scholarly journals A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

2020 ◽  
Author(s):  
Lucía Zhu ◽  
Natalia Yebra ◽  
Diana Retana ◽  
Lauritz Miarka ◽  
Elena Hernández-Encinas ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Human Brain ◽  
Drug Screening ◽  
Local Relapse ◽  
Organotypic Cultures ◽  
Systemic Spread ◽  
Screening Platform

AbstractExclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

OS06.7A METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii10-ii10
Author(s):  
L Zhu ◽  
C Blanco-Aparicio ◽  
L Bertero ◽  
R Soffietti ◽  
T Weiss ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Human Tumor ◽  
Response To Therapy ◽  
High Morbidity ◽  
Organotypic Cultures ◽  
The Brain

Abstract BACKGROUND The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. MATERIAL AND METHODS We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures - PDOCs -). We have also used METPlatform to perform unbiased proteomics of brain metastases in situ to identify potential novel mediators of this disease and explore resistance mechanisms to targeted therapy. Finally, we have exploited METPlatform as “avatars” to predict response to therapy in patients with primary brain tumors. RESULTS We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we show that brain tumor PDOCs predict the response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. CONCLUSION Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

scholarly journals 42. IDENTIFICATION OF BRAIN METASTASIS VULNERABILITIES USING METPLATFORM

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii8-ii8
Author(s):  
Lucía Zhu ◽  
Natalia Yebra ◽  
Diana Retana ◽  
Carmen Blanco-Aparicio ◽  
Sonia Martínez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Synergistic Effects ◽  
Human Tumor ◽  
Breast Adenocarcinoma ◽  
High Morbidity ◽  
Organotypic Cultures ◽  
The Brain

Abstract The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. In this study, we report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. We have applied this approach to clinically relevant stages of brain metastasis using both experimental models and human tumor tissue (by performing patient-derived organotypic cultures). We identified heat shock protein 90 (HSP90) as a promising therapeutic target for brain metastasis. Debio-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from melanoma, lung and breast adenocarcinoma with distinct oncogenomic profiles at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, we have also used METPlatform to perform unbiased proteomics of brain metastases in situ. By applying this analysis to brain metastases treated with the chaperone inhibitor, we uncovered non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

scholarly journals BSCI-02. METPlatform identifies brain metastasis vulnerabilities and predicts patient response to therapy

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii1-iii1
Author(s):  
Lucía Zhu ◽  
Carmen Blanco-Aparicio ◽  
Luca Bertero ◽  
Riccardo Soffietti ◽  
Tobias Weiss ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Drug Screening ◽  
Synergistic Effects ◽  
Combined Therapy ◽  
Response To Therapy ◽  
High Morbidity ◽  
Personalized Care ◽  
The Brain

Abstract The diagnosis of brain metastasis involves high morbidity and mortality and remains an unmet clinical need in spite of being the most common tumor in the brain. Exclusion of these cancer patients from clinical trials is a major cause of their limited therapeutic options. We report a novel drug-screening platform (METPlatform) based on organotypic cultures which allows identifying effective anti-metastasis agents in the presence of the organ microenvironment. By applying this approach to brain metastasis, we identified heat shock protein 90 (HSP90) as a promising therapeutic target for CNS dissemination. DEBIO-0932, a blood-brain barrier permeable HSP90 inhibitor, shows high potency against mouse and human brain metastases from different primary origin and oncogenomic profile at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis of brain metastases treated with the chaperone inhibitor revealed non-canonical clients of HSP90 as potential novel mediators of brain metastasis and actionable mechanisms of resistance driven by autophagy. Combined therapy using HSP90 and autophagy inhibitors showed synergistic effects compared to sublethal concentrations of each monotherapy, demonstrating the potential of METPlatform to design and test rationale combination therapies to target metastasis more effectively. Finally, we have exploited METPlatform as “avatars” to show that brain tumor PDOCs predict response of the corresponding patient to standard of care, thus proving the potential of METPlatform for improving personalized care in cancer. In conclusion, our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples and questions the rationale of excluding patients with brain metastasis from clinical trials. We envision that METPlatform will be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.

Rates of occult brain metastases in patients (pts) with advanced renal cell carcinoma (RCC): A cohort study from patients treated across 22 clinical trials.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 673-673
Author(s):  
Ritesh Kotecha ◽  
Almedina Redzematovic ◽  
Robert J. Motzer ◽  
Martin Henner Voss
Keyword(s):  
Clinical Trials ◽  
Cohort Study ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Brain Imaging ◽  
Metastatic Disease ◽  
Disease Assessment ◽  
Cns Disease ◽  
Local Progression ◽  
Metastatic Rcc

673 Background: National guidelines for RCC management only recommend brain imaging ‘if clinically indicated’; the rate of occult brain metastases is not defined. Early detection of CNS disease has major implications as it typically triggers early intervention with the aim to limit morbidity, including major complications of local progression. In an effort to define the utility of brain screening, we investigated the rate of occult brain metastasis in a large cohort of metastatic RCC pts. Methods: We performed a retrospective review of completed and actively accruing metastatic RCC clinical trials conducted at Memorial Sloan Kettering Cancer Center. Individual charts of pts screening for those studies with mandatory brain imaging at baseline were reviewed to identify subjects harboring occult brain metastases. We collected patient demographics, International Metastatic Database Consortium (IMDC) risk status, sites of metastatic disease, and tumor histology. Patients with neurologic symptoms were excluded. Descriptive statistics were applied to analyze findings across the cohort. Results: A total of 22 clinical trials for metastatic RCC conducted from 2004-2017 required brain imaging at baseline, and a total of 535 pts were screened in this context. A total of 25/535 pts were found to have occult brain metastasis (4.67%), which was multi-focal in 10/25 (40%) and sub-cm in 15/25 (60%). For these 25 pts, the mean age at diagnosis was 56 years (38-77), and IMDC risk score at enrollment was: 1/24 favorable (4%), 21/24 intermediate (88%), and 2/24 poor-risk (8%) patients. 18/25 patients presented with de novo metastatic disease; 13/25 had received prior therapies; and 24/25 patients (96%) had > 2 additional non-CNS sites of metastatic disease at time of screening. 21/23 pts and 2/23 pts were then treated with radiation and surgical resection, respectively. Conclusions: This retrospective cohort study shows a 5% rate of occult CNS disease in asymptomatic patients with advanced RCC. These findings can inform current screening guidelines for full disease assessment in metastatic RCC patients.

scholarly journals OTHR-09. Accelerating Research for Breast Cancer Brain Metastasis and Leptomeningeal Disease through Patient-led Collaborations

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii16-iii16
Author(s):  
Christine Hodgdon ◽  
Laurie Campbell
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Metastatic Breast ◽  
Basic Research ◽  
Leptomeningeal Disease ◽  
Eligibility Criteria ◽  
Cns Metastasis ◽  
Breast Cancer Brain Metastasis

Abstract Patient-driven Initiative of the Metastatic Breast Cancer (MBC) Alliance The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The Marina Project has grown to include 35members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or leptomeningeal disease (LMD). Disparities for Patients Living with BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year[1]. Approximately 10–15% of patients with MBC will develop brain metastases, and may be as high as 30–50% for certain subtypes[2]. A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. Values and Objectives The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (i) Increase the quality and quantity of basic research; (ii) Increase the number of clinical trials in areas where research is lacking; (iii) Diversify the type of clinical trial interventions; (iv) Eliminate restrictive eligibility criteria in clinical trials; (v) Incorporate clinically meaningful trial endpoints [1] Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nature reviews. Clinical oncology vol. 8,6 (2011): 344–56. doi: 10.1038/nrclinonc.2011.58 [2] Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35

Risk of intracranial hemorrhage and cerebrovascular accidents in non-small cell lung cancer brain metastasis patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7671-7671
Author(s):  
G. Srivastava ◽  
V. Rana ◽  
S. Taylor ◽  
M. Debnam ◽  
Y. Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cerebrovascular Accidents ◽  
Metastatic Nsclc ◽  
Nsclc Patients

7671 Background: Brain metastases confer significant morbidity and a poorer survival in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor-targeted antiangiogenic therapies (AAT) have demonstrated benefit for patients with metastatic NSCLC and are expected to directly inhibit the pathophysiology and morbidity of brain metastases, yet patients with brain metastases have been excluded from most clinical trials of AAT for fear of intracranial hemorrhage (ICH). This is a low suspected risk, but needs to be quantitated to plan clinical trials of AAT for NSCLC brain metastases. Methods: Data from MD Anderson Cancer Center Tumor Registry and electronic medical records from January 1998 to March 2006 was interrogated. 2143 patients with metastatic NSCLC registering from Jan 1998 to Sept 2005 were followed till March 2006. 776 patients with and 1367 patients without brain metastases were followed till death, date of ICH, or last date of study, whichever occurred first. Results: The incidence of ICH seemed to be higher in those with brain metastasis compared to those without. However, the rates of symptomatic ICH were not significantly different. All ICH patients with brain metastasis had received radiation therapy for them and were not anticoagulated. Most of the brain metastasis-associated ICH's were asymptomatic, detected during radiologic surveillance. The rates of symptomatic ICH, or cerebrovascular accidents were similar and not significantly different between the two groups. The following table depicts the rates of CVA and/or ICH in metastatic NSCLC patients. Conclusions: In metastatic NSCLC patients, the incidence of spontaneous ICH appeared to be higher in those with brain metastases compared to those without, but was very low in both groups nonetheless without a statistically significant difference. These data suggest minimal risk of clinically significant ICH for NSCLC brain metastasis patients and justifies for them clinical trials of AAT. No significant financial relationships to disclose. [Table: see text]

INNV-02. ACCELERATING RESEARCH FOR BREAST CANCER BRAIN METASTASIS AND LEPTOMENINGEAL DISEASE THROUGH PATIENT-LED COLLABORATIONS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi105-vi105
Author(s):  
Christine Hodgdon
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Metastatic Breast ◽  
Basic Research ◽  
Leptomeningeal Disease ◽  
Eligibility Criteria ◽  
Cns Metastasis ◽  
Breast Cancer Brain Metastasis

Abstract PATIENT-DRIVEN INITIATIVE OF THE METASTATIC BREAST CANCER (MBC) ALLIANCE The Breast Cancer Brain Metastasis (BCBM) Initiative: Marina Kaplan Project launched in June 2020 as an official project of the MBC Alliance which includes 32 nonprofits, 12 industry partners, and 30 individual patient advocates. The project has grown to include 35 members with representation from industry, research institutions, and individual patients. Nearly one-third of the group is comprised of patients living with brain metastases or LMD. DISPARITIES FOR PATIENTS LIVING WITH BCBM & LMD In the US, approximately 200,000 new cases of brain metastases are diagnosed each year.1 Approximately 10-15% of patients with MBC will develop brain metastases, and may be as high as 30-50% for certain subtypes.2 A diagnosis of central nervous system (CNS) metastasis often accelerates an already incurable diagnosis. CNS metastasis are difficult to image and detect, tend to have poorer prognoses with lower overall survival, and are treated with invasive therapies which can have lasting side effects. Furthermore, most clinical trials exclude patients with CNS metastasis which further hinders research. VALUES & OBJECTIVES The overarching goal of this initiative is to accelerate the scope and breadth of evidence-based CNS metastasis research by targeting entities conducting clinical trials and collaborating with them to do the following: (1) Increase the quality and quantity of basic research; (2) increase the number of clinical trials in areas where research is lacking; (3) diversify the type of clinical trial interventions; (4) eliminate restrictive eligibility criteria in clinical trials; (5) Incorporate clinically meaningful trial endpoints. References Eichler, April F et al. The biology of brain metastases-translation to new therapies. Nat Rev. Clinical oncology vol. 8,6 (2011): 344-56. doi: 10.1038/nrclinonc.2011.58 Brosnan EM, Anders CK. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018;6(9):163. doi: 10.21037/atm.2018.04.35

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