Cell Lung Cancer

Immunohistochemistry and Radiomic Features for Survival Prediction in Small Cell Lung Cancer

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Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent

Improved radiosynthesis of ¹²³I-MAPi, an auger theranostic agent