Research is a cornerstone of MD Anderson’s quest to end cancer. The Excellence in Science program is the online showcase for the Wall of Science, our quarterly program for honoring outstanding primary research selected from among publications in top journals by MD Anderson’s world-renowned scientists.
2021 Quarter 3 Awardees

Dr. Allison
A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitor–Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention — Cancer Discovery

Drs. Gay and Byers
Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities — Cancer Cell

Drs. Cascone, Heymach, and Sepesi
Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial — Nat Med

Drs. Flores and Mazur
Elevated NSD3 histone methylation activity drives squamous cell lung cancer — Nature

Drs. Kim and Lozano
Oncogenic KRAS Recruits an Expansive Transcriptional Network through Mutant p53 to Drive Pancreatic Cancer Metastasis — Cancer Discovery

Dr. Kopetz
Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses... — J Clin Oncol

Drs. Mao and Gan
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer — Nature
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
Read more
Natasha M. Flores, Ph.D. | Pawel K. Mazur, Ph.D.
Nature
Elevated NSD3 histone methylation activity drives squamous cell lung cancer
Read more
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
Read more
Chao Mao, Ph.D. | Boyi Gan, Ph.D.
Nature
DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer
Read more
Wenyi Wang, Ph.D.
Cell
Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
Read more
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
Read more
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
Read more
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
Read more
Darlan Conterno Minussi | Hanghui Ye | Nicholas Navin, Ph.D.
Nature
Breast tumours maintain a reservoir of subclonal diversity during expansion
Read more
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
Previous Recipients
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
Read more
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
Read more
John Victor Heymach, M.D., Ph.D.
Nature
Structure-based classification predicts drug response in EGFR-mutant NSCLC
Read more
Nicholas Navin, Ph.D.
Nature Biotechnology
Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes
Read more
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
Read more
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
June - August 2020
Pingping Hou, Ph.D. | Y. Alan Wang, Ph.D. | Ronald A. DePinho, M.D.
Cancer Discovery
Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
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Vivek Subbiah, M.D. | Maria Cabanillas, M.D.
The New England Journal of Medicine
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
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Pingping Hou, Ph.D., Y. Alan Wang, Ph.D. & Ronald A. DePinho, M.D.
Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer
Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53-/- PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.
SIGNIFICANCE: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.
Pingping Hou, Avnish Kapoor, Qiang Zhang, Jiexi Li, Chang-Jiun Wu, Jun Li, Zhengdao Lan, Ming Tang, Xingdi Ma, Jeffrey J. Ackroyd, Raghu Kalluri, Jianhua Zhang, Shan Jiang, Denise J. Spring, Y. Alan Wang, and Ronald A. DePinho
Second row (left to right) : Prasenjit Dey, Peiwen Chen, Di Zhao, Andrew Chang, Denise Spring, Abhishek Dasgupta
Third row (left to right) : Jasper R. Chen, Sagar Shah, Carolyn Guan, Rumi Lee, Y. Alan Wang, Hong Seok Shim
Postdoctoral Fellow, Department of Cancer Biology
Associate Professor, Departments of Cancer Biology and Research Oversight & Integrity
Laboratory Director, DePinho Laboratory
Past President
Professor, Departments of Cancer Biology and Genomic Medical Research
Vivek Subbiah, M.D. & Maria Cabanillas, 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
Professor, Department of Endocrine Neoplasia and HD
Efficacy of Selpercatinib in RET-Altered Thyroid Cancers
BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown.
RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion–positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events.
CONCLUSIONS: In this phase 1–2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials. gov number, NCT03157128.)
LJ Wirth, E Sherman, B Robinson, B Solomon, H Kang, J Lorch, F Worden, M Brose, J Patel, S Leboulleux, Y Godbert, F Barlesi, JC Morris, TK Owonikoko, DSW Tan, O Gautschi, J Weiss, C de la Fouchardière, ME Burkard, J Laskin, MH Taylor, M Kroiss, J Medioni, JW Goldman, TM Bauer, B Levy, VW Zhu, N Lakhani, V Moreno, K Ebata, M Nguyen, D Heirich, EY Zhu, X Huang, L Yang, J Kherani, SM Rothenberg, A Drilon, V Subbiah, MH Shah, and ME Cabanillas
March - May 2020
Michael Green, Ph.D.
Cancer Discovery
Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
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Daniel McGrail, Ph.D. | Nidhi Sahni, Ph.D. | Shiaw-Yih Lin, Ph.D.
Cancer Cell
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
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Vivek Subbiah, M.D.
Cancer Discovery
Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
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Xiaoguang Liu, Ph.D. | Boyi Gan, Ph.D.
Nature Cell Biology
Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer
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Pavlos Msaouel, M.D., Ph.D. | Giannicola Genovese, M.D. | Nizar Tannir, M.D., F.A.C.P.
Cancer Cell
Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma
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Rashmi Krishna Murthy, M.D.
The New England Journal of Medicine
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
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Michael Green, Ph.D.
Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6–HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II–dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.
SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.
Patrizia Mondello, Saber Tadros, Matt Teater, Lorena Fontan, Aaron Y. Chang, Neeraj Jain, Haopeng Yang, Shailbala Singh, Hsia-Yuan Ying, Chi-Shuen Chu, Man Chun John Ma, Eneda Toska, Stefan Alig, Matthew Durant, Elisa de Stanchina, Sreejoyee Ghosh, Anja Mottok, Loretta Nastoupil, Sattva S. Neelapu, Oliver Weigert, Giorgio Inghirami, José Baselga, Anas Younes, Cassian Yee, Ahmet Dogan, David A. Scheinberg, Robert G. Roeder, Ari M. Melnick, and Michael R. Green
Associate Professor, Departments of Lymphoma & Myeloma and Genomic Medicine
Xiaoguang Liu, Ph.D. & Boyi Gan, Ph.D.
Postdoctoral Fellow, Department of Experimental Radiation Oncology
Associate Professor, Departments of Experimental Radiation Oncology and Molecular & Cellular Oncology
Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer
SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.
Xiaoguang Liu, Kellen Olszewski, Yilei Zhang, Esther W. Lim, Jiejun Shi, Xiaoshan Zhang, Jie Zhang, Hyemin Lee, Pranavi Koppula, Guang Lei, Li Zhuang, M. James You, Bingliang Fang, Wei Li, Christian M. Metallo, Masha V. Poyurovsky, and Boyi Gan
Daniel McGrail, Ph.D., Nidhi Sahni, Ph.D. & Shiaw-Yih Lin, Ph.D.
Proteome Instability Is a Therapeutic Vulnerability in Mismatch Repair-Deficient Cancer
Deficient DNA mismatch repair (dMMR) induces a hypermutator phenotype that can lead to tumorigenesis; however, the functional impact of the high mutation burden resulting from this phenotype remains poorly explored. Here, we demonstrate that dMMR-induced destabilizing mutations lead to proteome instability in dMMR tumors, resulting in an abundance of misfolded protein aggregates. To compensate, dMMR cells utilize a Nedd8-mediated degradation pathway to facilitate clearance of misfolded proteins. Blockade of this Nedd8 clearance pathway with MLN4924 causes accumulation of misfolded protein aggregates, ultimately inducing immunogenic cell death in dMMR cancer cells. To leverage this immunogenic cell death, we combined MLN4924 treatment with PD1 inhibition and found the combination was synergistic, significantly improving efficacy over either treatment alone.
Daniel J. McGrail, Jeannine Garnett, Jun Yin, Hui Dai, David J.H. Shih, Truong Nguyen Anh Lam, Yang Li, Chaoyang Sun, Yongsheng Li, Rosemarie Schmandt, Ji Yuan Wu, Limei Hu, Yulong Liang, Guang Peng, Eric Jonasch, David Menter, Melinda S. Yates, Scott Kopetz, Karen H. Lu, Russell Broaddus, Gordon B. Mills, Nidhi Sahni, and Shiaw-Yih Lin
Postdoctoral Fellow, Department of Systems Biology
Assistant Professor, Departments of Epigenetics & Molecular Carcinogenesis and Bioinformatics & Computational Biology
Professor and Deputy Chair, Department of Systems Biology
Pavlos Msaouel, M.D., Ph.D., Giannicola Genovese, M.D. & Nizar Tannir, M.D., F.A.C.P.
Assistant Professor, Departments of Genitourinary Medical Oncology and Translational Molecular Pathology
Assistant Professor, Departments of Genitourinary Medical Oncology and Genomic Medical Research
Professor, Department of Genitourinary Medical Oncology
Comprehensive Molecular Characterization Identifies Distinct Genomic and Immune Hallmarks of Renal Medullary Carcinoma
Renal medullary carcinoma (RMC) is a highly lethal malignancy that mainly afflicts young individuals of African descent and is resistant to all targeted agents used to treat other renal cell carcinomas. Comprehensive genomic and transcriptomic profiling of untreated primary RMC tissues was performed to elucidate the molecular landscape of these tumors. We found that RMC was characterized by high replication stress and an abundance of focal copy-number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway. Replication stress conferred a therapeutic vulnerability to drugs targeting DNA-damage repair pathways. Elucidation of these previously unknown RMC hallmarks paves the way to new clinical trials for this rare but highly lethal malignancy
P Msaouel, GG Malouf, X Su, H Yao, DN Tripathi, M Soeung, J Gao, P Rao, C Coarfa, CJ Creighton, JP Bertocchio, S Kunnimalaiyaan, AS Multani, J Blando, R He, DD Shapiro, L Perelli, S Srinivasan, F Carbone, PG Pilié, M Karki, RNH Seervai, BH Vokshi, D Lopez-Terrada, EH Cheng, X Tang, W Lu, II Wistuba, TC Thompson, I Davidson, V Giuliani, K Schlacher, A Carugo, TP Heffernan, P Sharma, JA Karam, CG Wood, CL Walker, G Genovese, and NM Tannir
Vivek Subbiah, M.D.
Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
BRAFV600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.
SIGNIFICANCE: These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.
Vivek Subbiah, Igor Puzanov, Jean-Yves Blay, Ian Chau, A. Craig Lockhart, Noopur S. Raje, Juergen Wolf, José Baselga, Funda Meric-Bernstam, Jason Roszik, Eli L. Diamond, Gregory J. Riely, Eric J. Sherman, Todd Riehl, Bethany Pitcher, and David M. Hyman
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
Rashmi Krishna Murthy, M.D.
Associate Professor, Department of Breast Medical Oncology
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression- free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P=0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression- free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar–plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials. gov number, NCT02614794.)
R.K. Murthy, S. Loi, A. Okines, E. Paplomata, E. Hamilton, S.A. Hurvitz, N.U. Lin, V. Borges, V. Abramson, C. Anders, P.L. Bedard, M. Oliveira, E. Jakobsen, T. Bachelot, S.S. Shachar, V. Müller, S. Braga, F.P. Duhoux, R. Greil, D. Cameron, L.A. Carey, G. Curigliano, K. Gelmon, G. Hortobagyi, I. Krop, S. Loibl, M. Pegram, D. Slamon, M.C. Palanca‑Wessels, L. Walker, W. Feng, and E.P. Winer
December 2019 - February 2020
Moran Amit, M.D., Ph.D. | George A. Calin, M.D., Ph.D. | Jeffrey N. Myers, M.D., Ph.D.
Nature
Loss of p53 drives neuron reprogramming in head and neck cancer
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Sangeeta Goswami, M.D., Ph.D. | Padmanee Sharma, M.D., Ph.D.
Nature Medicine
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
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David Marin, M.D. | Katy Rezvani, M.D., Ph.D.
The New England Journal of Medicine
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
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Jianjun Gao, M.D., Ph.D. | Rafet Basar, M.D., Ph.D. | Jennifer A. Wargo, M.D. M.M.Sc
Nature
B cells and tertiary lymphoid structures promote immunotherapy response
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Karen Hoffman, M.D., M.H.Sc., M.P.H.
Journal of the American Medical Association
Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer
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Hussein Tawbi, M.D.
Nature
B cells are associated with survival and immunotherapy response in sarcoma
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Moran Amit, M.D., Ph.D., George A. Calin, M.D., Ph.D. & Jeffrey N. Myers, M.D., Ph.D.
Loss of p53 drives
neuron reprogramming in head and neck cancer
The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR- 34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
Moran Amit, Hideaki Takahashi, Mihnea Paul Dragomir, Antje Lindemann, Frederico O. Gleber-Netto, Curtis R. Pickering, Simone Anfossi, Abdullah A. Osman, Yu Cai, Rong Wang, Erik Knutsen, Masayoshi Shimizu, Cristina Ivan, Xiayu Rao, Jing Wang, Deborah A. Silverman, Samantha Tam, Mei Zhao, Carlos Caulin, Assaf Zinger, Ennio Tasciotti, Patrick M. Dougherty, Adel El-Naggar, George A. Calin, and Jeffrey N. Myers
Assistant Professor, Department of Head & Neck Surgery
Professor, Departments of Translation Molecular Pathology and Leukemia
Felix L. Hass Professorship in Basic Science
Chair, Department of Head & Neck Surgery
A.J. Ballantyne Distinguished Chair
Jianjun Gao, M.D., Ph.D., Rafet Basar, M.D., Ph.D. & Jennifer A. Wargo, M.D. M.M.Sc
Associate Professor, Department of Genitourinary Medical Oncology
Assistant Professor, Department of Stem Cell Transplantation
R. Lee Clark Professor of Surgical Oncology and Genomic Medicine
B cells and tertiary lymphoid structures promote immunotherapy response
Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity, although these have been less well-studied in ICB treatment. A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.
BA Helmink, SM Reddy, J Gao, S Zhang, R Basar, R Thakur, K Yizhak, M Sade-Feldman, J Blando, G Han, V Gopalakrishnan, Y Xi, H Zhao, RN Amaria, HA Tawbi, AP Cogdil, W Liu, VS LeBleu, FG Kugeratski, S Patel, MA Davies, P Hwu, JE Lee, JE Gershenwald, A Lucci, R Arora, S Woodman, E Keung, PO Gaudreau, A Reuben, CN Spencer, EM Burton, LE Haydu, AJ Lazar, R Zapassodi, CW Hudgens, DA Ledesma, S Ong, M Bailey, S Warren, D Rao, O Krijgsman, EA Rozeman, D Peeper, CU Blank, TN Schumacher, LH Butterfield, MA Zelazowska, KM McBride, R Kalluri, J Allison, F Petitprez, W Herman Fridman, C Sautès-Fridman, N Hacohen, K Rezvani, P Sharma, MT Tetzlaff, L Wang, and JA Wargo
Sangeeta Goswami, M.D., Ph.D. & Padmanee Sharma, M.D., Ph.D.
Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma
Immune checkpoint therapy with anti- CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73-/- mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.
Sangeeta Goswami, Thomas Walle, Andrew E. Cornish, Sreyashi Basu, Swetha Anandhan, Irina Fernandez, Luis Vence, Jorge Blando, Hao Zhao, Shalini Singh Yadav, Martina Ott, Ling Y. Kong, Amy B. Heimberger, John de Groot, Boris Sepesi, Michael Overman, Scott Kopetz, James P. Allison, Dana Pe’er, and Padmanee Sharma
Middle Row : Sreyashi Basu, Swetha Anandhan, Dr. Scott Kopetz
Bottom Row : Shalini Singh, Dr. Jim Allison
Assistant Professor, Departments of Genitourinary Medical Oncology and Immunology
Professor, Departments of Genitourinary Medical Oncology & Immunology
Co-Director, Parker Institute for Cancer Immunotherapy at MD Anderson
Scientific Director, Immunotherapy Platform (IMT)
T.C. and Jeanette Hsu Endowed Chair in Cell Biology
Karen Hoffman, M.D., M.H.Sc., M.P.H.
Associate Professor, Department of Radiation Oncology
Patient-Reported Outcomes Through 5 Years for Active Surveillance, Surgery, Brachytherapy, or External Beam Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer
IMPORTANCE: Understanding adverse effects of contemporary treatment approaches for men with favorable-risk and unfavorable-risk localized prostate cancer could inform treatment selection.
RESULTS: A total of 2005 men met inclusion criteria and completed the baseline and at least 1 postbaseline survey (median [interquartile range] age, 64 [59-70] years; 1529 of 1993 participants [77%] were non-Hispanic white). For men with favorable-risk prostate cancer, nerve-sparing prostatectomy was associated with worse urinary incontinence at 5 years (adjusted mean difference, -10.9 [95% CI, -14.2 to -7.6]) and sexual function at 3 years (adjusted mean difference, -15.2 [95% CI, -18.8 to -11.5]) compared with active surveillance. Low-dose-rate brachytherapy was associated with worse urinary irritative (adjusted mean difference, -7.0 [95% CI, -10.1 to -3.9]), sexual (adjusted mean difference, -10.1 [95% CI, -14.6 to -5.7]), and bowel (adjusted mean difference, -5.0 [95% CI, -7.6 to -2.4]) function at 1 year compared with active surveillance. EBRT was associated with urinary, sexual, and bowel function changes not clinically different from active surveillance at any time point through 5 years. For men with unfavorable-risk disease, EBRT with ADT was associated with lower hormonal function at 6 months (adjusted mean difference, -5.3 [95% CI, -8.2 to -2.4]) and bowel function at 1 year (adjusted mean difference, -4.1 [95% CI, -6.3 to -1.9]), but better sexual function at 5 years (adjusted mean difference, 12.5 [95% CI, 6.2-18.7]) and incontinence at each time point through 5 years (adjusted mean difference, 23.2 [95% CI, 17.7- 28.7]), than prostatectomy.
CONCLUSIONS AND RELEVANCE: In this cohort of men with localized prostate cancer, most functional differences associated with contemporary management options attenuated by 5 years. However, men undergoing prostatectomy reported clinically meaningful worse incontinence through 5 years compared with all other options, and men undergoing prostatectomy for unfavorable-risk disease reported worse sexual function at 5 years compared
Karen E. Hoffman, David F. Penson, Zhiguo Zhao, Li-Ching Huang, Ralph Conwill, Aaron A. Laviana, Daniel D. Joyce, Amy N. Luckenbaugh, Michael Goodman, Ann S. Hamilton, Xiao-Cheng Wu, Lisa E. Paddock, Antoinette Stroup, Matthew R. Cooperberg, Mia Hashibe, Brock B. O’Neil, Sherrie H. Kaplan, Sheldon Greenfield, Tatsuki Koyama, Daniel A. Barocas
David Marin, M.D., & Katy Rezvani, M.D., Ph.D.
Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors
BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
METHODS: In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin’s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
RESULTS: The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus- host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter’s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
CONCLUSIONS: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.)
Enli Liu, David Marin, Pinaki Banerjee, Homer A. Macapinlac, Philip Thompson, Rafet Basar, Lucila Nassif Kerbauy, Bethany Overman, Peter Thall, Mecit Kaplan, Vandana Nandivada, Indresh Kaur, Ana Nunez Cortes, Kai Cao, May Daher, Chitra Hosing, Evan N. Cohen, Partow Kebriaei, Rohtesh Mehta, Sattva Neelapu, Yago Nieto, Michael Wang, William Wierda, Michael Keating, Richard Champlin, Elizabeth J. Shpall, and Katayoun Rezvani
Second row (L-R) : Mecit Kaplan MS, Homer Macapinlac M.D., Peter Thall Ph.D., Partow Kebriaei M.D., Lucila Nassif Kerbauy M.D.
Third row (L-R) : Evan Cohen Ph.D., May Daher M.D., Kai Cao Ph.D., Sattva Neelapu M.D., Ana Nunez Cortes M.D.
Fourth row (L-R) : Rohtesh Mehta M.D., Pinaki Banerjee Ph.D., Vandana Nandivada M.D., Yago Nieto M.D., Richard Champlin M.D.
Professor, Department of Stem Cell Transplantation
Professor, Department of Stem Cell Transplantation
Director, Cellular Therapy
Director, Translation Research
Medical Director, GMP Cell Therapy
Hussein Tawbi, M.D.
Professor, Department of Melanoma Medical Oncology and Investigational Cancer Therapeutics
Deputy Chair, Department of Melanoma Medical Oncology
Director of Melanoma Clinical Research & Early Drug Development
Co-Director, MD Anderson Brain Metastasis Clinic
B cells are associated with survival and immunotherapy response in sarcoma
Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.
Florent Petitprez, Aurélien de Reyniès, Emily Z. Keung, Tom Wei-Wu Chen, Cheng-Ming Sun, Julien Calderaro, Yung-Ming Jeng, Li-Ping Hsiao, Laetitia Lacroix, Antoine Bougoüin, Marco Moreira, Guillaume Lacroix, Ivo Natario, Julien Adam, Carlo Lucchesi, Yec’han Laizet, Maud Toulmonde, Melissa A. Burgess, Vanessa Bolejack, Denise Reinke, Khalid M. Wani, Wei-Lien Wang, Alexander J. Lazar, Christina L. Roland, Jennifer A. Wargo, Antoine Italiano, Catherine Sautès-Fridman, Hussein A. Tawbi, and Wolf H. Fridman
• September - November 2019
Scott Kopetz, M.D., Ph.D.
The New England Journal of Medicine
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
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Padmanee Sharma, M.D., Ph.D.
Cell
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
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Jacqulyne Ponville Robichaux, Ph.D. | John Victor Heymach, M.D., Ph.D.
Cancer Cell
Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
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Scott Kopetz, M.D., Ph.D.
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.
RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.
CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015- 005805-35.)
S Kopetz, A Grothey, R Yaeger, E Van Cutsem, J Desai, T Yoshino, H Wasan, F Ciardiello, F Loupakis, YS Hong, N Steeghs, TK Guren, HT Arkenau, P Garcia‑Alfonso, P Pfeiffer, S Orlov, S Lonardi, E Elez, TW Kim, JHM Schellens, C Guo, A Krishnan, J Dekervel, V Morris, A Calvo Ferrandiz, LS Tarpgaard, M Braun, A Gollerkeri, C Keir, K Maharry, M Pickard, J Christy‑Bittel, L Anderson, V Sandor and J Tabernero
Professor, Department of GI Medical Oncology
Middle Row (L-R ): Tracy Trevino and Jamie Farber
Bottom Row: Alex Sorokin
Jacqulyne Robichaux, Ph.D. & John Heymach, M.D., Ph.D.
Assistant Professor, Department of Thoracic Head & Neck Medical Oncology
Professor, Departments of Thoracic Head & Neck Medical Oncology and Cancer Biology
Chair, Department of Thoracic Head & Neck Medical Oncology
Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity
We characterized the landscape and drug sensitivity of ERBB2 (HER2) mutations in cancers. In 11 datasets (n = 211,726), ERBB2 mutational hotspots varied across 25 tumor types. Common HER2 mutants yielded differential sensitivities to eleven EGFR/HER2 tyrosine kinase inhibitors (TKIs) in vitro, and molecular dynamics simulations revealed that mutants with a reduced drug-binding pocket volume were associated with decreased affinity for larger TKIs. Overall, poziotinib was the most potent HER2 mutant-selective TKI tested. Phase II clinical testing in ERBB2 exon 20-mutant non-small cell lung cancer resulted in a confirmed objective response rate of 42% in the first 12 evaluable patients. In pre-clinical models, poziotinib upregulated HER2 cell-surface expression and potentiated the activity of T-DM1, resulting in complete tumor regression with combination treatment.
Jacqulyne P. Robichaux, Yasir Y. Elamin, R.S.K. Vijayan, Monique B. Nilsson, Lemei Hu, Junqin He, Fahao Zhang, Marlese Pisegna, Alissa Poteete, Huiying Sun, Shuai Li, Ting Chen, Han Han, Marcelo Vailati Negrao, Jordi Rodon Ahnert, Lixia Diao, Jing Wang, Xiuning Le, Funda Meric-Bernstam, Mark Routbort, Brent Roeck, Zane Yang, Victoria M. Raymond, Richard B. Lanman, Garrett M. Frampton, Vincent A. Miller, Alexa B.Schrock, Lee A. Albacker, Kwok-kin Wong, Jason B. Cross and John V. Heymach
Middle (L-R ): Yasir Elamin & Xiuning Le
Back (L-R ): Monique Nilsson & Jacqulyne Robichaux
Not pictured : Jason Cross
Padmanee Sharma, M.D., Ph.D.
Differences in Tumor Microenvironment Dictate T Helper Lineage Polarization and Response to Immune Checkpoint Therapy
Immune checkpoint therapy (ICT) shows encouraging results in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC) but still elicits a sub-optimal response among those with bone metastases. Analysis of patients’ bone marrow samples revealed increased Th17 instead of Th1 subsets after ICT. To further evaluate the different tumor microenvironments, we injected mice with prostate tumor cells either subcutaneously or intraosseously. ICT in the subcutaneous CRPC model significantly increases intra-tumoral Th1 subsets and improves survival. However, ICT fails to elicit an anti- tumor response in the bone CRPC model despite an increase in the intra-tumoral CD4 T cells, which are polarized to Th17 rather than Th1 lineage. Mechanistically, tumors in the bone promote osteoclast- mediated bone resorption that releases TGF-β, which restrains Th1 lineage development. Blocking TGF-β along with ICT increases Th1 subsets and promotes clonal expansion of CD8 T cells and subsequent regression of bone CRPC and improves survival.
Shiping Jiao, Sumit K. Subudhi, Ana Aparicio, Zhongqi Ge, Baoxiang Guan, Yuji Miura and Padmanee Sharma
Professor, Departments of Genitourinary Medical Oncology & Immunology
Co-Director, Parker Institute for Cancer Immunotherapy at MD Anderson
Scientific Director, Immunotherapy Platform (IMT)