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Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFV600E inhibition resistance in melanoma

Zhang, Ze-Yan; Ding, Yingwen; Ezhilarasan, Ravesanker; Lhakhang, Tenzin; Wang, Qianghu; Yang, Jie; Modrek, Aram S; Zhang, Hua; Tsirigos, Aristotelis; Futreal, Andrew; Draetta, Giulio F; Verhaak, Roel G W; Sulman, Erik P
Targeted cancer therapies have revolutionized treatment but their efficacies are limited by the development of resistance driven by clonal evolution within tumors. We developed "CAPTURE", a single-cell barcoding approach to comprehensively trace clonal dynamics and capture live lineage-coupled resistant cells for in-depth multi-omics analysis and functional exploration. We demonstrate that heterogeneous clones, either preexisting or emerging from drug-tolerant persister cells, dominated resistance to vemurafenib in BRAFV600E melanoma. Further integrative studies uncovered diverse resistance mechanisms. This includes a previously unrecognized and clinically relevant mechanism, chromosome 18q21 gain, which leads to vulnerability of the cells to BCL2 inhibitor. We also identified targetable common dependencies of captured resistant clones, such as oxidative phosphorylation and E2F pathways. Our study provides new therapeutic insights into overcoming therapy resistance in BRAFV600E melanoma and presents a platform for exploring clonal evolution dynamics and vulnerabilities that can be applied to study treatment resistance in other cancers.
PMID: 36202798
ISSN: 2056-5968
CID: 5361762

Modern Hearing Preservation Outcomes After Vestibular Schwannoma Stereotactic Radiosurgery

Berger, Assaf; Alzate, Juan Diego; Bernstein, Kenneth; Mullen, Reed; McMenomey, Sean; Jethanemest, Daniel; Friedmann, David R; Smouha, Eric; Sulman, Erik P; Silverman, Joshua S; Roland, J Thomas; Golfinos, John G; Kondziolka, Douglas
BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.
PMID: 35973088
ISSN: 1524-4040
CID: 5299902

DNA methylation-based epigenetic signatures predict somatic genomic alterations in gliomas

Yang, Jie; Wang, Qianghu; Zhang, Ze-Yan; Long, Lihong; Ezhilarasan, Ravesanker; Karp, Jerome M; Tsirigos, Aristotelis; Snuderl, Matija; Wiestler, Benedikt; Wick, Wolfgang; Miao, Yinsen; Huse, Jason T; Sulman, Erik P
Molecular classification has improved diagnosis and treatment for patients with malignant gliomas. However, classification has relied on individual assays that are both costly and slow, leading to frequent delays in treatment. Here, we propose the use of DNA methylation, as an emerging clinical diagnostic platform, to classify gliomas based on major genomic alterations and provide insight into subtype characteristics. We show that using machine learning models, DNA methylation signatures can accurately predict somatic alterations and show improvement over existing classifiers. The established Unified Diagnostic Pipeline (UniD) we develop is rapid and cost-effective for genomic alterations and gene expression subtypes diagnostic at early clinical phase and improves over individual assays currently in clinical use. The significant relationship between genetic alteration and epigenetic signature indicates broad applicability of our approach to other malignancies.
PMID: 35906213
ISSN: 2041-1723
CID: 5277052

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

Berger, Assaf; Bernstein, Kenneth; Alzate, Juan Diego; Mullen, Reed; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Pavlick, Anna C; Gurewitz, Jason; Mureb, Monica; Mehnert, Janice; Madden, Kathleen; Palermo, Amy; Weber, Jeffrey S; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
PMID: 35665462
ISSN: 1573-7373
CID: 5248172

Risk of Second Primary Neoplasms of the Central Nervous System

Liu, Elisa K; Oh, Cheongeun; Kondziolka, Douglas; Sulman, Erik P
Purpose/UNASSIGNED:Second primary (SP) neoplasms of the central nervous system (CNS) among cancer survivors are devastating but poorly understood processes. The absolute risk, or true incidence, of developing an SP CNS tumor among cancer survivors is not well characterized. Methods and Materials/UNASSIGNED:Patients diagnosed with cancer between 1975 and 2016 were queried using the Surveillance, Epidemiology, and End Results Program. Cumulative incidence rates (CIRs) were estimated using competitive risk analysis. The effects of covariates were assessed using multivariate competitive risk regression. Results/UNASSIGNED: = 7e-5). Conclusions/UNASSIGNED:The risk of developing a second primary CNS neoplasm is elevated in patients with a prior CNS cancer independent of treatment history. The association between cranial radiation therapy and risk for subsequent cancers may be limited to the pediatric population.
PMID: 35814854
ISSN: 2452-1094
CID: 5279782

Radiation Therapy for Brain Metastases: ASCO Guideline Endorsement of ASTRO Guideline

Schiff, David; Messersmith, Hans; Brastianos, Priscilla K; Brown, Paul D; Burri, Stuart; Dunn, Ian F; Gaspar, Laurie E; Gondi, Vinai; Jordan, Justin T; Maues, Julia; Mohile, Nimish; Redjal, Navid; Stevens, Glen H J; Sulman, Erik P; van den Bent, Martin; Wallace, H James; Zadeh, Gelareh; Vogelbaum, Michael A
PURPOSE/OBJECTIVE:American Society of Radiation Oncology (ASTRO) has developed a guideline on appropriate radiation therapy for brain metastases. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS:was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS:. RECOMMENDATIONS/CONCLUSIONS:is conditionally recommended.Additional information is available at
PMID: 35561283
ISSN: 1527-7755
CID: 5214992

Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline

Vogelbaum, Michael A.; Brown, Paul D.; Messersmith, Hans; Brastianos, Priscilla K.; Burri, Stuart; Cahill, Dan; Dunn, Ian F.; Gaspar, Laurie E.; Gatson, Na Tosha N.; Gondi, Vinai; Jordan, Justin T.; Lassman, Andrew B.; Maues, Julia; Mohile, Nimish; Redjal, Navid; Stevens, Glen; Sulman, Erik; Van Den Bent, Martin; Wallace, H. James; Weinberg, Jeffrey S.; Zadeh, Gelareh; Schiff, David
Purpose: To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors. Methods: ASCO convened an Expert Panel and conducted a systematic review of the literature. Results: Thirty-two randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base. Recommendations: Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.
ISSN: 1522-8517
CID: 5198312

Glioblastoma Clinical Trials: Current Landscape and Opportunities for Improvement

Bagley, Stephen J; Kothari, Shawn; Rahman, Rifaquat; Lee, Eudocia Q; Dunn, Gavin P; Galanis, Evanthia; Chang, Susan M; Nabors, Louis Burt; Ahluwalia, Manmeet S; Stupp, Roger; Mehta, Minesh P; Reardon, David A; Grossman, Stuart A; Sulman, Erik P; Sampson, John H; Khagi, Simon; Weller, Michael; Cloughesy, Timothy F; Wen, Patrick Y; Khasraw, Mustafa
Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on as "recruiting" or "not yet recruiting" as of February 2021.
PMID: 34561269
ISSN: 1557-3265
CID: 5178432

Update on Radiation Therapy for Central Nervous System Tumors

Rahman, Rifaquat; Sulman, Erik; Haas-Kogan, Daphne; Cagney, Daniel N
Radiation therapy has long been a critical modality of treatment of patients with central nervous system tumors, including primary brain tumors, brain metastases, and meningiomas. Advances in radiation technology and delivery have allowed for more precise treatment to optimize patient outcomes and minimize toxicities. Improved understanding of the molecular underpinnings of brain tumors and normal brain tissue response to radiation will allow for continued refinement of radiation treatment approaches to improve clinical outcomes for brain tumor patients. With continued advances in precision and delivery, radiation therapy will continue to be an important modality to achieve optimal outcomes of brain tumor patients.
PMID: 34711456
ISSN: 1558-1977
CID: 5042732

Author Correction: Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling

Danussi, Carla; Bose, Promita; Parthasarathy, Prasanna T; Silberman, Pedro C; Van Arnam, John S; Vitucci, Mark; Tang, Oliver Y; Heguy, Adriana; Wang, Yuxiang; Chan, Timothy A; Riggins, Gregory J; Sulman, Erik P; Lang, Frederick F; Creighton, Chad J; Deneen, Benjamin; Miller, C Ryan; Picketts, David J; Kannan, Kasthuri; Huse, Jason T
PMID: 34987156
ISSN: 2041-1723
CID: 5107202