September 2020 - August 2021 Awardees (FY 2021)
June – August 2021
Jaffer A. Ajani, M.D.
The Lancet
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
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Nathan Fowler, M.D.
Cancer Cell
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
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Chi-Lin Tsai, Ph.D. | John Tainer, Ph.D.
Molecular Cell
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart
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Shuxing Zhang, Ph.D., Pharm.D. | Chunru Lin, M.D., Ph.D. | Liuqing Yang, Ph.D.
Science
A noncoding RNA modulator potentiates phenylalanine metabolism in mice
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Mauro Di Pilato, Ph.D.
Cell
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
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Cara Haymaker, Ph.D. | Adi Diab, M.D.
Cancer Discovery
Tilsotolimod with Ipilimumab drives tumor responses in Anti–PD-1 Refractory Melanoma
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Zu Ye, Ph.D. | John Tainer, Ph.D. | Zamal Ahmed, Ph.D.
Science Advances
GRB2 enforces homology-directed repair initiation by MRE11
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Jaffer A. Ajani, M.D.
First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
Background
First-line chemotherapy for ad-vanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gas-tro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemother-apy alone.
Findings
From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we con-currently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7–19·1) for nivolumab plus chemotherapy and 11·1 months (5·8–16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in signifi-cant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59–0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56–0·81]; p<0·0001) versus che-motherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improve-ment in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all ran-domly assigned patients. Among all treated pa-tients, 462 (59%) of 782 patients in the nivolum-ab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3–4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-re-lated. No new safety signals were identified.
Interpretation
Nivolumab is the first PD-1 inhib-itor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesoph-ageal adenocarcinoma. Nivolumab plus chemo-therapy represents a new standard first-line treat-ment for these patients.
Yelena Y. Janjigian, Kohei Shitara, Markus Moehler, Marcelo Garrido, Pamela Salman, Lin Shen, Lucjan Wyrwicz, Kensei Yamaguchi, Tomasz Skoczylas, Arinilda Campos Bragagnoli, Tianshu Liu, Michael Schenker, Patricio Yanez, Mustapha Tehfe, Ruben Kowalyszyn, Michalis V. Karamouzis, Ricardo Bruges, Thomas Zander, Roberto Pazo-Cid, Erika Hitre, Kynan Feeney, James M. Cleary, Valerie Poulart, Dana Cullen, Ming Lei, Hong Xiao, Kaoru Kondo, Mingshun Li, Jaffer A. Ajani
Mauro Di Pilato, Ph.D.
CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.
Mauro Di Pilato, Raphael Kfuri-Rubens, Jasper N. Pruessmann, Aleksandra J. Ozga, Marius Messemaker, Bruno L. Cadilha, Ramya Sivakumar, Chiara Cianciaruso, Ross D. Warner, Francesco Marangoni, Esteban Carrizosa, Stefanie Lesch, James Billingsley, Daniel Perez-Ramos, Fidel Zavala, Esther Rheinbay, Andrew D. Luster, Michael Y. Gerner, Sebastian Kobold, Mikael J. Pittet, Thorsten R. Mempel
Nathan Fowler, M.D.
Conserved pan-cancer microenvironment subtypes predict response to immunotherapy
The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the tumor microenvironment (TME), a crucial mediator of cancer progression and therapeutic outcome. TME classification by transcriptomic analysis of >10,000 cancer patients identifies four distinct TME subtypes conserved across 20 different cancers. The TME subtypes correlate with patient response to immunotherapy in multiple cancers, with patients possessing immune-favorable TME subtypes benefiting the most from immunotherapy. Thus, the TME subtypes act as a generalized immunotherapy biomarker across many cancer types due to the inclusion of malignant and microenvironment components. A visual tool integrating transcriptomic and genomic data provides a global tumor portrait, describing the tumor framework, mutational load, immune composition, anti-tumor immunity, and immunosuppressive escape mechanisms. Integrative analyses plus visualization may aid in biomarker discovery and the personalization of therapeutic regimens.
Alexander Bagaev, Nikita Kotlov, Krystle Nomie, Viktor Svekolkin, Azamat Gafurov, Olga Isaeva, Nikita Osokin, Ivan Kozlov, Felix Frenkel, Olga Gancharova, Nava Almog, Maria Tsiper, Ravshan Ataullakhanov, Nathan Fowler
Cara Haymaker, Ph.D. & Adi Diab, M.D.
Tilsotolimod with Ipilimumab drives tumor responses in Anti–PD-1 Refractory Melanoma
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing
Significance: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.
Cara Haymaker, Daniel H. Johnson, Ravi Murthy, Salah Eddine Bentebibel, Marc I. Uemura, Courtney W. Hudgens, Houssein Safa, Marihella James, Robert H.I. Andtbacka, Douglas B. Johnson, Montaser Shaheen, Michael A. Davies, Shah Rahimian, Srinivas K. Chunduru, Denái R. Milton, Michael T. Tetzlaff, Willem W. Overwijk, Patrick Hwu, Nashat Gabrail, Sudhir Agrawal, Gary Doolittle, Igor Puzanov, Joseph Markowitz, Chantale Bernatchez, Adi Diab
Chi-Lin Tsai, Ph.D. & John Tainer, Ph.D.
EXO5-DNA structure and BLM interactions direct DNA resection critical for ATR-dependent replication restart
Stalled DNA replication fork restart after stress as orchestrated by ATR kinase, BLM helicase, and structure-specific nucleases enables replication, cell survival, and genome stability. Here we unveil human exonuclease V (EXO5) as an ATR-regulated DNA structure-specific nuclease and BLM partner for replication fork restart. We find that elevated EXO5 in tumors correlates with increased mutation loads and poor patient survival, suggesting that EXO5 upregulation has oncogenic potential. Structural, mechanistic, and mutational analyses of EXO5 and EXO5-DNA complexes reveal a single-stranded DNA binding channel with an adjacent ATR phosphorylation motif (T88Q89) that regulates EXO5 nuclease activity and BLM binding identified by mass spectrometric analysis. EXO5 phospho-mimetic mutant rescues the restart defect from EXO5 depletion that decreases fork progression, DNA damage repair, and cell survival. EXO5 depletion furthermore rescues survival of FANCA-deficient cells and indicates EXO5 functions epistatically with SMARCAL1 and BLM. Thus, an EXO5 axis connects ATR and BLM in directing replication fork restart.
Shashank Hambarde, Chi Lin Tsai, Raj K. Pandita, Albino Bacolla, Anirban Maitra, Vijay Charaka, Clayton R. Hunt, Rakesh Kumar, Oliver Limbo, Remy Le Meur, Walter J. Chazin, Susan E. Tsutakawa, Paul Russell, Katharina Schlacher, Tej K. Pandita, John A. Tainer
Zu Ye, Ph.D., John Tainer, Ph.D., and Zamal Ahmed, Ph.D.
GRB2 enforces homology-directed repair initiation by MRE11
DNA double-strand break (DSB) repair is initiated by MRE11 nuclease for both homology-directed repair (HDR) and alternative end joining (Alt-EJ). Here, we found that GRB2, crucial to timely proliferative RAS/MAPK pathway activation, unexpectedly forms a biophysically validated GRB2-MRE11 (GM) complex for efficient HDR initiation. GRB2-SH2 domain targets the GM complex to phosphorylated H2AX at DSBs. GRB2 K109 ubiquitination by E3 ubiquitin ligase RBBP6 releases MRE11 promoting HDR. RBBP6 depletion results in prolonged GM complex and HDR defects. GRB2 knockout increased MRE11-XRCC1 complex and Alt-EJ. Reconstitution with separation-of-function GRB2 mutant caused HDR deficiency and synthetic lethality with PARP inhibitor. Cell and cancer genome analyses suggest biomarkers of low GRB2 for noncanonical HDR deficiency and high MRE11 and GRB2 expression for worse survival in HDR-proficient patients. These findings establish GRB2’s role in binding, targeting, and releasing MRE11 to promote efficient HDR over Alt-EJ DSB repair, with implications for genome stability and cancer biology.
Zu Ye, Shengfeng Xu, Yin Shi, Albino Bacolla, Aleem Syed, Davide Moiani, Chi Lin Tsai, Qiang Shen, Guang Peng, Paul G. Leonard, Darin E. Jones, Bin Wang, John A. Tainer, Zamal Ahmed
Shuxing Zhang, Ph.D., Pharm.D., Chunru Lin, M.D., Ph.D., and Liuqing Yang, Ph.D.
A noncoding RNA modulator potentiates phenylalanine metabolism in mice
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-HULC mimics reduced excessive Phe in Pair -/- and Pah R408W/R408W mice and improved the Phe tolerance of these mice.
Yajuan Li, Zhi Tan, Yaohua Zhang, Zhao Zhang, Qingsong Hu, Ke Liang, Yao Jun, Youqiong Ye, Yi Chuan Li, Chunlai Li, Lan Liao, Jianming Xu, Zhen Xing, Yinghong Pan, Sujash S. Chatterjee, Tina K. Nguyen, Heidi Hsiao, Sergey D. Egranov, Nagireddy Putluri, Cristian Coarfa, David H. Hawke, Preethi H. Gunaratne, Kuang Lei Tsai, Leng Han, Mien Chie Hung, George A. Calin, Fares Namour, Jean Louis Guéant, Ania C. Muntau, Nenad Blau, V. Reid Sutton, Manuel Schiff, François Feillet, Shuxing Zhang, Chunru Lin, Liuqing Yang
March – May 2021
James Allison, Ph.D.
Cancer Discovery
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor–Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention
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Natasha M. Flores, Ph.D. | Pawel K. Mazur, Ph.D.
Nature
Elevated NSD3 histone methylation activity drives squamous cell lung cancer
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Michael Kim, M.D. | Guillermina Lozano, Ph.D.
Cancer Discovery
Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis
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Chao Mao, Ph.D. | Boyi Gan, Ph.D.
Nature
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
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Wenyi Wang, Ph.D.
Cell
Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
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Tina Cascone, M.D., Ph.D. | John V. Heymach, M.D., Ph.D. | Boris Sepesi, M.D.
Nature Medicine
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
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Carl M. Gay, M.D., Ph.D. | Lauren Averett Byers, M.D.
Cancer Cell
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities
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Scott Kopetz, M.D., Ph.D.
Journal of Clinical Oncology
Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study
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Darlan Conterno Minussi | Hanghui Ye | Nicholas Navin, Ph.D.
Nature
Breast tumours maintain a reservoir of subclonal diversity during expansion
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James Allison, Ph.D.
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor–Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention
Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4–Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis.
SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4–Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.
Spencer C. Wei, Wouter C. Meijers, Margaret L. Axelrod, Nana-Ama A.S. Anang, Elles M. Screever, Elizabeth C. Wescott, Douglas B. Johnson, Elizabeth Whitley, Lorenz Lehmann, Pierre-Yves Courand, James J. Mancuso, Lauren E. Himmel, Benedicte Lebrun-Vignes, Matthew J. Wleklinski, Bjorn C. Knollmann, Jayashree Srinivasan, Yu Li, Oluwatomisin T. Atolagbe, Xiayu Rao, Yang Zhao, Jing Wang, Lauren I.R. Ehrlich, Padmanee Sharma, Joe-Elie Salem, Justin M. Balko, Javid J. Moslehi, and James P. Allison
VP and Chair, Immunobiology
Regental Professor, Departments of Immunology and Cancer Biology
Olga Keith Wiess Distinguished University Chair for Cancer Research
Tina Cascone, M.D., Ph.D., John V. Heymach, M.D., Ph.D. & Boris Sepesi, M.D.
Assistant Professor, Department of Thoracic Head & Neck Medical Oncology
Chair, Thoracic Head & Neck Medical Oncology
Professor, Departments of Thoracic Head & Neck Medical Oncology and Cancer Biology
David Bruton, Jr. Chair
Associate Professor, Department of Thoracic and Cardiovascular Surgery
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial
Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
Tina Cascone, William N. William Jr, Annikka Weissferdt, Cheuk H. Leung, Heather Y. Lin, Apar Pataer, Myrna C. B. Godoy, Brett W. Carter, Lorenzo Federico, Alexandre Reuben, Md Abdul Wadud Khan, Hitoshi Dejima, Alejandro Francisco-Cruz, Edwin R. Parra, Luisa M. Solis, Junya Fujimoto, Hai T. Tran, Neda Kalhor, Frank V. Fossella, Frank E. Mott, Anne S. Tsao, George Blumenschein Jr, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M. Kurie, Mehmet Altan, Charles Lu, Bonnie S. Glisson, Lauren Averett Byers, Yasir Y. Elamin, Reza J. Mehran, David C. Rice, Garrett L. Walsh, Wayne L. Hofstetter, Jack A. Roth, Mara B. Antonoff, Humam Kadara, Cara Haymaker, Chantale Bernatchez, Nadim J. Ajami, Robert R. Jenq, Padmanee Sharma, James P. Allison, Andrew Futreal, Jennifer A. Wargo, Ignacio I. Wistuba, Stephen G. Swisher, J. Jack Lee, Don L. Gibbons, Ara A. Vaporciyan, John V. Heymach, and Boris Sepesi
Natasha M. Flores, Ph.D. & Pawel K. Mazur, Ph.D.
Elevated NSD3 histone methylation activity drives squamous cell lung cancer
Amplification of chromosomal region 8p11–12 is a common genetic alteration that has been implicated in the aetiology of lung squamous cell carcinoma (LUSC) The FGFR1 gene is the main candidate driver of tumorigenesis within this region. However, clinical trials evaluating FGFR1 inhibition as a targeted therapy have been unsuccessful. Here we identify the histone H3 lysine 36 (H3K36) methyltransferase NSD3, the gene for which is located in the 8p11–12 amplicon, as a key regulator of LUSC tumorigenesis. In contrast to other 8p11–12 candidate LUSC drivers, increased expression of NSD3 correlated strongly with its gene amplification. Ablation of NSD3, but not of FGFR1, attenuated tumour growth and extended survival in a mouse model of LUSC. We identify an LUSC-associated variant NSD3(T1232A) that shows increased catalytic activity for dimethylation of H3K36 (H3K36me2) in vitro and in vivo. Structural dynamic analyses revealed that the T1232A substitution elicited localized mobility changes throughout the catalytic domain of NSD3 to relieve auto-inhibition and to increase accessibility of the H3 substrate. Expression of NSD3(T1232A) in vivo accelerated tumorigenesis and decreased overall survival in mouse models of LUSC. Pathological generation of H3K36me2 by NSD3(T1232A) reprograms the chromatin landscape to promote oncogenic gene expression signatures. Furthermore, NSD3, in a manner dependent on its catalytic activity, promoted transformation in human tracheobronchial cells and growth of xenografted human LUSC cell lines with amplification of 8p11–12. Depletion of NSD3 in patient-derived xenografts from primary LUSCs containing NSD3 amplification or the NSD3(T1232A)-encoding variant attenuated neoplastic growth in mice. Finally, NSD3-regulated LUSC-derived xenografts were hypersensitive to bromodomain inhibition. Thus, our work identifies NSD3 as a principal 8p11–12 amplicon-associated oncogenic driver in LUSC, and suggests that NSD3-dependency renders LUSC therapeutically vulnerable to bromodomain inhibition.
Gang Yuan, Natasha M. Flores, Simone Hausmann, Shane M. Lofgren, Vladlena Kharchenko, Maria Angulo-Ibanez, Deepanwita Sengupta, Xiaoyin Lu, Iwona Czaban, Dulat Azhibek, Silvestre Vicent, Wolfgang Fischle, Mariusz Jaremko, Bingliang Fang, Ignacio I. Wistuba, Katrin F. Chua, Jack A. Roth, John D. Minna, Ning-Yi Shao, Łukasz Jaremko, Pawel K. Mazur, and Or Gozani
Postdoctoral Fellow, Department of Experimental Radiation Oncology
Assistant Professor, Department of Experimental Radiation Oncology
Carl M. Gay, M.D., Ph.D. & Lauren Averett Byers, M.D.
Assistant Professor, Department of Thoracic Head & Neck Medical Oncology
Associate Professor, Department of Thoracic Head & Neck Medical Oncology
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities
Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
CM Gay, CA Stewart, EM Park, L Diao, SM Groves, S Heeke, BY Nabet, J Fujimoto, LM Solis, W Lu, Y Xi, RJ Cardnell, Q Wang, G Fabbri, KR Cargill, NI Vokes, K Ramkumar, B Zhang, CM Della Corte, P Robson, SG Swisher, JA Roth, BS Glisson, DS Shames, II Wistuba, J Wang, V Quaranta, J Minna, JVHeymach, and LA Byers
Michael Kim, M.D. & Guillermina Lozano, Ph.D.
Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis, yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate CREB1 to allow physical interactions with mutant p53 that hyperactivate multiple prometastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the prometastatic, pioneer transcription factor FOXA1, activating its transcriptional network while promoting WNT/β-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and β-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
SIGNIFICANCE: Oncogenic KRAS and mutant p53 are the most commonly mutated oncogene and tumor suppressor gene in human cancers, yet direct interactions between these genetic drivers remain undefined. We identified a cooperative node between oncogenic KRAS effectors and mutant p53 that can be therapeutically targeted to undermine cooperation and mitigate metastasis.
Michael P. Kim, Xinqun Li, Jenying Deng, Yun Zhang, Bingbing Dai, Kendra L. Allton, Tara G. Hughes, Christian Siangco, Jithesh J. Augustine, Ya'an Kang, Joy M. McDaniel, Shunbin Xiong, Eugene J. Koay, Florencia McAllister, Christopher A. Bristow, Timothy P. Heffernan, Anirban Maitra, Bin Liu, Michelle C. Barton, Amanda R. Wasylishen, Jason B. Fleming, and Guillermina Lozano
Assistant Professor, Departments of Surgical Oncology & Genetics
Chair and Professor, Department of Genetics
Administrative Director, George and Cynthia Mitchell Basic Sciences Research Building
Hubert L. Olive Stringer Distinguished Chair in Oncology in Honor of Sue Gribble Stringer
Scott Kopetz, M.D., Ph.D.
Professor, Department of GI Medical Oncology
Del and Dennis McCarthy Distinguished Professorship in Gastrointestinal Cancer Research
Middle Row (L-R) : Tracy Trevino and Jamie Farber
Bottom Row : Alex Sorokin
Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study
PURPOSE: BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data.
RESULTS: Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively.
CONCLUSION: In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.
Josep Tabernero, M.D., Ph.D., Axel Grothey, M.D., Eric Van Cutsem, M.D., Ph.D., Rona Yaeger, M.D., Harpreet Wasan, M.D., Takayuki Yoshino, M.D., Ph.D., Jayesh Desai, MBBS, Fortunato Ciardiello, M.D., Ph.D., Fotios Loupakis, M.D., Ph.D., Yong Sang Hong, M.D., Ph.D., Neeltje Steeghs, M.D., Ph.D., Tormod Kyrre Guren, M.D., Ph.D., Hendrik-Tobias Arkenau, M.D., Ph.D., Pilar Garcia-Alfonso, M.D., Elena Elez, M.D., Ph.D., Ashwin Gollerkeri, M.D., Kati Maharry, Ph.D., Janna Christy-Bittel, MSN, and Scott Kopetz, M.D., Ph.D.
Chao Mao, Ph.D. & Boyi Gan, Ph.D.
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
Ferroptosis, a form of regulated cell death that is induced by excessive lipid peroxidation, is a key tumour suppression mechanism. Glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1) constitute two major ferroptosis defence systems. Here we show that treatment of cancer cells with GPX4 inhibitors results in acute depletion of N-carbamoyl-L-aspartate, a pyrimidine biosynthesis intermediate, with concomitant accumulation of uridine. Supplementation with dihydroorotate or orotate—the substrate and product of dihydroorotate dehydrogenase (DHODH)—attenuates or potentiates ferroptosis induced by inhibition of GPX4, respectively, and these effects are particularly pronounced in cancer cells with low expression of GPX4 (GPX4low). Inactivation of DHODH induces extensive mitochondrial lipid peroxidation and ferroptosis in GPX4low cancer cells, and synergizes with ferroptosis inducers to induce these effects in GPX4high cancer cells. Mechanistically, DHODH operates in parallel to mitochondrial GPX4 (but independently of cytosolic GPX4 or FSP1) to inhibit ferroptosis in the mitochondrial inner membrane by reducing ubiquinone to ubiquinol (a radical-trapping antioxidant with anti-ferroptosis activity). The DHODH inhibitor brequinar selectively suppresses GPX4low tumour growth by inducing ferroptosis, whereas combined treatment with brequinar and sulfasalazine, an FDA-approved drug with ferroptosis-inducing activity, synergistically induces ferroptosis and suppresses GPX4high tumour growth. Our results identify a DHODH-mediated ferroptosis defence mechanism in mitochondria and suggest a therapeutic strategy of targeting ferroptosis in cancer treatment.
Chao Mao, Xiaoguang Liu, Yilei Zhang, Guang Lei, Yuelong Yan, Hyemin Lee, Pranavi Koppula, Shiqi Wu, Li Zhuang, Bingliang Fang, Masha V. Poyurovsky, Kellen Olszewski, and Boyi Gan
Postdoctoral Fellow, Department of Experimental Radiation Oncology
Professor, Departments of Experimental Radiation Oncology and Molecular & Cellular Oncology
Director, Radiation and Cancer Metabolism Research Program
Darlan Conterno Minussi, Hanghui Ye & Nicholas Navin, Ph.D.
Graduate Research Assistant-GSBS, Department of Genetics
Graduate Research Assistant-GSBS, Department of Genetics
Professor, Departments of Genetics and Bioinformatics & Computational Biology
Director, CPRIT Single Cell Sequencing Core
The Grady F. Saunders, PhD Distinguished Professorship for Molecular Biology
Breast tumours maintain a reservoir of subclonal diversity during expansion
Our knowledge of copy number evolution during the expansion of primary breast tumours is limited. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178 single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7–22) that are organized into a few (3–5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.
Darlan C. Minussi, Michael D. Nicholson, Hanghui Ye, Alexander Davis, Kaile Wang, Toby Baker, Maxime Tarabichi, Emi Sei, Haowei Du, Mashiat Rabbani, Cheng Peng, Min Hu, Shanshan Bai, Yu-wei Lin, Aislyn Schalck, Asha Multani, Jin Ma, Thomas O. McDonald, Anna Casasent, Angelica Barrera, Hui Chen, Bora Lim, Banu Arun, Funda Meric-Bernstam, Peter Van Loo, Franziska Michor, and Nicholas E. Navin
Wenyi Wang, Ph.D.
Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
SC Dentro, I Leshchiner, K Haase, M Tarabichi, J Wintersinger, AG Deshwar, Kaixian Yu, Y Rubanova, G Macintyre, J Demeulemeester, I Vazquez-Garcıa, K Kleinheinz, DG Livitz, Malikic, N Donmez, S Sengupta, P Anur, C Jolly, M Cmero, D Rosebrock, SE Schumacher, Yu Fan, M Fittall, RM Drews, X Yao, TBK Watkins, J Lee, M Schlesner, H Zhu, DJ Adams, N McGranahan, C Swanton, G Getz, PC Boutros, M Imielinski, R Beroukhim, SC Sahinalp,15 Y Ji, M Peifer, I Martincorena, F Markowetz, V Mustonen, K Yuan, M Gerstung PT Spellman, Wenyi Wang, QD Morris, DC Wedge, P Van Loo, and on behalf of the PCAWG Evolution and Heterogeneity Working Group and the PCAWG Consortium
Professor, Department of Bioinformatics & Comp Biology
- Pan-cancer resource of comprehensively annotated intra-tumor heterogeneity (ITH)
- ITH is pervasive across cancers and shows cancer type-specific patterns
- Branching phylogenies are common
- Dynamic changes in mutational processes between subclonal expansions
December 2020 - February 2021
Han Chen, Ph.D. | Han Liang, Ph.D.
Cancer Cell
A High-Resolution Map of Human Enhancer RNA Loci Characterizes Super-enhancer Activities in Cancer
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Jun Li, Ph.D.| Han Liang, Ph.D.
Cancer Cell
Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines
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Shao-Cong Sun, Ph.D.
Nature Immunology
NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
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Sriram Yennu, M.D. | Eduardo Bruera, M.D.
JAMA Oncology
Frequency of and Factors Associated With Nonmedical Opioid Use Behavior Among Patients With Cancer Receiving Opioids for Cancer Pain
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John Victor Heymach, M.D., Ph.D.
Nature
Structure-based classification predicts drug response in EGFR-mutant NSCLC
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Nicholas Navin, Ph.D.
Nature Biotechnology
Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes
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Ruiping Wang, Ph.D. | Jaffer A. Ajani, M.D. | Linghua Wang, Ph.D.
Nature Medicine
Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma
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Han Chen, Ph.D. & Han Liang, Ph.D.
A High-Resolution Map of Human Enhancer RNA Loci Characterizes Super-enhancer Activities in Cancer
Although enhancers play critical roles in cancer, quantifying enhancer activities in clinical samples remains challenging, especially for super-enhancers. Enhancer activities can be inferred from enhancer RNA (eRNA) signals, which requires enhancer transcription loci definition. Only a small proportion of human eRNA loci has been precisely identified, limiting investigations of enhancer-mediated oncogenic mechanisms. Here, we characterize super-enhancer regions using aggregated RNA sequencing (RNA-seq) data from large cohorts. Super-enhancers usually contain discrete loci featuring sharp eRNA expression peaks. We identify >300,000 eRNA loci in ~377 Mb super-enhancer regions that are regulated by evolutionarily conserved, well-positioned nucleosomes and are frequently dysregulated in cancer. The eRNAs provide explanatory power for cancer phenotypes beyond that provided by mRNA expression through resolving intratumoral heterogeneity with enhancer cell-type specificity. Our study provides a high-resolution map of eRNA loci through which super-enhancer activities can be quantified by RNA-seq and a user-friendly data portal, enabling a broad range of biomedical investigations.
Han Chen, Ph.D. and Han Liang, Ph.D.
Postdoctoral Fellow, Department of Bioinformatics and Computational Biology
Deputy Chair, Bioinformatics and Computational Biology
Professor, Departments of Bioinformatics and Computational Biology & Systems Biology
Barnhart Family Distinguished Professorship in Targeted Therapies
John Victor Heymach, M.D., Ph.D.
Chair, Thoracic Head & Neck Medical Oncology
Professor, Departments of Thoracic Head & Neck Medical Oncology and Cancer Biology
David Bruton, Jr. Chair
Structure-based classification predicts drug response in EGFR-mutant NSCLC
Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18–21 and are established driver mutations in non-small cell lung cancer (NSCLC). Targeted therapies are approved for patients with ‘classical’ mutations and a small number of other mutations. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure–function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure–function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
JP Robichaux, X Le, RSK Vijayan, JK Hicks, S Heeke, YY Elamin, HY Lin, H Udagawa, F Skoulidis, H Tran, S Varghese, J He, F Zhang, MB Nilsson, L Hu, A Poteete, W Rinsurongkawong, X Zhang, C Ren, X Liu, L Hong, J Zhang, L Diao, R Madison, AB Schrock, J Saam, V Raymond, B Fang, J Wang, MJ Ha, JB Cross, JE Gray, and JV Heymach
Jun Li, Ph.D. & Han Liang, Ph.D.
Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines
Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, largescale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of ~210 clinically relevant proteins in >12,000 cancer cell line samples in response to ~170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.
W Zhao, J Li, MJM Chen, Y Luo, Z Ju, NK Nesser, K Johnson-Camacho, CT Boniface, Y Lawrence, NT Pande, MA Davies, M Herlyn, T Muranen, IK Zervantonakis, E von Euw, A Schultz, SV Kumar, A Korkut, PT Spellman, R Akbani, DJ Slamon, JW Gray, JS Brugge, Y Lu, GB Mills, and H Liang
Row Two (L-R) : Yiling Lu, Shwetha Kumar, and Mei-Ju Chen
Row Three (L-R) : Wei Zhao, Yikai Luo, and Zhenlin Ju
Assistant Professor, Department of Bioinformatics and Computational Biology
Deputy Chair, Bioinformatics and Computational Biology
Professor, Departments of Bioinformatics and Computational Biology & Systems Biology
Barnhart Family Distinguished Professorship in Targeted Therapies
Nicholas Navin, Ph.D.
Professor, Departments of Genetics and Bioinformatics & Computational Biology
Director, CPRIT Single Cell Sequencing Core
The Grady F. Saunders, PhD Distinguished Professorship for Molecular Biology
Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes
Single-cell transcriptomic analysis is widely used to study human tumors. However, it remains challenging to distinguish normal cell types in the tumor microenvironment from malignant cells and to resolve clonal substructure within the tumor. To address these challenges, we developed an integrative Bayesian segmentation approach called copy number karyotyping of aneuploid tumors (CopyKAT) to estimate genomic copy number profiles at an average genomic resolution of 5 Mb from read depth in high-throughput single-cell RNA sequencing (scRNA-seq) data. We applied CopyKAT to analyze 46,501 single cells from 21 tumors, including triple-negative breast cancer, pancreatic ductal adenocarcinoma, anaplastic thyroid cancer, invasive ductal carcinoma and glioblastoma, to accurately (98%) distinguish cancer cells from normal cell types. In three breast tumors, CopyKAT resolved clonal subpopulations that differed in the expression of cancer genes, such as KRAS, and signatures, including epithelial-to-mesenchymal transition, DNA repair, apoptosis and hypoxia. These data show that CopyKAT can aid in the analysis of scRNA-seq data in a variety of solid human tumors.
Ruli Gao, Shanshan Bai, Ying C. Henderson, Yiyun Lin, Aislyn Schalck, Yun Yan, Tapsi Kumar, Min Hu, Emi Sei, Alexander Davis, Fang Wang, Simona F. Shaitelman, Jennifer Rui Wang, Ken Chen, Stacy Moulder, Stephen Y. Lai, and Nicholas E. Navin
Shao-Cong Sun, Ph.D.
NF-κB-inducing kinase maintains T cell metabolic fitness in antitumor immunity
Metabolic reprograming toward aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show that deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8+ effector T cells hypofunctional in the tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8+ T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via a NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular reactive oxygen species levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that mediates production of the antioxidant NADPH. We show that the G6PD–NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a post-translational mechanism of metabolic regulation.
Meidi Gu, Xiaofei Zhou, Jee Hyung Sohn, Lele Zhu, Zuliang Jie, Jin-Young Yang, Xiaofeng Zheng, Xiaoping Xie, Jie Yang, Yaoyao Shi, Hans D. Brightbill, Jae Bum Kim, Jing Wang, Xuhong Cheng, and Shao-Cong Sun
Professor and Deputy Chair, Department of Immunology
Administrative Director, South Campus Research Bldg
Moshe Talpaz Endowed Chair in Immunology
Ruiping Wang, Ph.D., Jaffer A. Ajani, M.D. & Linghua Wang, Ph.D.
Postdoctoral Fellow, Department of Genomic Medicine
Professor, Department of GI Medical Oncology
Committee Chair, Institutional Review Board
Assistant Professor, Department of Genomic Medicine
Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma
Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
R Wang, M Dang, K Harada, G Han, F Wang, MP Pizzi, M Zhao, G Tatlonghari, S Zhang, D Hao, Y Lu, S Zhao, BD Badgwell, MB Murphy, N Shanbhag, JS Estrella, S Roy-Chowdhuri, AAF Abdelhakeem, Y Wang, G Peng, S Hanash, GA Calin, X Song, Y Chu, J Zhang, M Li, K Chen, AJ Lazar, A Futreal, S Song, JA Ajani, and L Wang
Row Two (L-R) : Guangchun Han, Dapeng Hao, and Jaffer A. Ajani
Row Three (L-R) : Shumei Song, Namita D Shanbhag, and Melissa Pool Pizzi
Sriram Yennu, M.D. & Eduardo Bruera, M.D.
Frequency of and Factors Associated With Nonmedical Opioid Use Behavior Among Patients With Cancer Receiving Opioids for Cancer Pain
Importance One of the main aims of research on nonmedical opioid use (NMOU) is to reduce the frequency of NMOU behaviors through interventions such as universal screening, reduced opioid exposure, and more intense follow-up of patients with elevated risk. The absence of data on the frequency of NMOU behavior is the major barrier to conducting research on NMOU.
Results A total of 1554 patients (median [interquartile range (IQR)] age, 61 [IQR, 52-69] years; 816 women [52.5%]; 1124 White patients [72.3%]) were evaluable for the study, and 299 patients (19.2%) had 1 or more NMOU behaviors. The median (IQR) number of NMOU behaviors per patient was 1 (IQR, 1-3). A total of 576 of 745 NMOU behaviors (77%) occurred by the first 2 follow-up visits. The most frequent NMOU behavior was unscheduled clinic visits for inappropriate refills (218 of 745 [29%]). Eighty-eight of 299 patients (29.4%) scored 7 or higher on SOAPP, and 48 (16.6%) scored at least 2 out of 4 points on the CAGE-AID survey. Results from the multivariate model suggest that marital status (single, hazard ratio [HR], 1.58; 95% CI, 1.15-2.18; P = .005; divorced, HR, 1.43; 95% CI, 1.01-2.03; P = .04), SOAPP score (positive vs negative, HR, 1.35; 95% CI, 1.04-1.74; P = .02), morphine equivalent daily dose (MEDD) (HR, 1.003; 95% CI, 1.002-1.004; P < .001), and Edmonton Symptom Assessment Scale pain level (HR, 1.11; 95% CI, 1.06-1.16; P < .001) were independently associated with the presence of NMOU behavior. In recursive partition analysis, single marital status, MEDD greater than 50 mg, and SOAPP scores greater than 7 were associated with a higher risk (56%) for the presence of NMOU behavior.
Conclusions and Relevance This prognostic study of patients with cancer taking opioids for cancer pain found that 19% of patients developed NMOU behavior within a median duration of 8 weeks after initial supportive care clinic consultation. Marital status (single or divorced), SOAPP score greater than 7, higher levels of pain severity, and MEDD level were independently associated with NMOU behavior. This information will assist clinicians and investigators designing clinical and research programs in this important field.
Sriram Yennurajalingam, MD, MS; Joseph Arthur, MD; Suresh Reddy, MD; Tonya Edwards, MS, MSN, FNP-C; Zhanni Lu, Dr Ph; Aline Rozman de Moraes, MD; Susamma M. Wilson, RN, CDN; Elif Erdogan, MD; Manju P. Joy, MSN, BSN, RN, CMSRN; Shirley Darlene Ethridge, BSN, RN, CHPN; Leela Kuriakose, BSN, CHPN; Jimi S. Malik, MD; John M. Najera, MA, LPC; Saima Rashid, MD; Yu Qian, MD; Michal J. Kubiak, MD; Kristy Nguyen; PharmD; Jimin Wu, MS; David Hui, MD; Eduardo Bruera, MD
Professor, Department of Palliative, Rehabilitation, & Integrative Medicine
Chair, Department of Palliative Care, Rehabilitation and Integrative Medicine
Professor, Department of Palliative Care, Rehabilitation and Integrative Medicine
Frank T. McGraw Memorial Chair in the Treatment of Cancer
September - November 2020
Qing Deng, Ph.D. | Guangchun Han, Ph.D. | Sattva S. Neelapu, M.D. | Linghua Wang, Ph.D. | Michael Green, Ph.D.
Nature Medicine
Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas
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Jianjun Gao, M.D., Ph.D. | Padmanee Sharma, M.D., Ph.D.
Nature Medicine
Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
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Yaohua Zhang, Ph.D. | Chunru Lin, Ph.D. | Liuqing Yang, Ph.D.
Nature Cell Biology
The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin
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Courtney DiNardo, M.D. | Marina Konopleva, M.D., Ph.D.
The New England Journal of Medicine
Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
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Vivek Subbiah, M.D.
The New England Journal of Medicine
Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer
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Di Zhao, Ph.D. | Li Cai, Ph.D. | Y. Alan Wang, Ph.D. | Ronald A. DePinho, M.D.
Cancer Discovery
Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer
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Qing Deng, Ph.D., Guangchun Han, Ph.D., Sattva S. Neelapu, M.D., Linghua Wang, Ph.D. & Michael Green, Ph.D.
Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas
Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10−149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy.
Qing Deng, Guangchun Han, Nahum Puebla-Osorio, Man Chun John Ma, Paolo Strati, Beth Chasen, Enyu Dai, Minghao Dang, Neeraj Jain, Haopeng Yang, Yuanxin Wang, Shaojun Zhang, Ruiping Wang, Runzhe Chen, Jordan Showell, Sreejoyee Ghosh, Sridevi Patchva, Qi Zhang, Ryan Sun, Frederick Hagemeister, Luis Fayad, Felipe Samaniego, Hans C. Lee, Loretta J. Nastoupil, Nathan Fowler, R. Eric Davis, Jason Westin, Sattva S. Neelapu, Linghua Wang & Michael R. Green
Middle Row (L-R) : Drs. Han & Neelapu
Bottom Row : Dr. Wang
Associate Professor, Departments of Lymphoma-Myeloma & Genomic Medicine
Instructor, Department of Lymphoma-Myeloma
Postdoctoral Fellow, Department of Genomic Medicine
Professor, Department of Lymphoma-Myeloma
Assistant Professor, Department of Genomic Medicine
Courtney DiNardo, M.D. & Marina Konopleva, M.D., Ph.D.
Associate Professor, Department of Leukemia
Associate Chair, Institutional Review Board
Deputy Chair, Department of Leukemia
Professor, Departments of Leukemia and Stem Cell Transportation & Cellular Therapy
Frances King Black Memorial Professorship for Cancer Research
Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.
RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine–venetoclax group and 145 in the azacitidine–placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine–venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine–venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine–venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 84% of the patients in the azacitidine–venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively.
CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax–azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.)
Courtney D. DiNardo, M.D., Brian A. Jonas, M.D., Ph.D., Vinod Pullarkat, M.D., Michael J. Thirman, M.D., Jacqueline S. Garcia, M.D., Andrew H. Wei, M.B., B.S., Ph.D., Marina Konopleva, M.D., Ph.D., Hartmut Döhner, M.D., Anthony Letai, M.D., Ph.D., Pierre Fenaux, M.D., Ph.D., Elizabeth Koller, M.D., Violaine Havelange, M.D., Ph.D., Brian Leber, M.D., Jordi Esteve, M.D., Ph.D., Jianxiang Wang, M.D., Vlatko Pejsa, M.D., Ph.D., Roman Hájek, M.D., Ph.D., Kimmo Porkka, M.D., Ph.D., Árpád Illés, M.D., D.Sci., David Lavie, M.D., Roberto M. Lemoli, M.D., Kazuhito Yamamoto, M.D., Ph.D., Sung-Soo Yoon, M.D., Ph.D., Jun-Ho Jang, M.D., Su-Peng Yeh, M.D., Mehmet Turgut, M.D., Wan-Jen Hong, M.D., Ying Zhou, Ph.D., Jalaja Potluri, M.D., and Keith W. Pratz, M.D.
Jianjun Gao, M.D., Ph.D. & Padmanee Sharma, M.D., Ph.D.
Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma
Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%. Here we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment.
Jianjun Gao, Neema Navai, Omar Alhalabi, Arlene Siefker-Radtke, Matthew T. Campbell, Rebecca Slack Tidwell, Charles C. Guo, Ashish M. Kamat, Surena F. Matin, John C. Araujo, Amishi Y. Shah, Pavlos Msaouel, Paul Corn, Jianbo Wang, John N. Papadopoulos, Shalini S. Yadav, Jorge M. Blando, Fei Duan, Sreyashi Basu, Wenbin Liu, Yu Shen, Yuwei Zhang, Marc Daniel Macaluso, Ying Wang, Jianfeng Chen, Jianhua Zhang, Andrew Futreal, Colin Dinney, James P. Allison, Sangeeta Goswami & Padmanee Sharma
Associate Professor, Department of Genitourinary Medical Oncology
Professor, Departments of Genitourinary Medical Oncology & Immunology
Associate Vice President, Immunobiology
T.C. and Jeanette Hsu Endowed Chair in Cell Biology
Vivek Subbiah, M.D.
Associate Professor, Departments of Investigational Cancer Therapeutics and Pediatrics
Chair, GMEC Curriculum Subcommittee
Clinical Medical Director, Clinical Center for Targeted Therapy
Executive Director, Cancer Medicine Research
Efficacy of Selpercatinib in RET Fusion–Positive Non–Small-Cell Lung Cancer
BACKGROUND: RET fusions are oncogenic drivers in 1 to 2% of non–small-cell lung cancers (NSCLCs). In patients with RET fusion–positive NSCLC, the efficacy and safety of selective RET inhibition are unknown.
RESULTS: In the first 105 consecutively enrolled patients with RET fusion–positive NSCLC who had previously received at least platinum-based chemotherapy, the percentage with an objective response was 64% (95% confidence interval [CI], 54 to 73). The median duration of response was 17.5 months (95% CI, 12.0 to could not be evaluated), and 63% of the responses were ongoing at a median follow-up of 12.1 months. Among 39 previously untreated patients, the percentage with an objective response was 85% (95% CI, 70 to 94), and 90% of the responses were ongoing at 6 months. Among 11 patients with measurable central nervous system metastasis at enrollment, the percentage with an objective intracranial response was 91% (95% CI, 59 to 100). The most common adverse events of grade 3 or higher were hypertension (in 14% of the patients), an increased alanine aminotransferase level (in 12%), an increased aspartate aminotransferase level (in 10%), hyponatremia (in 6%), and lymphopenia (in 6%). A total of 12 of 531 patients (2%) discontinued selpercatinib because of a drug-related adverse event.
CONCLUSIONS: Selpercatinib had durable efficacy, including intracranial activity, with mainly low-grade toxic effects in patients with RET fusion–positive NSCLC who had previously received platinum-based chemotherapy and those who were previously untreated. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.)
Alexander Drilon, M.D., Geoffrey R. Oxnard, M.D., Daniel S.W. Tan, M.B., B.S., Ph.D., Herbert H.F. Loong, M.B., B.S., Melissa Johnson, M.D., Justin Gainor, M.D., Caroline E. McCoach, M.D., Ph.D., Oliver Gautschi, M.D., Benjamin Besse, M.D., Ph.D., Byoung C. Cho, M.D., Ph.D., Nir Peled, M.D., Ph.D., Jared Weiss, M.D., Yu-Jung Kim, M.D., Ph.D., Yuichiro Ohe, M.D., Ph.D., Makoto Nishio, M.D., Keunchil Park, M.D., Ph.D., Jyoti Patel, M.D., Takashi Seto, M.D., Tomohiro Sakamoto, M.D., Ezra Rosen, M.D., Ph.D., Manisha H. Shah, M.D., Fabrice Barlesi, M.D., Ph.D., Philippe A. Cassier, M.D., Lyudmila Bazhenova, M.D., Filippo De Braud, M.D., Elena Garralda, M.D., Vamsidhar Velcheti, M.D., Miyako Satouchi, M.D., Ph.D., Kadoaki Ohashi, M.D., Ph.D., Nathan A. Pennell, M.D., Ph.D., Karen L. Reckamp, M.D., Grace K. Dy, M.D., Jürgen Wolf, M.D., Benjamin Solomon, M.B., B.S., Ph.D., Gerald Falchook, M.D., Kevin Ebata, Ph.D., Michele Nguyen, B.S., Binoj Nair, Ph.D., Edward Y. Zhu, Ph.D., Luxi Yang, M.P.H., Xin Huang, Ph.D., Elizabeth Olek, M.D., S. Michael Rothenberg, M.D., Ph.D., Koichi Goto, M.D., Ph.D., and Vivek Subbiah, M.D.
Yaohua Zhang, Ph.D., Chunru Lin, Ph.D & Liuqing Yang, Ph.D.
The lncRNA H19 alleviates muscular dystrophy by stabilizing dystrophin
Dystrophin proteomic regulation in muscular dystrophies (MDs) remains unclear. We report that a long noncoding RNA (lncRNA), H19, associates with dystrophin and inhibits E3-ligase-dependent polyubiquitination at Lys 3584 (referred to as Ub-DMD) and its subsequent protein degradation. In-frame deletions in BMD and a DMD non-silent mutation (C3340Y) resulted in defects in the ability of the protein to interact with H19, which caused elevated Ub-DMD levels and dystrophin degradation. Dmd C3333Y mice exhibited progressive MD, elevated serum creatine kinase, heart dilation, blood vessel irregularity and respiratory failure with concurrently reduced dystrophin and increased Ub-DMD status. H19 RNA oligonucleotides conjugated with agrin (AGR–H19) and nifenazone competed with or inhibited TRIM63. Dmd C3333Y animals, induced-pluripotent-stem-cell-derived skeletal muscle cells from patients with Becker MD and mdx mice subjected to exon skipping exhibited inhibited dystrophin degradation, preserved skeletal and cardiac muscle histology, and improved strength and heart function following AGR–H19 or nifenazone treatment. Our study paves the way for meaningful targeted therapeutics for Becker MD and for certain patients with Duchenne MD.
Yaohua Zhang, Yajuan Li, Qingsong Hu, Yutao Xi, Zhen Xing, Zhao Zhang, Lisa Huang, Jianbo Wu, Ke Liang, Tina K. Nguyen, Sergey D. Egranov, Chengcao Sun, Zilong Zhao, David H. Hawke, Jin Li, Deqiang Sun, Jean J. Kim, Ping Zhang, Jie Cheng, Abid Farida, Mien-Chie Hung, Leng Han, Radbod Darabi, Chunru Lin & Liuqing Yang
Postdoctoral Fellow, Department of Molecular & Cellular Biology
Associate Professor, Department of Molecular & Cellular Biology
Associate Professor, Department of Molecular & Cellular Biology
Di Zhao, Ph.D., Li Cai, Ph.D., Y. Alan Wang, Ph.D. & Ronald A. DePinho, M.D.
Assistant Professor
Department of Experimental Radiation Oncology
Graduate Research Assistant, Department of Cancer Biology
Associate Professor, Department of Cancer Biology
Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer
Genetic inactivation of PTEN is common in prostate cancer and correlates with poorer prognosis. We previously identified CHD1 as an essential gene in PTEN-deficient cancer cells. Here, we sought definitive in vivo genetic evidence for, and mechanistic understanding of, the essential role of CHD1 in PTEN-deficient prostate cancer. In Pten and Pten/Smad4 genetically engineered mouse models, prostate-specific deletion of Chd1 resulted in markedly delayed tumor progression and prolonged survival. Chd1 deletion was associated with profound tumor microenvironment (TME) remodeling characterized by reduced myeloid-derived suppressor cells (MDSC) and increased CD8+ T cells. Further analysis identified IL6 as a key transcriptional target of CHD1, which plays a major role in recruitment of immunosuppressive MDSCs. Given the prominent role of MDSCs in suppressing responsiveness to immune checkpoint inhibitors (ICI), our genetic and tumor biological findings support combined testing of anti-IL6 and ICI therapies, specifically in PTEN-deficient prostate cancer.
SIGNIFICANCE: We demonstrate a critical role of CHD1 in MDSC recruitment and discover CHD1/IL6 as a major regulator of the immunosuppressive TME of PTEN-deficient prostate cancer. Pharmacologic inhibition of IL6 in combination with immune checkpoint blockade elicits robust antitumor responses in prostate cancer.
Di Zhao, Li Cai, Xin Lu, Xin Liang, Jiexi Li, Peiwen Chen, Michael Ittmann, Xiaoying Shang, Shan Jiang, Haoyan Li, Chenling Meng, Ivonne Flores, Jian H. Song, James W. Horner, Zhengdao Lan, Chang-Jiun Wu, Jun Li, Qing Chang, Ko-Chien Chen, Guocan Wang, Pingna Deng, Denise J. Spring, Y. Alan Wang and Ronald A. DePinho
Past President
Professor, Departments of Cancer Biology and Genomic Medical Research
Harry Graves Burkhart III Distinguished University Chair in Cancer Research