September 2017 - August 2018 Awardees (FY 2018)
• June - August 2018
Yonathan Lissanu Deribe, M.D., Ph.D. | Andrew Futreal, Ph.D.
Nature Medicine
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer
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John Heymach, M.D., Ph.D.
Cancer Discovery
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma
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Jennifer Litton, M.D.
The New England Journal of Medicine
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation
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Eduardo Vilar Sanchez, M.D., Ph.D.
JAMA Oncology
Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome
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Michael Frumovitz, M.D.
The Lancet Oncology
Near-infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non-inferiority trial
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R. Tyler Hillman, M.D., Ph.D. | Andrew Futreal, Ph.D.
Nature Communications
KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary
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Hussein Tawbi, M.D., Ph.D.
The New England Journal of Medicine
Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain
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Yonathan Lissanu Deribe, M.D., Ph.D. & Andrew Futreal, Ph.D.
Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer
Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium. We demonstrate that Smarca4 acts as a bona fide tumor suppressor and cooperates with p53 loss and Kras activation. Gene expression analyses revealed the signature of enhanced oxidative phosphorylation (OXPHOS) in SMARCA4 mutant tumors. We further show that SMARCA4 mutant cells have enhanced oxygen consumption and increased respiratory capacity. Importantly, SMARCA4 mutant lung cancer cell lines and xenograft tumors have marked sensitivity to inhibition of OXPHOS by a novel small molecule, IACS-010759, that is under clinical development. Mechanistically, we show that SMARCA4-deficient cells have a blunted transcriptional response to energy stress creating a therapeutically exploitable synthetic lethal interaction. These findings provide the mechanistic basis for further development of OXPHOS inhibitors as therapeutics against SWI/SNF mutant tumors.
Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A. Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M. Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I. Wistuba, Kunal Rai, Joseph Marszalek and P. Andrew Futreal
Standing : Tapsi Kumar, Yonathan Lissanu Deribe, Kadir C. Akdemir, Won-Chul Lee, Marcus D. Coyle, Curtis Gumbs, Rebecca L Thornton, Kiyomi Morita and Runzhe Chen
Michael Frumovitz, M.D.
Professor, Department of Gynecologic Oncology and Reproductive Medicine
Near-infrared fluorescence for detection of sentinel lymph nodes in women with cervical and uterine cancers (FILM): a randomised, phase 3, multicentre, non-inferiority trial
BACKGROUND: Accurate identification of sentinel lymph nodes in patients with cancer improves detection of metastatic disease and decreases surgical morbidity. We sought to establish whether indocyanine green fluorescent dye is non-inferior to isosulfan blue dye in detecting sentinel lymph nodes in women with cervical and uterine cancers.
FINDINGS: Between Dec 21, 2015, and June 19, 2017, 180 patients were enrolled and randomly assigned to the two groups (90 to each group); 176 patients received the intervention and were evaluable (modified intention- to-treat population). 13 patients with major protocol violations were subsequently excluded from the per-protocol population. 517 sentinel nodes were identified in the per-protocol population (n=163), of which 478 (92%) were confirmed to be lymph nodes on pathological processing: 219 (92%) of 238 nodes that were both blue and green, all seven nodes that were blue only, and 252 (95%) of 265 nodes that were green only (p=0·33). Seven sentinel lymph nodes were neither blue nor green but were removed for appearing suspicious or enlarged on visual examination. In total, 471 (97%) of 485 lymph nodes were identified with the green dye and 226 (47%) with the blue dye (difference 50%, 95% CI 39–62; p<0·0001). In the modified intention-to-treat population (n=176), 545 nodes were identified, of which 513 (94%) were confirmed to be lymph nodes on pathological processing: 229 (92%) of 248 nodes that were both blue and green, all nine nodes that were blue only, and 266 (95%) of 279 nodes that were green only (p=0·30). Nine sentinal lymph nodes were neither blue nor green but were removed for appearing suspicious or enlarged on visual examination. 495 (96%) of 513 nodes were identified with the green dye and 238 (46%) with the blue dye (50%, 39–61; p<0·0001).
INTERPRETATION: Indocyanine green dye with near-infrared fluorescence imaging identified more sentinel nodes than isosulfan blue dye in women with cervical and uterine cancers, with no difference in the pathological confirmation of nodal tissue between the two mapping substances.
Prof Michael Frumovitz M.D., Prof Marie Plante M.D., Paula S Lee M.D., Samith Sandadi M.D., James F Lilja M.D., Pedro F Escobar M.D., Lilian T Gien M.D., Diana L Urbauer M.S. and Prof Nadeem R Abu-Rustum M.D.
John Heymach, M.D., Ph.D.
STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma
KRAS is the most common oncogenic driver in lung adenocarcinoma (LUAC). We previously reported that STK11/LKB1 (KL) or TP53 (KP) co-mutations define distinct subgroups of KRAS-mutant LUAC. Here, we examine the efficacy of PD-1 inhibitors in these subgroups. Objective response rates to PD-1 blockade differed significantly among KL (7.4%), KP (35.7%), and K-only (28.6%) subgroups (P<0.001) in the SU2C cohort (174 patients) with KRAS-mutant LUAC and in patients treated with nivolumab in the CheckMate-057 phase 3 trial (0% vs 57.1% vs 18.2%, P=0.047). In the SU2C cohort, KL LUAC exhibited shorter progression-free (P<0.001) and overall survival (P=0.0015) compared to KRASMUT; STK11/LKB1 WT LUAC. Among 924 LUAC, STK11/LKB1 alterations were the only marker significantly associated with PD-L1 negativity in TMBIntermediate/High LUAC. The impact of STK11/LKB1 alterations on clinical outcomes with PD-1/PD-L1 inhibitors extended to PD-L1-positive NSCLC. In Kras-mutant murine LUAC models, STK11/LKB1 loss promoted PD-1/PD-L1 inhibitor resistance, suggesting a causal role. Our results identify STK11/LKB1 alterations as a major driver of primary resistance to PD-1 blockade in KRAS-mutant LUAC.
Ferdinandos Skoulidis, Michael E. Goldberg, Danielle M. Greenawalt, Matthew D. Hellmann, Mark M. Awad, Justin F. Gainor, Alexa B. Schrock, Ryan J. Hartmaier, Sally E. Trabucco, Laurie Gay, Siraj M. Ali, Julia A. Elvin, Gaurav Singal, Jeffrey S. Ross, David Fabrizio, Peter M. Szabo, Han Chang, Ariella Sasson, Sujaya Srinivasan, Stefan Kirov, Joseph Szustakowski, Patrik Vitazka, Robin Edwards, Jose A. Bufill, Neelesh Sharma, Sai-Hong I. Ou, Nir Peled, David R. Spigel, Hira Rizvi, Elizabeth Jimenez Aguilar, Brett W. Carter, Jeremy Erasmus, Darragh F. Halpenny, Andrew J. Plodkowski, Niamh M. Long, Mizuki Nishino, Warren L. Denning, Ana Galan-Cobo, Haifa Hamdi, Taghreed Hirz, Pan Tong, Jing Wang, Jaime Rodriguez-Canales, Pamela A. Villalobos, Edwin R. Parra, Neda Kalhor, Lynette M. Sholl, Jennifer L. Sauter, Achim A. Jungbluth, Mari Mino-Kenudson, Roxana Azimi, Yasir Y. Elamin, Jianjun Zhang, Giulia C. Leonardi, Fei Jiang, Kwok-Kin Wong, J. Jack Lee, Vassiliki A. Papadimitrakopoulou, Ignacio I. Wistuba, Vincent A. Miller, Garrett M. Frampton, Jedd D. Wolchok, Alice T. Shaw, Pasi A. Jänne, Philip J. Stephens, Charles M. Rudin, William J. Geese, Lee A. Albacker and John V. Heymach
Chair, Department of Thoracic/Head and Neck Medical Oncology
Professor, Department of Cancer Biology
David Bruton, Jr., Chair
Not featured : Brett Carter, Jeremy Erasmus, Neda Kalhor, Yasir Elamin Vali Papadimitrakopoulou, Ignacio Ivan Wistuba
R. Tyler Hillman, M.D., Ph.D. & Andrew Futreal, Ph.D.
Fellow, Department of Gynecologic Oncology and Reproductive Medicine
Chair, Department of Genomic Medicine
Robert A. Welch Distinguished University Chair
KMT2D/MLL2 inactivation is associated with recurrence in adult-type granulosa cell tumors of the ovary
Adult-type granulosa cell tumors of the ovary (aGCTs) are rare gynecologic malignancies that exhibit a high frequency of somatic FOXL2 c.C402G (p.Cys134Trp) mutation. Treatment of relapsed aGCT remains a significant clinical challenge. Here we show, using whole-exome and cancer gene panel sequencing of 79 aGCTs from two independent cohorts, that truncating mutation of the histone lysine methyltransferase gene KMT2D (also known as MLL2) is a recurrent somatic event in aGCT. Mono-allelic KMT2D-truncating mutations are more frequent in recurrent (10/44, 23%) compared with primary (1/35, 3%) aGCTs (p=0.02, two-sided Fisher's exact test). IHC detects additional non KMT2D-mutated aGCTs with loss of nuclear KMT2D expression, suggesting that non-genetic KMT2D inactivation may occur in this tumor type. These findings identify KMT2D inactivation as a novel driver event in aGCTs and suggest that mutation of this gene may increase the risk of disease recurrence.
R. Tyler Hillman, Joseph Celestino, Christopher Terranova, Hannah C. Beird, Curtis Gumbs, Latasha Little,Tri Nguyen, Rebecca Thornton, Samantha Tippen, Jianhua Zhang, Karen H. Lu, David M. Gershenson, Kunal Rai, Russell R. Broaddus and P. Andrew Futreal
Jennifer Litton, M.D.
Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation
BACKGROUND: The poly(adenosine diphosphate–ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 (BRCA1/2).
RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P<0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3–4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status–quality-of-life and breast symptoms scales were observed.
CONCLUSIONS: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials. gov number, NCT01945775.)
Jennifer K. Litton, Hope S. Rugo, Johannes Ettl, Sara A. Hurvitz, Anthony Gonçalves, Kyung-Hun Lee, Louis Fehrenbacher, Rinat Yerushalmi1, Lida A. Mina, Miguel Martin, Henri Roché, Young-Hyuck Im, Ruben G.W. Quek, Denka Markova, Julia C. Tudor, Alison L. Hannah, Wolfgang Eiermann and Joanne L. Blum
Associate Professor, Department of Breast Medical Oncology
Not pictured : Banu Arun, M.D.
Hussein Tawbi, M.D., Ph.D.
Associate Professor, Departments of Melanoma Medical Oncology and Investigational Cancer Therapeutics
Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain
BACKGROUND: Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.
RESULTS: Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.
CONCLUSIONS: Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058.)
Hussein A. Tawbi, Peter A. Forsyth, Alain Algazi, Omid Hamid, F. Stephen Hodi, Stergios J. Moschos, Nikhil I. Khushalani, Karl Lewis, Christopher D. Lao, Michael A. Postow, Michael B. Atkins, Marc S. Ernstoff, David A. Reardon, Igor Puzanov, Ragini R. Kudchadkar, Reena P. Thomas, Ahmad Tarhini, Anna C. Pavlick, Joel Jiang, Alexandre Avila, Sheena Demelo and Kim Margolin
Eduardo Vilar Sanchez, M.D., Ph.D.
Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome
IMPORTANCE: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS.
OBJECTIVE: To characterize the immune profile of premalignant lesions from a cohort of patients with LS.
RESULTS: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte–associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling).
CONCLUSIONS AND RELEVANCE: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS.
Kyle Chang, Melissa W. Taggart, Laura Reyes-Uribe, Ester Borras, Erick Riquelme, Reagan M. Barnett, Guido Leoni, F. Anthony San Lucas, Maria T. Catanese, Federica Mori, Maria G. Diodoro, Y. Nancy You, Ernest T. Hawk, Jason Roszik, Paul Scheet, Scott Kopetz, Alfredo Nicosia, Elisa Scarselli, Patrick M. Lynch, Florencia McAllister and Eduardo Vilar
Associate Professor, Departments of Clinical Cancer Prevention and GI Medical Oncology
• March - May 2018
Rehan Akbani, Ph.D.
Cancer Cell
A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers
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Xiaodong Cheng, Ph.D.
Cell
DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins
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Frederick F. Lang, M.D., FAANS, FACS
Journal of Clinical Oncology
Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma
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Han Liang, Ph.D.
Cell
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples
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Guang Peng, Ph.D.
Nature Medicine
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
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Padmanee Sharma, M.D., Ph.D.
New England Journal of Medicine
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
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Michael Wang, M.D.
The Lancet
Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial
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Blaine Bartholomew, Ph.D.
Nature Communications
INO80 exchanges H2A.Z for H2A by translocating on DNA proximal to histone dimers
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Jason Huse, M.D., Ph.D.
Nature
Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
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Han Liang, Ph.D.
Cancer Cell
A-to-I RNA Editing Contributes to Proteomic Diversity in Cancer
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Nicholas Navin, Ph.D.
Cell
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing
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Jacqulyne Robichaux, Ph.D. | John V. Heymach, M.D., Ph.D.
Nature Medicine
Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer
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Anne Tsao, M.D.
Cancer Cell
The Integrated Genomic Landscape of Thymic Epithelial Tumors
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Rehan Akbani, Ph.D.
A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant sub-types, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified sub-types with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
Ashton C. Berger, Anil Korkut, Rupa S. Kanchi, Apurva M. Hegde, Walter Lenoir, Wenbin Liu, Yuexin Liu, Huihui Fan, Hui Shen, Visweswaran Ravikumar, Arvind Rao, Andre Schultz, Xubin Li, Pavel Sumazin, Cecilia Williams, Pieter Mestdagh, Preethi H. Gunaratne, Christina Yau,9 Reanne Bowlby, A. Gordon Robertson, Daniel G. Tiezzi, Chen Wang, Andrew D. Cherniack, Andrew K. Godwin, Nicole M. Kuderer, Janet S. Rader, Rosemary E. Zuna, Anil K. Sood, Alexander J. Lazar, Akinyemi I. Ojesina, Clement Adebamowo, Sally N. Adebamowo, Keith A. Baggerly, Ting-Wen Chen, Hua-Sheng Chiu, Steve Lefever, Liang Liu, Karen MacKenzie, Sandra Orsulic, Jason Roszik, Carl Simon Shelley, Qianqian Song, Christopher P. Vellano, Nicolas Wentzensen, The Cancer Genome Atlas Research Network, John N. Weinstein, Gordon B. Mills, Douglas A. Levine and Rehan Akbani
Associate Professor, Department of Bioinformatics and Computational Biology
Blaine Bartholomew, Ph.D.
Professor, Department of Epigenetics and Molecular Carcinogenesis
Front row : Jim Persinger, Blaine Bartholomew, Solomon Hailu and Somnath Paul
INO80 exchanges H2A.Z for H2A by translocating on DNA proximal to histone dimers
ATP-dependent chromatin remodellers modulate nucleosome dynamics by mobilizing or disassembling nucleosomes, as well as altering nucleosome composition. These chromatin remodellers generally function by translocating along nucleosomal DNA at the H3–H4 interface of nucleosomes. Here we show that, unlike other remodellers, INO80 translocates along DNA at the H2A–H2B interface of nucleosomes and persistently displaces DNA from the surface of H2A–H2B. DNA translocation and DNA torsional strain created near the entry site of nucleosomes by INO80 promotes both the mobilization of nucleosomes and the selective exchange of H2A.Z–H2B dimers out of nucleosomes and replacement by H2A–H2B dimers without any additional histone chaperones. We find that INO80 translocates and mobilizes H2A.Z-containing nucleosomes more efficiently than those containing H2A, partially accounting for the preference of INO80 to replace H2A.Z with H2A. Our data suggest that INO80 has a mechanism for dimer exchange that is distinct from other chromatin remodellers including its paralogue SWR1.
Sandipan Brahma, Maheshi I. Udugama, Jongseong Kim, Arjan Hada, Saurabh K. Bhardwaj, Solomon G. Hailu, Tae-Hee Lee and Blaine Bartholomew
Xiaodong Cheng, Ph.D.
DNA Conformation Induces Adaptable Binding by Tandem Zinc Finger Proteins
Tandem zinc finger (ZF) proteins are the largest and most rapidly diverging family of DNA-binding transcription regulators in mammals. ZFP568 represses a transcript of placental-specific insulin like growth factor 2 (Igf2-P0) in mice. ZFP568 binds a 24-base pair sequence-specific element upstream of Igf2-P0 via the eleven-ZF array. Both DNA and protein conformations deviate from the conventional one finger-three bases recognition, with individual ZFs contacting 2, 3, or 4 bases and recognizing thymine on the opposite strand. These interactions arise from a shortened minor groove caused by an AT-rich stretch, suggesting adaptability of ZF arrays to sequence variations. Despite conservation in mammals, mutations at Igf2 and ZFP568 reduce their binding affinity in chimpanzee and humans. Our studies provide important insights into the evolutionary and structural dynamics of ZF-DNA interactions that play a key role in mammalian development and evolution.
Anamika Patel, Peng Yang, Matthew Tinkham, Mihika Pradhan, Ming-An Sun, Yixuan Wang, Don Hoang, Gernot Wolf, John R. Horton, Xing Zhang, Todd Macfarlan and Xiaodong Cheng
Professor, Department of Molecular and Cellular Oncology
Jason Huse, M.D., Ph.D.
Associate Professor, Department of Pathology
Back row from left to right : Carla Danussi, Vladislav Sharin, Jason Huse, David Irvin
Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts.
Carla Danussi, Promita Bose, Prasanna T. Parthasarathy, Pedro C. Silberman, John S. Van Arnam, Mark Vitucci, Oliver Y. Tang, Adriana Heguy, Yuxiang Wang, Timothy A. Chan, Gregory J. Riggins, Erik P. Sulman, Frederick Lang, Chad J. Creighton, Benjamin Deneen, C. Ryan Miller, David J. Picketts, Kasthuri Kannan and Jason T. Huse
Frederick F. Lang, M.D., FAANS, FACS
Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma
DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.
METHODS: A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.
RESULTS: In group A (n=25), 20% of patients survived > 3 years from treatment, and three patients had a ≥95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.
CONCLUSION: Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent highgrade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.
Frederick F. Lang, Charles Conrad, Candelaria Gomez-Manzano, W.K. Alfred Yung, Raymond Sawaya, Jeffrey S. Weinberg, Sujit S. Prabhu, Ganesh Rao, Gregory N. Fuller, Kenneth D. Aldape, Joy Gumin, Luis M. Vence, Ignacio Wistuba, Jaime Rodriguez-Canales, Pamela A. Villalobos, Clemens M.F. Dirven, Sonia Tejada, Ricardo D. Valle, Marta M. Alonso, Brett Ewald, Joanna J. Peterkin, Frank Tufaro and Juan Fueyo
Professor and Chair, Department of Neurosurgery
Beau Biden Chair for Brain Cancer Research
Back Row – Candelaria Gomez-Manzano, M.D., W.K. Alfred Yung, M.D., Juan Fueyo, M.D.
Han Liang, Ph.D.
Professor, Departments of Bioinformatics and Computational Biology and Systems Biology
Back: from Left Shuangxing Yu (Research investigator, Systems Biology), 'Kamalika Mojumdar (Research Scientist, BCB), Zhicheng Zhou (Postdoc BCB) and Yumeng Wang (postdoc, BCB)
A-to-I RNA Editing Contributes to Proteomic Diversity in Cancer
Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels. The edited COPA protein increases proliferation, migration, and invasion of cancer cells in vitro. Our study suggests an important contribution of A-to-I RNA editing to protein diversity in cancer and highlights its translational potential.
Xinxin Peng, Xiaoyan Xu, Yumeng Wang, David H. Hawke, Shuangxing Yu, Leng Han, Zhicheng Zhou, Kamalika Mojumdar, Kang Jin Jeong, Marilyne Labrie, Yiu Huen Tsang, Minying Zhang, Yiling Lu, Patrick Hwu, Kenneth L. Scott, Han Liang and Gordon B. Mills
Han Liang, Ph.D.
A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples
The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ~1140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.
Han Chen, Chunyan Li, Xinxin Peng, Zhicheng Zhou, John N. Weinstein, The Cancer Genome Atlas Research Network and Han Liang
Professor, Departments of Bioinformatics and Computational Biology and Systems Biology
Nicholas Navin, Ph.D.
Associate Professor
Department of Genetics
Department of Bioinformatics and Computational Biology
Upper group from left to right : Anna Casasent, Charissa Kim, Annalyssa Long, Rachel Brandt, Pei-Ching Tsai, Ruli Gao and Aislyn Schalck (Click image to enlarge)
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing
Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients.
Charissa Kim, Ruli Gao, Emi Sei, Rachel Brandt, Johan Hartman, Thomas Hatschek, Nicola Crosetto, Theodoros Foukakis and Nicholas E. Navin
Guang Peng, Ph.D.
ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade
ARID1A (the AT-rich interaction domain 1A, also known as BAF250a) is one of the most commonly mutated genes in cancer. The majority of ARID1A mutations are inactivating mutations and lead to loss of ARID1A expression, which makes ARID1A a poor therapeutic target. Therefore, it is of clinical importance to identify molecular consequences of ARID1A deficiency that create therapeutic vulnerabilities in ARID1A-mutant tumors. In a proteomic screen, we found that ARID1A interacts with mismatch repair (MMR) protein MSH2. ARID1A recruited MSH2 to chromatin during DNA replication and promoted MMR. Conversely, ARID1A inactivation compromised MMR and increased mutagenesis. ARID1A deficiency correlated with microsatellite instability genomic signature and a predominant C>T mutation pattern and increased mutation load across multiple human cancer types. Tumors formed by an ARID1A-deficient ovarian cancer cell line in syngeneic mice displayed increased mutation load, elevated numbers of tumor-infiltrating lymphocytes, and PD-L1 expression. Notably, treatment with anti-PD-L1 antibody reduced tumor burden and prolonged survival of mice bearing ARID1A-deficient but not ARID1A-wild-type ovarian tumors. Together, these results suggest ARID1A deficiency contributes to impaired MMR and mutator phenotype in cancer, and may cooperate with immune checkpoint blockade therapy.
Jianfeng Shen, Zhenlin Ju, Wei Zhao, Lulu Wang, Yang Peng, Zhongqi Ge, Zachary D. Nagel, Jun Zou, Chen Wang, Prabodh Kapoor, Xiangyi Ma, Ding Ma, Jiyong Liang, Shumei Song,Jinsong Liu, Leona D. Samson, Jaffer A. Ajani, Guo-Min Li, Han Liang, Xuetong Shen, Gordon B. Mills and Guang Peng
Associate Professor, Departments of Clinical Cancer Prevention and Systems Biology
Jacqulyne Robichaux, Ph.D. & John V. Heymach, M.D., Ph.D.
Instructor, Department of Thoracic/Head and Neck Medical Oncology
Chair, Department of Thoracic/Head and Neck Medical Oncology
Professor, Department of Cancer Biology
David Bruton, Jr., Chair
Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer
Although most activating mutations of epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancers (NSCLCs) are sensitive to available EGFR tyrosine kinase inhibitors (TKIs), a subset with alterations in exon 20 of EGFR and HER2 are intrinsically resistant and lack an effective therapy. We used in silico, in vitro, and in vivo testing to model structural alterations induced by exon 20 mutations and to identify effective inhibitors. 3D modeling indicated alterations restricted the size of the drug-binding pocket, limiting the binding of large, rigid inhibitors. We found that poziotinib, owing to its small size and flexibility, can circumvent these steric changes and is a potent inhibitor of the most common EGFR and HER2 exon 20 mutants. Poziotinib demonstrated greater activity than approved EGFR TKIs in vitro and in patient-derived xenograft models of EGFR or HER2 exon 20 mutant NSCLC and in genetically engineered mouse models of NSCLC. In a phase 2 trial, the first 11 patients with NSCLC with EGFR exon 20 mutations receiving poziotinib had a confirmed objective response rate of 64%. These data identify poziotinib as a potent, clinically active inhibitor of EGFR and HER2 exon 20 mutations and illuminate the molecular features of TKIs that may circumvent steric changes induced by these mutations.
Jacqulyne P. Robichaux, Yasir Y. Elamin, Zhi Tan, Brett W. Carter, Shuxing Zhang, Shengwu Liu, Shuai Li, Ting Chen, Alissa Poteete, Adriana Estrada-Bernal, Anh T. Le, Anna Truini, Monique B. Nilsson, Huiying Sun, Emily Roarty, Sarah B. Goldberg, Julie R. Brahmer, Mehmet Altan, Charles Lu, Vassiliki Papadimitrakopoulou, Katerina Politi, Robert C. Doebele, Kwok-Kin Wong and John V. Heymach
Padmanee Sharma, M.D., Ph.D.
Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma
Nivolumab plus ipilimumab produced objective responses in patients with advanced renal-cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear-cell advanced renal-cell carcinoma. We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level, 0.001), and progression-free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk. A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow-up of 25.2 months in intermediate- and poor-risk patients, the 18-month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression-free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment-related adverse events occurred in 509 of 547 patients (93%) in the nivolumab-plus-ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment-related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups.
Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate- and poor-risk patients with previously untreated advanced renal-cell carcinoma.
Robert J. Motzer, M.D., Nizar M. Tannir, M.D., David F. McDermott, M.D., Osvaldo Arén Frontera, M.D., Bohuslav Melichar, M.D., Ph.D., Toni K. Choueiri, M.D., Elizabeth R. Plimack, M.D., Philippe Barthélémy, M.D., Ph.D., Camillo Porta, M.D., Saby George, M.D., Thomas Powles, M.D., Frede Donskov, M.D., Ph.D., et al., for the CheckMate 214 Investigators (Padmanee Sharma, M.D., Ph.D.)
Professor, Departments of Genitourinary Medical Oncology and Immunology
TC and Jeanette Hsu Endowed Chair in Cell Biology
Anne Tsao, M.D.
Professor, Department of Thoracic/Head and Neck Medical Oncology
The Integrated Genomic Landscape of Thymic Epithelial Tumors
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.
Milan Radovich, Curtis R. Pickering, Ina Felau, Gavin Ha, Hailei Zhang, Heejoon Jo, Katherine A. Hoadley, Pavana Anur, Jiexin Zhang, Mike McLellan, Reanne Bowlby, Thomas Matthew, Ludmila Danilova, Apurva M. Hegde, Jaegil Kim, Mark D.M. Leiserson, Geetika Sethi, Charles Lu, Michael Ryan, Xiaoping Su, Andrew D. Cherniack, Gordon Robertson, Rehan Akbani, Paul Spellman, John N. Weinstein, D. Neil Hayes, Ben Raphael, Tara Lichtenberg, Kristen Leraas, Jean Claude Zenklusen, The Cancer Genome Atlas Network, Junya Fujimoto, Cristovam Scapulatempo-Neto, Andre L. Moreira, David Hwang, James Huang, Mirella Marino, Robert Korst, Giuseppe Giaccone, Yesim Gokmen-Polar, Sunil Badve, Arun Rajan, Philipp Strobel, Nicolas Girard, Ming S. Tsao, Alexander Marx, Anne S. Tsao and Patrick J. Loehrer
Michael Wang, M.D.
Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial
Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimize off-target activity. In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926. From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1–2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62–80), 67% (58–75), and 87% (79–92%), respectively. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 [31%]) and adverse events (seven [6%]). Acalabrutinib treatment provided a high rate of durable responses and a favorable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.
Michael Wang, Simon Rule, Pier Luigi Zinzani, Andre Goy, Olivier Casasnovas, Stephen D Smith, Gandhi Damaj, Jeanette Doorduijn, Thierry Lamy, Franck Morschhauser, Carlos Panizo, Bijal Shah, Andrew Davies, Richard Eek, Jehan Dupuis, Eric Jacobsen, Arnon P Kater, Steven Le Gouill, Lucie Oberic, Taduesz Robak, Todd Covey, Richa Dua, Ahmed Hamdy, Xin Huang, Raquel Izumi, Priti Patel, Wayne Rothbaum, J Greg Slatter and Wojciech Jurczak
Associate Professor, Departments of Lymphoma/Myeloma and Stem Cell Transplantation
• December 2017 - February 2018
Michael Andreeff, M.D., Ph.D.
Cancer Cell
Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy
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Xiaodong Cheng, Ph.D.
Molecular Cell
Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA
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Simona Colla, Ph.D.
Cancer Cell
ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma
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Robert Jenq, M.D. | Jennifer A. Wargo, M.D., M.M.Sc.
Science
Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients
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Nicholas Navin, Ph.D.
Cell
Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing
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Spencer Wei, Ph.D. | James Allison, Ph.D.
Cell
Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade
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Menashe Bar-Eli, Ph.D.
Nature Communications
A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression
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Francesca Cole, Ph.D.
Cell
Age-Dependent Alterations in Meiotic Recombination Cause Chromosome Segregation Errors in Spermatocytes
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Bita Esmaeli, M.D., M.A. | Scott E. Woodman M.D., Ph.D.
Cancer Cell
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma
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Alexander Lazar, M.D., Ph.D.
Cell
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas
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Sattva Neelapu, M.D.
New England Journal of Medicine
Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
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Liuqing Yang, Ph.D. | Chunru Lin, Ph.D.
Journal of Clinical Investigation
JAK2-binding long noncoding RNA promotes breast cancer brain metastasis
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Michael Andreeff, M.D., Ph.D.
Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy
Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition. Moreover, Bcl-2 inhibition reciprocally overcomes apoptosis resistance to p53 activation by switching cellular response from G1 arrest to apoptosis. The efficacy, together with the mechanistic findings, reveals the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach.
Rongqing Pan, Vivian Ruvolo, Hong Mu, Joel D. Leverson, Gwen Nichols, John C. Reed, Marina Konopleva and Michael Andreeff
Professor, Departments of Leukemia and Stem Cell Transplantation
Paul and Mary Hass Chair in Genetics in Honor of Amanda White
Menashe Bar-Eli, Ph.D.
Professor, Department of Cancer Biology
A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression
Previously we have reported that metastatic melanoma cell lines and tumor specimens have reduced expression of ADAR1 and consequently are impaired in their ability to perform A-to-I microRNA (miRNA) editing. The effects of A-to-I miRNAs editing on melanoma growth and metastasis are yet to be determined. Here we report that miR-378a–3p is undergoing A-to-I editing only in the non-metastatic but not in metastatic melanoma cells. The function of the edited form is different from its wild-type counterpart. The edited form of miR-378a-3p preferentially binds to the 3’-UTR of the PARVA oncogene and inhibits its expression, thus preventing the progression of melanoma towards the malignant phenotype. Indeed, edited miR-378a-3p but not its WT form inhibits melanoma metastasis in vivo. These results further emphasize the role of RNA editing in melanoma progression.
Guermarie Velazquez-Torres, Einav Shoshan, Cristina Ivan, Li Huang, Enrique Fuentes-Mattei, Harrison Paret, Sun Jin Kim, Cristian Rodriguez-Aguayo, Victoria Xie, Denise Brooks, Steven J.M. Jones, A. Gordon Robertson, George Calin, Gabriel Lopez-Berenstein, Anil Sood and Menashe Bar-Eli
Xiaodong Cheng, Ph.D.
Structural Basis for the Versatile and Methylation-Dependent Binding of CTCF to DNA
The multidomain CCCTC-binding factor (CTCF), containing a tandem array of 11 zinc fingers (ZFs), modulates the three-dimensional organization of chromatin. We crystallized the human CTCF DNA-binding domain in complex with a known CTCF-binding site. While ZF2 does not make sequence-specific contacts, each finger of ZF3–7 contacts three bases of the 15-bp consensus sequence. Each conserved nucleotide makes base-specific hydrogen bonds with a particular residue. Most of the variable base pairs within the core sequence also engage in interactions with the protein. These interactions compensate for deviations from the consensus sequence, allowing CTCF to adapt to sequence variations. CTCF is sensitive to cytosine methylation at position 2, but insensitive at position 12 of the 15-bp core sequence. These differences can be rationalized structurally. Although included in crystallizations, ZF10 and ZF11 are not visible, while ZF8 and ZF9 span the backbone of the DNA duplex, conferring no sequence specificity but adding to overall binding stability.
Hideharu Hashimoto, Dongxue Wang, John R. Horton, Xing Zhang, Victor G. Corces and Xiaodong Cheng
Professor, Department of Molecular and Cellular Oncology
Francesca Cole, Ph.D.
Assistant Professor, Department of Epigenetics and Molecular Carcinogenesis
Age-Dependent Alterations in Meiotic Recombination Cause Chromosome Segregation Errors in Spermatocytes
Faithful chromosome segregation in meiosis requires crossover (CO) recombination, which is regulated to ensure at least one CO per homolog pair. We investigate the failure to ensure COs in juvenile male mice. By monitoring recombination genome-wide using cytological assays and at hotspots using molecular assays, we show that juvenile mouse spermatocytes have fewer COs relative to adults. Analysis of recombination in the absence of MLH3 provides evidence for greater utilization in juveniles of pathways involving structure-selective nucleases and alternative complexes, which can act upon pre-cursors to generate noncrossovers (NCOs) at the expense of COs. We propose that some designated CO sites fail to mature efficiently in juveniles owing to inappropriate activity of these alternative repair pathways, leading to chromosome mis-segregation. We also find lower MutLγ focus density in juvenile human spermatocytes, suggesting that weaker CO maturation efficiency may explain why younger men have a higher risk of fathering children with Down syndrome.
Maciej J. Zelazowski, Maria Sandoval, Lakshmi Paniker, Holly M. Hamilton, Jiaying Han, Mikalah A. Gribbell, Rhea Kang and Francesca Cole
Simona Colla, Ph.D.
ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma
Amplification of 1q21 occurs in approximately 30% of denovo and 70% of relapsed multiple myeloma (MM) and is correlated with disease progression and drug resistance. Here, we provide evidence that the 1q21 amplification-driven overexpression of ILF2 in MM promotes tolerance of genomic instability and drives resistance to DNA-damaging agents. Mechanistically, elevated ILF2 expression exerts resistance to genotoxic agents by modulating YB-1 nuclear localization and interaction with the splicing factor U2AF65, which promotes mRNA processing and the stabilization of transcripts involved in homologous recombination in response to DNA damage. The intimate link between 1q21-amplified ILF2 and the regulation of RNA splicing of DNA repair genes may be exploited to optimize the use of DNA-damaging agents in patients with high-risk MM.
Matteo Marchesini, Yamini Ogoti, Elena Fiorini, Anil Aktas Samur, Luigi Nezi, Marianna D’Anca, Paola Storti, Mehmet Kemal Samur, Irene Ganan-Gomez, Maria Teresa Fulciniti, Nipun Mistry, Shan Jiang, Naran Bao, Valentina Marchica, Antonino Neri, Carlos Bueso-Ramos, Chang-Jiun Wu, Li Zhang, Han Liang, Xinxin Peng, Nicola Giuliani, Giulio Draetta, Karen Clise-Dwyer, Hagop Kantarjian, Nikhil Munshi, Robert Orlowski, Guillermo Garcia-Manero, Ronald A. DePinho and Simona Colla
Associate Professor, Departments of Leukemia and Experimental Therapeutics
Bita Esmaeli, M.D., M.A. & Scott E. Woodman M.D., Ph.D.
Professor, Ophthalmic Plastic and Orbital Oncology
Department of Plastic Surgery
Associate Professor
Department of Melanoma Medical Oncology
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma
Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.
A. Gordon Robertson, Juliann Shih, Christina Yau, Ewan A. Gibb, Junna Oba, Karen L. Mungall, Julian M. Hess, Vladislav Uzunangelov, Vonn Walter, Ludmila Danilova, Tara M. Lichtenberg, Melanie Kucherlapati, Patrick K. Kimes, Ming Tang, Alexander Penson, Ozgun Babur, Rehan Akbani, Christopher A. Bristow, Katherine A. Hoadley, Lisa Iype, Matthew T. Chang, TCGA Research Network, Andrew D. Cherniack, Christopher Benz, Gordon B. Mills, Roel G.W. Verhaak, Klaus G. Griewank, Ina Felau, Jean C. Zenklusen, Jeffrey E. Gershenwald, Lynn Schoenfield, Alexander J. Lazar, Mohamed H. Abdel-Rahman, Sergio Roman-Roman, Marc-Henri Stern, Colleen M. Cebulla, Michelle D. Williams, Martine J. Jager, Sarah E. Coupland, Bita Esmaeli, Cyriac Kandoth and Scott E. Woodman
Robert Jenq, M.D. & Jennifer A. Wargo, M.D., M.M.Sc.
Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n=112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n=43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P<0.01) and relative abundance of bacteria of the Ruminococcaceae family (P<0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
Vidya Gopalakrishnan, C. N. Spencer, L. Nezi, Alexandre Reuben, M. C. Andrews, T. V. Karpinets, P. A. Prieto, D. Vicente, Karen Elizabeth Hoffman, S. C. Wei, A. P. Cogdill, L. Zhao, C. W. Hudgens, D. S. Hutchinson, T. Manzo, M. Petaccia de Macedo, T. Cotechini, T. Kumar, W. S. Chen, S. M. Reddy, R. Szczepaniak Sloane, J. Galloway-Pena, Hong Jiang, P. L. Chen, Elizabeth J. Shpall, Katy Rezvani, Amin M. Alousi, Roy F. Chemaly, Samuel A. Shelburne, L. M. Vence, Pablo C. Okhuysen, Vanessa Jensen, A. G. Swennes, Florencia McAllister, E. Marcelo Riquelme Sanchez, Y. Zhang, E. Le Chatelier, L. Zitvogel, N. Pons, J. L. Austin- Breneman, L. E. Haydu, E. M. Burton, J. M. Gardner, E. Sirmans, J. Hu, Alexander J. Lazar, T. Tsujikawa, Adi Diab, Hussein A. Tawbi, Isabella C. Glitza, W. J. Hwu, S. P. Patel, Scott E. Woodman, Rodabe N. Amaria, Michael A. Davies, Jeffrey E. Gershenwald, P. Hwu, Jeffrey E. Lee, J. Zhang, L. M. Coussens, Z. A. Cooper, P. A. Futrea, Carrie R Daniel-MacDougall, N. J. Ajami, J. F. Petrosino, M. T. Tetzlaff, Padmanee Sharma, James P. Allison, Robert R. Jenq and Jennifer Wargo
Assistant Professor, Departments of Genomic Medicine and Stem Cell Transplantation
Associate Professor, Departments of Surgical Oncology and Genomic Medicine
Alexander Lazar, M.D., Ph.D.
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas
Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.
The Cancer Genome Atlas Research Network - Lead: Alexander J. Lazar
Nicholas Navin, Ph.D.
Multiclonal Invasion in Breast Tumors Identified by Topographic Single Cell Sequencing
Ductal carcinoma in situ (DCIS) is an early-stage breast cancer that infrequently progresses to invasive ductal carcinoma (IDC). Genomic evolution has been difficult to delineate during invasion due to intratumor heterogeneity and the low number of tumor cells in the ducts. To overcome these challenges, we developed Topographic Single Cell Sequencing (TSCS) to measure genomic copy number profiles of single tumor cells while preserving their spatial context in tissue sections. We applied TSCS to 1,293 single cells from 10 synchronous patients with both DCIS and IDC regions in addition to exome sequencing. Our data reveal a direct genomic lineage between in situ and invasive tumor subpopulations and further show that most mutations and copy number aberrations evolved within the ducts prior to invasion. These results support a multiclonal invasion model, in which one or more clones escape the ducts and migrate into the adjacent tissues to establish the invasive carcinomas.
Anna K. Casasent, Aislyn Schalck, Ruli Gao, Emi Sei, Annalyssa Long, William Pangburn, Tod Casasent, Funda Meric-Bernstam, Mary E. Edgerton and Nicholas E. Navin
Associate Professor
Department of Genetics
Department of Bioinformatics and Computational Biology
Upper group from left to right : Anna Casasent, Charissa Kim, Annalyssa Long, Rachel Brandt, Pei-Ching Tsai, Ruli Gao and Aislyn Schalck
Sattva Neelapu, M.D.
Professor, Department of Lymphoma/Myeloma
Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%. With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events.
Sattva S. Neelapu, F.L. Locke, N.L. Bartlett, L.J. Lekakis, D.B. Miklos, C.A. Jacobson, I. Braunschweig, O.O. Oluwole, T. Siddiqi, Y. Lin, J.M. Timmerman, P.J. Stiff, J.W. Friedberg, I.W. Flinn, A. Goy, B.T. Hill, M.R. Smith, A. Deol, U. Farooq, P. McSweeney, J. Munoz, I. Avivi, J.E. Castro, Jason Westin, J.C. Chavez, A. Ghobadi, K.V. Komanduri, R. Levy, E.D. Jacobsen, T.E. Witzig, P. Reagan, A. Bot, J. Rossi, L. Navale, Y. Jiang, J. Aycock, M. Elias, D. Chang, J. Wiezorek and W.Y. Go
Spencer Wei, Ph.D. & James Allison, Ph.D.
Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade
Immune-checkpoint blockade is able to achieve durable responses in a subset of patients; however, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4- and anti-PD-1-induced tumor rejection. To address these issues, we utilized mass cytometry to comprehensively profile the effects of checkpoint blockade on tumor immune infiltrates in human melanoma and murine tumor models. These analyses reveal a spectrum of tumor-infiltrating T cell populations that are highly similar between tumor models and indicate that checkpoint blockade targets only specific subsets of tumor-infiltrating T cell populations. Anti-PD-1 predominantly induces the expansion of specific tumor-infiltrating exhausted-like CD8 T cell subsets. In contrast, anti-CTLA-4 induces the expansion of an ICOS+ Th1-like CD4 effector population in addition to engaging specific subsets of exhausted like CD8 T cells. Thus, our findings indicate that anti-CTLA-4 and anti-PD-1 checkpoint- blockade induced immune responses are driven by distinct cellular mechanisms.
Spencer C. Wei, Jacob H. Levine, Alexandria P. Cogdill, Yang Zhao, Nana-Ama A.S. Anang, Miles C. Andrews, Padmanee Sharma, Jing Wang, Jennifer A. Wargo, Dana Pe’er and James P. Allison
Odyssey Fellow, Department of Immunology
Chair, Department of Immunology
Vivian Smith Distinguished Chair
Liuqing Yang, Ph.D. & Chunru Lin, Ph.D.
Assistant Professor, Department of Molecular and Cellular Oncology
Assistant Professor, Department of Molecular and Cellular Oncology
JAK2-binding long noncoding RNA promotes breast cancer brain metastasis
Conventional therapies for breast cancer brain metastases (BCBMs) have been largely ineffective because of chemoresistance and impermeability of the blood-brain barrier. A comprehensive understanding of the underlying mechanism that allows breast cancer cells to infiltrate the brain is necessary to circumvent treatment resistance of BCBMs. Here, we determined that expression of a long noncoding RNA (lncRNA) that we have named lncRNA associated with BCBM (Lnc-BM) is prognostic of the progression of brain metastasis in breast cancer patients. In preclinical murine models, elevated Lnc-BM expression drove BCBM, while depletion of Lnc-BM with nanoparticle-encapsulated siRNAs effectively treated BCBM. Lnc-BM increased JAK2 kinase activity to mediate oncostatin M– and IL-6–triggered STAT3 phosphorylation. In breast cancer cells, Lnc-BM promoted STAT3-dependent expression of ICAM1 and CCL2, which mediated vascular cooption and recruitment of macrophages in the brain, respectively. Recruited macrophages in turn produced oncostatin M and IL-6, thereby further activating the Lnc-BM/JAK2/STAT3 pathway and enhancing BCBM. Collectively, our results show that Lnc-BM and JAK2 promote BCBMs by mediating communication between breast cancer cells and the brain microenvironment. Moreover, these results suggest targeting Lnc-BM as a potential strategy for fighting this difficult disease.
Shouyu Wang, Ke Liang, Qingsong Hu, Ping Li, Jian Song, Yuedong Yang, Jun Yao, Lingegowda Selanere Mangala, Chunlai Li, Wenhao Yang, Peter K. Park, David H. Hawke, Jianwei Zhou, Yan Zhou, Weiya Xia, Mien-Chie Hung, Jeffrey R. Marks, Gary E. Gallick, Gabriel Lopez-Berestein, Elsa R. Flores, Anil K. Sood, Suyun Huang, Dihua Yu, Liuqing Yang and Chunru Lin